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Background We developed an assay to measure DNA-incorporated 6-thioguanine (DNA-TG) and validated its clinical applicability in Korean pediatric patients with acute lymphoblastic leukemia (ALL) in order to improve individualized thiopurine treatment and reduce the life-threatening cytotoxicity. Methods The DNA-TG assay was developed based on liquid chromatography-tandem mass spectrometry, with isotope-labeled TG-d3 and guanine-d3 as internal standards. This method was applied to 257 samples of pediatric ALL patients. The DNA-TG level was compared with erythrocyte TG nucleotide (RBC-TGN) level in relation to the TPMT and NUDT15 genotypes, which affect thiopurine metabolism, using Spearman’s rank test and repeated measure ANOVA. Results For DNA-TG quantification, a linearity range of 10.0-5,000.0 fmol TG/µg DNA; bias for accuracy of –10.4% –3.5%; coefficient of variation for intra- and inter-day precision of 3.4% and 5.8% at 80 fmol TG/µg DNA and of 4.9% and 5.3% at 800 fmol TG/µg DNA, respectively; and recovery of 85.7%–116.2% were achieved without matrix effects or carry-over. The median DNA-TG level in the 257 samples was 106.0 fmol TG/µg DNA (interquartile range, 75.8–150.9). There was a strong correlation between DNA-TG and RBC-TGN levels (ρ = 0.68, P < 0.0001). The DNA-TG/RBC-TGN ratio was significantly higher in NUDT15 intermediate metabolizers (*1/*2 and *1/*3) than in patients with wildtype alleles (P < 0.0001). Conclusions This simple and sensitive method for measuring DNA-TG level can improve therapeutic drug monitoring for thiopurine treatment.

Protein glycosylation is known to be involved in biological progresses such as cell recognition, growth, differentiation, and apoptosis. Fucosylation of glycoproteins plays an important role for structural stability and function of N-linked glycoproteins. Although many of biological and clinical studies of protein fucosylation by fucosyltransferases has been reported, structural classification of fucosylated N-glycoproteins such as core or outer isoforms remains a challenge. Here, we report for the first time the classification of N-glycopeptides as core- and outer-fucosylated types using tandem mass spectrometry (MS/MS) and machine learning algorithms such as the deep neural network (DNN) and support vector machine (SVM). Training and test sets of more than 800 MS/MS spectra of N-glycopeptides from the immunoglobulin gamma and alpha 1-acid-glycoprotein standards were selected for classification of the fucosylation types using supervised learning models. The best-performing model had an accuracy of more than 99% against manual characterization and area under the curve values greater than 0.99, which were calculated by probability scores from target and decoy datasets. Finally, this model was applied to classify fucosylated N-glycoproteins from human plasma. A total of 82N-glycopeptides, with 54 core-, 24 outer-, and 4 dual-fucosylation types derived from 54 glycoproteins, were commonly classified as the same type in both the DNN and SVM. Specifically, outer fucosylation was dominant in tri- and tetra-antennary N-glycopeptides, while core fucosylation was dominant in the mono-, bi-antennary and hybrid types of N-glycoproteins in human plasma. Thus, the machine learning methods can be combined with MS/MS to distinguish between different isoforms of fucosylated N-glycopeptides.

Background Teicoplanin is used to treat serious gram-positive infections. Optimal teicoplanin trough levels are considered to be ≥ 10 μg/mL. Despite its wide use in various clinical settings, data on teicoplanin trough level in pediatric patients are limited. Therefore, the aim of this study was to investigate the therapeutic drug level monitoring of teicoplanin in Korean pediatric patients, including those with impaired renal function. Methods A retrospective study was performed in pediatric patients (age ≤ 18 years old) who received teicoplanin from September 2014 to April 2018. The regimen included a loading dose of 10 mg/kg/dose at 12 hours' interval three times in a row, and a maintenance dose of 10 mg/kg/dose commenced at 24 hours of interval after the loading dose, with a maximum of 400 mg/dose, respectively. The first therapeutic drug levels were measured. Distribution and characteristics of trough levels in patients with decreased renal function and those with bacteremia were also assessed. Results A total of 187 trough levels were collected from 143 patients. Hematologic and oncologic diseases were the most common underlying diseases (83.2%, n = 119). One hundred eighty trough levels were first measured, and their median value was 16.2 μg/mL (range, 2.3–100 μg/mL) and the median interval between initial teicoplanin injection and 1st trough level was 96.5 hours (range 47.6–179.3 hours). Lower steady-state levels were observed in younger age group (median, 13.5 vs. 18.0 μg/mL, P = 0.038). Median trough levels were higher in patients with decreased renal functions (P < 0.001). In addition, among eight with gram-positive bacteremia, seven of them had a favorable outcome. Conclusion This study provides additive information on trough level monitoring of teicoplanin in children with impaired renal function and treatment effect in patients with gram-positive bacteremia. Careful monitoring for steady state trough levels of teicoplanin is warranted., Graphical Abstract

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Background: Concentrations of 6-thioguanine (6TG) nucleotides and 6-methylmercaptopurine (6MMP) nucleotides in RBCs were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). This assay was validated for clinical use and was applied to blood samples from patients taking mercaptopurine (6MP). Methods: RBCs were hemolyzed and deproteinized using perchloric acid, followed by heating for the hydrolysis of nucleotides, and the resultant base was measured using LC-MS/MS. Precision, recovery, linearity, matrix effect, and limit of quantification was validated for clinical application. Our results were compared with another institution's established LC-MS/MS assay. We measured the concentrations of 6TG and 6MMP in RBCs of pediatric patients with acute lymphoblastic leukemia (ALL), and the clinical impact of those metabolites was investigated. Results: The imprecision coefficient of variations of 6TG and 6MMP were 5.7%–8.1%, and the bias was within 5%. Lower limits of quantification were set at 54 ng/mL for 6TG and 1036 ng/mL for 6MMP. Correlation coefficients for 6TG and 6MMP were 0.997 and 1.0 in a comparison study. For clinical proof-of-concept, 74 blood samples were collected from 37 pediatric ALL patients receiving maintenance therapy. Concentration of 6TG ranged from 16.1 to 880 pmol/8 × 108 RBCs and that of 6MMP from 55 to 20,937 pmol/8 × 108 RBCs. The 6MP metabolites were not correlated with WBC or absolute neutrophil count. On the other hand, the higher 6MMP level was associated with elevated alanine aminotransferase and aspartate aminotransferase. Conclusions: In this study, an assay for the quantification of 6TG and 6MMP in RBCs was established and applied to pediatric ALL patients. Interindividual variability in 6MP metabolite concentrations was considerable and associated with elevation of liver enzymes, which may be useful in the clinical monitoring of 6MP maintenance therapy in pediatric ALL patients.

Vitamin D deficiency is a common health issue; however, the effect of vitamin D deficiency on the survival of T‐cell lymphoma is still not clear. We evaluated the impact of serum vitamin D level of patients with peripheral T‐cell lymphoma (PTCL) and extranodal natural killer/T‐cell lymphoma (ENKTL) on survival outcome. Pretreatment levels of 25‐hydroxyvitamin D [25(OH)D] and inflammatory cytokines were measured in serum samples that were archived at diagnosis, and we evaluated their association with survival in newly diagnosed patients with PTCL (n = 137) and ENKTL (n = 114) at a university‐based hospital in Korea. An independent cohort from Rui Jin Hospital (Shanghai, China) was used for validation. The median 25(OH)D serum level was 12.0 ng/mL (1.3‐60.0 ng/mL), and 40% had less than 10 ng/mL, which was defined as vitamin D deficiency. Median serum 25(OH)D levels were similar between PTCL (11.5 ng/mL) and ENKTL (12.9 ng/mL); however, vitamin D deficiency was associated with inferior survival in ENKTL but not with PTCL. The independent validation cohort (n = 115) also showed a significant association of vitamin D deficiency with poor survival in ENKTL. The 25(OH)D level had an inverse relation with inflammatory cytokines; this association had a negative effect only on survival of ENKTL, and not on PTCL. In conclusion, vitamin D deficiency was associated with inferior survival outcome of patients with ENKTL.

Background Electrical dyssynchrony (ED) is one of the important contributing mechanisms in the progression of heart failure. We hypothesized that ED would interfere with cardiac reverse remodeling and affect prognosis after aortic valve surgery. Methods A total of 411 consecutive patients (233 males, mean age 65 ± 11 years) who underwent aortic valve surgery were retrospectively analyzed. The patients were divided into two groups according to the presence of ED [Group 1: no ED (n = 382, 93%), Group 2: ED (n = 29, 7%)]. ED was defined as either left ventricular bundle branch block, or electrical pacing rhythm. Cardiac reverse remodeling was assessed at 1 year after surgery by the changes in left ventricular ejection fraction (LVEF), LV end-systolic volume (LVESV), and left atrial volume index (LAVI). The primary endpoint was a composite of hospitalization for heart failure, and all-cause mortality. Results At 1 year after surgery, group 2 showed lower LVEF (58 ± 15% vs. 64 ± 9%, p = 0.044), and higher LAVI (42 ± 18 ml/m2 vs. 33 ± 13 ml/m2, p = 0.018) than group 1. However, LVESV values (55 ± 38 ml vs. 42 ± 24 ml, p = 0.076) were not significantly different. In particular, in patients with reduced preoperative LVEF, the LVEF was markedly increased in group 1 but not in group 2 after 1 year. During a median follow-up of 39 months, group 2 showed a worse clinical outcome than group 1 (20.7% vs. 7.6%, p = 0.031). After adjusting for confounding factors in the multivariate analyses, age [hazard ratio (HR) 1.11, 95% confidence interval (CI) 1.06–1.16, p Conclusions ED after aortic valve surgery negatively affected cardiac remodeling and prognosis.

Gastric cancer is the fourth most common cancer worldwide. Despite the high incidence of gastric cancer, efficient chemotherapy treatments still need to be developed. In this study, we examined the anticancer effects of endoplasmic reticulum (ER) stress inducer tunicamycin in gastric cancer. Previously, we found that overexpression of WLS1/GPR177 correlated with poor prognosis in patients with gastric cancer. Furthermore, tunicamycin treatment downregulated GPR177 expression in a dose-dependent manner. GPR177 transports WNT ligand from ER to the plasma membrane, mediating its secretion to the extracellular matrix. In gastric cancer cells, GPR177 preferentially localizes to the ER. Small interfering RNA-mediated knockdown of GPR177 leads to sensitization to ER stress and induces apoptosis of cancer cells along with tunicamycin treatment. GPR177 suppression promoted the ER stress-mediated proapoptotic pathway, such as PERK-CHOP cascade. Furthermore, fluorouracil treatment combined with tunicamycin dramatically reduced cancer cell proliferation. Efficacy of tunicamycin chemotherapy treatments depended on GPR177 expression in gastric cancer cell lines. Together, our results indicate that ER stress can potentiate anticancer effects and suggest GPR177 as a potential gastric cancer therapeutic target.

Sphingobium chungbukense DJ77 is a Gram-negative bacterium has metabolic capability of producing exopolysaccharide (EPS) as a potential reducing and stabilizing agent for metallic nanoparticle synthesis. In this study, we investigated the genomic and proteomic analysis to verify metabolic pathway and involved genes and enzymes related to EPS biosynthesis in S. chungbukense DJ77. End-sequencing results of randomly selected fosmid library, which were prepared from high molecular weight DNA of S. chungbukense DJ77, showed identity to sequences from genes related the EPS biosynthesis pathways in several bacteria. We also observed that proteomic responses in S. chungbukense DJ77 by heterogeneously expressing gelA and gelN involved in gellan biosynthesis in Sphingomonas elodea. Comparative two-dimensional gel electrophoresis revealed that both GelA and GelN altered internal expression levels of proteins involved in EPS biosynthesis in S. chungbukense DJ77. The results might provide the genomic and proteomic evidences for presence of EPS biosynthesis pathways in S. chungbukense DJ77.

Bacterial exopolymer Levan (β-(2,6) polyfructan) synthesized by levansucrase has attracted interest for various applications due to its low intrinsic viscosity compared with other polysaccharides. We report a novel levansucrase (Lsc) isolated from Sphingobium chunbukense DJ77 and verify its biochemical characteristics by comparative analysis of molecular docking analysis (MOE) and catalytic residue analysis. The complete sequence of the Lsc encoding gene ( lsc) was cloned under the direction of the T7 promoter and purified in an Escherichia coli BL21 (DE3) protein expression system. The enzyme activity analysis and ligand docking MOE study of S. chungbukense DJ77 Lsc revealed that Arg 77, Ser112, Arg 195, Asp196, Glu257, and Gln275 were involved in the sucrose binding and splitting as well as transfructosylation activity. A catalytic comparison of Lsc of S. chungbukense DJ77 with the results of site-directed mutational analysis indicated that Gln275 may coordinate a favorable substrate binding environment, offering broad pH resistance in the range of 5-10. The results suggest that the recombinant E. coli carrying S. chungbukense DJ77 Lsc might produce levan under the regular growth conditions with less need for pH manipulation.

Background/aims Maternal thyroid dysfunction has been associated with adverse pregnancy outcomes. The purpose of our study was to establish trimester-specific reference intervals for thyroid hormones in pregnant women in Korea, where iodine intake is more than adequate and to examine pregnancy and perinatal outcomes in their offspring. Methods Among 459 healthy pregnant women who were screened, we enrolled 417 subjects who had negative results for thyroid autoantibodies. Serum thyroid stimulating hormone (TSH) and free thyroxine were measured using an immunoradiometric assay. Urine iodine concentration was measured using inductively coupled plasma-mass spectrometry in 275 women. Reference ranges of thyroid hormones were determined according to the guidelines of the National Academy of Clinical Biochemistry. Pregnancy and perinatal outcomes were compared according to maternal thyroid function. Results The reference ranges of serum TSH were 0.03 to 4.24 mIU/L in the first trimester, 0.13 to 4.84 mIU/L in the second trimester, and 0.30 to 5.57 mIU/L in the third trimester. Pregnancy and perinatal outcomes did not vary in mothers with subtle changes in thyroid function. Conclusions Trimester-specific thyroid hormone reference intervals in Korean pregnant women differ from those of other countries with different iodine nutrition status and ethnicity. The establishment of population-based, reliable trimester-specific reference intervals is critical for the interpretation of thyroid function in pregnant women to avoid unnecessary tests and treatments.

Muscarinic acetylcholine receptors (mAChRs) are members of G-protein-coupled receptors. They can induce agonist-dependent neoplastic transformation and facilitate colon cancer proliferation via promoting rapid expression of a variety of early responsive genes. In this study, we used 2-dimensional gel electrophoresis (2-DE) approach with subsequent mass spectrometry (MS) to identify up- and down-regulated proteins (a total of 23 protein spots) involved in mAChRs-related signaling pathway, energy metabolism, transcription/translation, oxidative stress metabolism and cytoskeleton organization in agonist carbachol stimulated HT-29 human colon cells. We found that the increased expression of adenocarcinoma biomarker, annexin A5 (ANXA5) induced by carbachol treatment, which was confirmed by immunoblot. This study contributes to the understanding of mechanisms underlying mAChRs agonist-induced expression of whole proteins in HT-29 colon cancer cells. Our results indicated that ANXA5 might serve as a potential biomarker for the diagnosis of colon cancer.

Obesity is one of the major public concerns due to its various side-effects such as metabolic and chronic ailments. In this study, two lactic acid bacteria (LAB) strains, Leuconostoc mesenteroides and Lactobacillus sakei, isolated from Kimchi were investigated for their anti-obesity activity in obese mice model. To induce obesity in model mice (C57BL/6), high fat diet (HFD) with 60 kcal% fat was fed for 10 weeks. LAB supplementation reduced blood urea nitrogen, glucose, and triglyceride levels in serum from obesity induced mice. The study also observed significant decrease of fibrosis, triglyceride, and total cholesterol level in fatty liver tissue by LAB supplementation. The results suggest that supplementation of L. mesenteroides and L. sakei could be used as alternative nutritional interventions to decrease symptoms caused by obesity with no safety or intolerance related problem.

We developed and validated a quantification method for methotrexate (MTX) polyglutamates (MTX-PGs, MTX-PG1 to MTX-PG5) by liquid chromatography-tandem mass spectrometry using stable isotope-labeled internal standards and applied to 196 clinical samples collected from pediatric acute lymphoblastic leukemia patients treated with MTX. MTX-PGs levels and their proportions (%) in sum of all MTX-PGs (MTXSum) were evaluated in relation to TPMT, NUDT15, and MTHFR genotypes. For the developed method, linearity ranges 1-500 nmol/L, bias for accuracy 0.3-13.5 %, coefficient of variation for within- and between-run imprecision of 3.2-9.5% and 1.5-12.0%, respectively. Recoveries achieved were 74.2-105.8 %. There was no significant carryover. The median level of the MTXSum for 196 clinical samples was 129.4 nmol/L (interquartile range 28.1-241.2). MTX dose and MTX-PGs were associated (P < 0.05) and among five MTX-PGs, MTX-PG3 was the predominant form (median 41.7 %). The MTX-PG3 level was significantly higher in patients with TPMT *1/*3C than in patients with wild type and MTX-PG3% was significantly higher and MTX-PG5% was significantly lower in NUDT15 intermediate metabolizers than normal or indeterminate phenotypes (P < 0.05). This validated MTX-PGs quantification method can facilitate a better understanding of MTX metabolism and therapeutic drug monitoring for MTX treatment.

Chlamydia pneumoniae is an intracellular bacterium associated with several acute respiratory diseases and is an obligate intracellular parasite in eukaryotic cells. Heterogeneous and overexpression of virulence-associated C. pneumoniae “effector” proteins with structurally designed epitope-focused antigens in recombinant forms in Escherichia coli is a prerequisite in the study of the organism’s pathogenic mechanisms and for use in medical applications such as vaccine and therapeutics development. In this study, seven antigen candidates from C. pneumoniae TW-183 (OmpH, Omp11, Eno, ArtJ, IncA, IncB and IncC) were screened in silico genome. Immunogenicity of the heterogeneously overexpressed antigen candidates in E. coli BL21 (DE3) was investigated by Western blot analysis using in sera from C. pneumoniae infected individuals. The soluble forms of three inclusion membrane proteins (IncA, IncB and IncC), carrying unique bilobal hydrophobic domains, were also successfully expressed in E. coli BL21 (DE3) through truncation of their membrane bound transmembrane domains.

Lactic acid bacteria (LAB) provide numerous beneficial effects on the host body, especially on the intestine. Two LAB strains isolated from Kimchi, Leuconostoc mesenteroides and Lactobacillus sakei, were studied for its anti-inflammatory activity in acidinduced acute colitis in mice. To induce acute colitis in model mice (C57BL/6), 3% of dextran sulfate sodium treatment was treated for 7 days. Assessment of necropsy and histopathology analysis showed that oral supplementation of both L. mesenteroides and L. sakei ameliorated the symptoms of acute colitis. Moreover, the mixture of L. meseneroides and L. sakei showed synergistic effect on colitis. The results suggest that the formulation of L. mesenteroides and L. sakei mixture could be used as an oral supplementation to decrease the inflammatory harmful environment associated with colitis.

// Hye In Woo 1, * , Se Kyung Lee 2, * , Jiyoung Kim 3 , Seok Won Kim 2 , Jonghan Yu 2 , Soo Youn Bae 4 , Jeong Eon Lee 2 , Seok Jin Nam 2, ** and Soo-Youn Lee 5, 6, ** 1 Department of Laboratory Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea 2 Division of Breast Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 3 Department of Surgery, Jeju National University School of Medicine, Jeju National University Hospital, Jeju, Korea 4 Division of Breast and Endocrine Surgery, Department of Surgery, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Korea 5 Department of Clinical Pharmacology & Therapeutics, Samsung Medical Center, Seoul, Korea 6 Department of Laboratory Medicine & Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea * Co-primary authors ** These authors contributed equally to this work Correspondence to: Seok Jin Nam, email: seokjin.nam@samsung.com Soo-Youn Lee, email: sy117.lee@samsung.com Keywords: tamoxifen; metabolite; drug monitoring; genotype; variation Received: April 28, 2017 Accepted: October 12, 2017 Published: November 01, 2017 ABSTRACT Inter-individual variation in tamoxifen metabolism in breast cancer patients is caused by various genetic and clinical factors. We measured the plasma concentrations of tamoxifen and its metabolites and investigated genetic polymorphisms influencing those concentrations. We measured the concentrations of tamoxifen, endoxifen, N-desmethyltamoxifen (NDM), and 4-hydroxytamoxifen (4-OH tamoxifen) in 550 plasma specimens from 281 breast cancer patients treated with tamoxifen. Duplicate or triplicate specimens were obtained from 179 patients at 3-month intervals. In 80 patients, genotyping for tamoxifen metabolizing enzymes was performed using the DMET Plus array and long-range PCR. Plasma concentrations of tamoxifen and its metabolites showed wide variations among patients. The following genetic polymorphisms were associated with the plasma concentrations when body mass index and tamoxifen concentrations were considered as co-variables: CYP1A2 -2467delT, CYP2B6 genotype, CYP2D6 activity score (AS), and FMO3 441C>T. CYP2D6 AS and three variants in the SULT1E1 gene showed correlation with ratios of tamoxifen metabolites. CYP2D6 AS was the only variable that showed associations with both metabolite concentration and ratio: endoxifen ( P < 0.001), NDM ( P < 0.001), endoxifen/NDM ( P < 0.001), NDM/tamoxifen ( P < 0.001), and 4-OH tamoxifen/tamoxifen ( P = 0.005). Serial measurements of 448 plasma concentrations in 179 patients at 3-month intervals showed wide intra-individual variation. Our study showed that genetic polymorphisms can in part determine the baseline concentrations of tamoxifen and its metabolites. However, marked intra-individual variations during follow-up monitoring were observed, and this could not be explained by genotype. Therefore, serial measurements of tamoxifen and its metabolites would be helpful in monitoring in vivo tamoxifen metabolic status.

Purpose We aimed to identify the impact of NUDT15 variants on thiopurine intolerance and 6-thioguanine nucleotide (6-TGN) levels in Korean children with acute lymphoblastic leukemia (ALL). Materials and methods Genotyping of NUDT15 was tested in 258 patients with ALL registered at Samsung Medical Center. Patients were classified into normal-activity (wild-type), intermediate-activity (heterozygous variant), and low-activity groups (homozygous or compound heterozygous variant). Clinical and laboratory features during the first year of maintenance therapy were investigated. Results A total of 182 patients were included in the final analysis. There were five (2.7%), 46 (25.3%), and 131 (72.0%) patients in low-, intermediate-, and normal-activity groups, respectively. The lowest 6-mercaptopurine (6-MP) dose (mg/m2/day) was administered to the low-activity group (low-activity group 7.5 vs. intermediate-activity group 24.4 vs. normalactivity group 31.1, p l 0.01) from three months to a year after beginning maintenance therapy. The low-activity group experienced the longest duration of therapy interruption during the first year (low-activity group 169 days vs. intermediate-activity group 30 days vs. normal-activity group 16 days, p l 0.01). They also showed the lowest blood cell counts and had a longer duration of leukopenia (low-activity group 131 days vs. intermediate-activity group 92 days vs. normal-activity group 59 days, p l 0.01). 6-TGN level and its ratio to 6-MP dose were lowest in the low-activity group. Conclusion NUDT15 variants cause hematopoietic toxicity with low 6-TGN levels. NUDT15 genotyping should be conducted before administering thiopurine, and dose adjustments require caution regardless of 6-TGN levels.

Setting Tertiary referral centre, Samsung Medical Center, South Korea. Objective To evaluate the pharmacokinetic parameters and toxicities of once-daily amikacin (AMK) dosing for lung disease due to Mycobacterium abscessus. Design A retrospective review of 48 patients with M. abscessus lung disease who received once-daily AMK for 4 weeks between January 2012 and June 2015. Results With a starting dose of 15 mg/kg/day and adjustment of AMK dose according to the peak serum level (Cmax), the Cmax target of 55-65 μg/ml was achieved in 31.3% (15/48) of patients in the first week, 68.8% (33/48) in week 2, 91.7% (44/48) in week 3 and 95.8% (46/48) in week 4. Transient nephrotoxicity developed in 6.3% (3/48) of patients and ototoxicity in 25.0% (6/24), which was determined by audiogram as hearing loss, asymptomatic in five patients and tinnitus in one. Multivariate analysis revealed that the highest drug concentration 12 h after administration was significantly associated with the development of toxicities (adjusted odds ratio 1.862, P = 0.047). Conclusion Our results suggest that once-daily AMK for 4 weeks with a target Cmax of 55-65 μg/ml can be used in patients with M. abscessus lung disease, with careful monitoring of toxicity.

// Jisook Park 1 , Eunjung Lee 2 , Kyoung-Jin Park 3 , Hyung-Doo Park 3 , Jong-Won Kim 3 , Hye In Woo 4 , Kwang Hyuck Lee 5 , Kyu-Taek Lee 5 , Jong Kyun Lee 5 , Joon-Oh Park 6 , Young Suk Park 6 , Jin Seok Heo 7 , Seong Ho Choi 7 , Dong Wook Choi 7 , Kee-Taek Jang 8 and Soo-Youn Lee 3, 9 1 Samsung Biomedical Research Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 2 Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, MA, United States 3 Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 4 Department of Laboratory Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea 5 Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 6 Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 7 Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 8 Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 9 Department of Clinical Pharmacology and Therapeutics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea Correspondence to: Soo-Youn Lee, email: suddenbz@skku.edu Keywords: pancreatic cancer, biomarker, validation, proteomics, mass spectrometry Received: October 06, 2016 Accepted: April 15, 2017 Published: April 27, 2017 ABSTRACT We performed an integrated analysis of proteomic and transcriptomic datasets to develop potential diagnostic markers for early pancreatic cancer. In the discovery phase, a multiple reaction monitoring assay of 90 proteins identified by either gene expression analysis or global serum proteome profiling was established and applied to 182 clinical specimens. Nine proteins ( P < 0.05) were selected for the independent validation phase and quantified using stable isotope dilution-multiple reaction monitoring-mass spectrometry in 456 specimens. Of these proteins, four proteins (apolipoprotein A-IV, apolipoprotein CIII, insulin-like growth factor binding protein 2 and tissue inhibitor of metalloproteinase 1) were significantly altered in pancreatic cancer in both the discovery and validation phase ( P < 0.01). Moreover, a panel including carbohydrate antigen 19-9, apolipoprotein A-IV and tissue inhibitor of metalloproteinase 1 showed better performance for distinguishing early pancreatic cancer from pancreatitis (Area under the curve = 0.934, 86% sensitivity at fixed 90% specificity) than carbohydrate antigen 19-9 alone (71% sensitivity). Overall, we present the panel of robust biomarkers for early pancreatic cancer diagnosis through bioinformatics analysis that combined transcriptomic and proteomic data as well as rigorous validation on a large number of independent clinical samples.

Vitamins are known to be associated with immunity and nutrition. Moreover, vitamin deficiency can affect host immunity to various infectious diseases, including tuberculosis. Although patients with tuberculosis often have vitamin D deficiency, little is known about the levels of other vitamins. Here, we aimed to investigate the status of vitamins A, BWe performed a case-control study to investigate the serum vitamin concentrations in 152 patients with tuberculosis and 137 control subjects. The concentrations of vitamin A, vitamin D, vitamin E, homocysteine, and methylmalonic acid were measured using high-performance liquid chromatography (HPLC) or HPLC-tandem mass spectrometry. Patient demographic data and other biochemical parameters were also analyzed.The serum concentrations of vitamins A, D, and E were significantly lower in patients with tuberculosis than in control subjects (1.4 vs. 2.0 μmol/L, P 0.001; 10.6 vs. 19.3 ng/mL, P 0.001; and 22.8 vs. 30.6 μmol/L, P 0.001, respectively). In contrast, the methylmalonic acid levels were higher in patients with tuberculosis (134.9 vs. 110.8 nmol/L, P 0.001). The prevalences of vitamin deficiencies were significantly higher in patients with tuberculosis. Moreover, multiple vitamin deficiencies were only observed in patients with tuberculosis (22.4% of all patients with tuberculosis vs. 0% of all control subjects). Positive correlations among vitamin A, D, and E concentrations were observed (vitamins A and D, r = 0.395; vitamins D and E, r = 0.342; and vitamins A and E, r = 0.427, P 0.001). Body mass index, total cholesterol, low-density lipoprotein, iron, and total iron-binding capacity all showed positive correlations with vitamin A, D, and E concentrations.Vitamin deficiencies are common in patients with tuberculosis. Further research investigating the clinical importance of vitamin and nutritional status in patients with tuberculosis is needed.

Pharmacogenetic testing for clinical applications is steadily increasing. Correct and adequate use of pharmacogenetic tests is important to reduce unnecessary medical costs and adverse patient outcomes. This document contains recommended pharmacogenetic testing guidelines for clinical application, interpretation, and result reporting through a literature review and evidence-based expert opinions for the clinical pharmacogenetic testing covered by public medical insurance in Korea. This document aims to improve the utility of pharmacogenetic testing in routine clinical settings.

Sphingomonas elodea is a Gram-negative bacterium capable of producing ‘gellan gum’ exopolysaccharide that is the most extensively studied expolysaccharides of microbial origin. In this study, we investigated the phenotypic and proteomic alterations in S. elodea by homogeneously expressing both gelA and gelN involved in positive regulation and extracellular secretion of metabolites in gellan biosynthesis, respectively. Expression of six histidine-tagged GelA and GelN was determined by Western blot analysis. Successful expression of GelA and GelN resulted in both morphological changes of colonies and enhanced secretion of gellan into the growth medium (GelA, 21.2% more and GelN, 48.3% more) overexpressed compared to the wile-type. Comparative two-dimensional gel electrophoresis analysis revealed a differential proteome expression in S. elodea overexpressing GelA and GelN. Proteins up- or down-regulated by GelA and GelN overexpression were found to be mainly sugar transportation proteins, two-compone...

Biological drugs, such as proteins and immunogens, are increasingly used to treat various diseases, including tumors and autoimmune diseases, and biological molecules have almost completely replaced synthetic drugs in rheumatology. Although biological treatments such as anti-tumor necrosis factor (TNF) drugs seem to be quite safe, they cause some undesirable effects, such as the onset of infections due to weakening of the immune system. Given the biological nature of these drugs, they might be recognized as extraneous; this would induce an immune reaction that neutralizes their effectiveness or lead to more serious consequences. Laboratories play a pivotal role in appropriate therapeutic management. The aim of this review was to underline the production of anti-drug antibodies during treatment with biological drugs and highlight the role of laboratories in ensuring appropriate use of these drugs.

Therapeutic drug monitoring (TDM) of teicoplanin is aimed at minimizing the clinical impact of pharmacokinetic variability; however, its benefits are still being defined. We performed a retrospective study of teicoplanin TDM focusing on the dose-serum concentration relationship and clinical outcomes in a clinical setting. From January 2017 to December 2018, patients receiving teicoplanin ≥ 72 h with TDM were enrolled. Patients were divided into three groups: non-loading (NL) group, low-dose loading (LD) group (loading dose 20 mg/L within 10 days were significantly different among the groups (25.0%, 38.9%, and 68.6% in the NL, LD, and HD groups, respectively; P = 0.014). Fourteen patients (21.5%) had AEs, and higher Cmin over 10 days (adjusted odds ratio 2.08 per every 20 mg/L increases, 95% CI 1.13–3.84, P = 0.019) and age ≥ 65 years (P = 0.009) were identified as independent risk factors. In the subgroup analysis, HD regimen (P = 0.050) and high mean Cmin over 10 days (P = 0.025) were significantly associated with treatment success. Although HL regimen could achieve Cmin targets and improve clinical outcome during teicoplanin treatment, high Cmin was associated with AEs during treatment. Routine TDM can be helpful to optimize teicoplanin administration.

In this work, a new stress-based method for rapid induction of triacylglycerol (TAG) and total and polyunsaturated fatty acid accumulations in Chlorella sp. by mild electric stimulation is presented. When a cathodic current of 31 mA (voltage: 4 V) was applied to the algal cells for 4 h, the TAG content of the electro-treated cells was sharply increased to a level 2.1 times that of the untreated control. The contents of the polyunsaturated linoleic (C18:2n6) and linolenic (C18:3n3) acids in the electro-treated cells were also 36 and 57% higher than those in the untreated cells, respectively. Cyclic voltammetry and various biochemical analyses indicate that TAG and fatty acid formations are electro-stimulated via de novo fatty acid biosynthesis and metabolic transformation in the Chlorella cells.

Background Differences in the performance of suggested warfarin dosing algorithms among different ethnicities and genotypes have been reported; this necessitates the development of an algorithm with enhanced performance for specific population groups. Previous warfarin dosing algorithms underestimated warfarin doses in VKORC1 1173C carriers. We aimed to develop and validate a new warfarin dosing algorithm for Korean patients with VKORC1 1173C. Methods A total of 109 patients carrying VKORC1 1173CT (N=105) or 1173CC (N=4) were included in this study. Multiple regression analysis was performed to deduce a new dosing algorithm. Following literature searches for genotype-guided warfarin dosing algorithms, 21 algorithms were selected and evaluated using the correlation coefficient (ρ) of actual dose and estimated dose, mean error, and root mean square error. Results The developed algorithm is as follows: maintenance dose (mg/week)=exp [3.223−0.009×(age)+0.577×(body surface area [BSA])+0.178×(sex)−0.481×(CYP2C9 genotype)+0.227×(VKORC1 genotype)]. Integrated variables explained 44% of the variance in the maintenance dose. The predicted and actual doses showed moderate correlation (ρ=0.641) with the best performance with a mean error of −1.30 mg/week. The proportion of underestimated groups was 17%, which was lower than with the other algorithms. Conclusions This is the first study to develop and validate a warfarin dosing algorithm based on data from VKORC1 1173C carriers; it showed superior predictive performance compared with previously published algorithms.

As microbiological diagnostic techniques improve and the frequency of nontuberculous mycobacterial pulmonary disease (NTM-PD) infection increases worldwide, NTM-PD is becoming increasingly important to clinicians and researchers. Vitamin activity has been associated with the host immune response in tuberculosis, however, such information is very limited in NTM-PD. We performed a case-control study in 150 patients with NTM-PD and 150 healthy controls to investigate serum vitamin status. We measured concentrations of vitamins A, D, and E along with homocysteine and methylmalonic acid (MMA) as indicators of vitamin B12 deficiency, using high-performance liquid chromatography (HPLC) or HPLC-tandem mass spectrometry. The serum concentrations of vitamins A and E were significantly lower in patients with NTM-PD than in healthy controls (1.5 vs. 2.1 &micro, mol/L, p &lt, 0.01 for vitamin A, and 27.3 vs. 33.1 &micro, 0.01 for vitamin E). In contrast, the serum concentrations of vitamin D and homocysteine were not significantly different between the two groups. Vitamin A deficiency (&lt, 1.05 &micro, mol/L) was significantly more prevalent in patients with NTM-PD than in healthy controls (p &lt, 0.01) and was associated with an 11-fold increase in risk of NTM-PD. Multiple vitamin deficiencies were only observed in patients with NTM-PD (7.3% of all NTM-PD patients). Positive correlations were observed among vitamins (vitamins A and D, r = 0.200, p &lt, 0.05, vitamins D and E, r = 0.238, p &lt, vitamins A and E, r = 0.352, p &lt, 0.05). Serum vitamin status, demographic variables, and biochemical indicators were not associated with treatment outcomes. Vitamin A deficiency was strongly associated with patients with NTM-PD. Our study suggests that altered vitamin status is associated with mycobacterial disease. Future well-designed prospective studies with large patient cohorts addressing these issues are needed to clarify the significance of vitamins in NTM-PD.

Vitamin B12 deficiency is a common complication in patients after gastrectomy. Elevated methylmalonic acid (MMA) and homocysteine are better indications of vitamin B12 deficiency than vitamin B12 serum level. We compared MMA and homocysteine levels of patients with gastric cancer after gastrectomy (n = 151) with controls (n = 142) and evaluated the prevalence of vitamin B12 deficiency using MMA and homocysteine in patients. MMA and homocysteine levels were significantly higher (p < 0.05) in patients with gastric cancer after gastrectomy. Of the 151 patients assessed after gastrectomy, 32 patients (21.2%) were vitamin B12 deficient as defined by serum MMA levels > 350 nmol/L, and 8 patients (5.3%) were vitamin B12 deficient as defined by serum homocysteine levels > 15 μmol/L. Both MMA and homocysteine levels were elevated in 7 patients. Among 33 patients with elevated MMA or homocysteine levels, 8 patients (24.2%) were vitamin B12 deficient based on a serum vitamin B12 level < 200 pg/mL. Additionally, levels of MMA and homocysteine were compared pre- and post-gastrectomy in 27 patients. The median MMA level was higher in patients with post-gastrectomy compared to pre-gastrectomy, while the median serum homocysteine level was not significantly different. These results indicate that using serum vitamin B12 levels alone may fail to detect vitamin B12 deficiency. Additional assessments of MMA and homocysteine levels are useful to evaluate possible vitamin B12 deficiency in patients who underwent a gastrectomy, and MMA is a better indicator than homocysteine to detect early changes in vitamin B12 levels.

The multiple roles of extracellular vesicles (EVs) in pathogenesis have received much attention, as they are valuable as diagnostic and prognostic biomarkers. We employed polymeric EV precipitation to isolate EVs from clinical specimens to overcome the limitations of ultracentrifugation (UC), such as low protein yields, a large volume of specimens used, and time requirements. Multiple-cycle polymeric EV precipitation was applied to enhance the purity of the EV fractions with a small sample volume. Then, the purity was assessed using a multiple reaction monitoring (MRM) panel consisting of alpha-2-macroglobulin (A2M), thrombospondin 1 (THBS 1), galectin 3 binding protein (LGALS3BP), and serum albumin (ALB). For purity evaluation, the EV fractions isolated from blood specimens were subjected to shotgun proteomics and MRM-based targeted proteomics analyses. We demonstrate that the modified method is an easy and convenient method compared with UC. In the shotgun proteomics analysis, the proteome profile of EV fraction contains 89% EV-related proteins by matching with the EVpedia database. In conclusion, we suggest that multiple-cycle polymeric EV precipitation is not only a more effective method for EV isolation for further proteomics-based experiments, but may also be useful for further clinical applications due to the higher EV yield and low sample requirements.

PURPOSE Fucosylation of alpha-fetoprotein (AFP) is closely correlated with the diagnosis of patients with hepatocellular carcinoma (HCC). In current, a micro-total analysis system (μTAS) using immunoassay has been developed for determining fucosylated AFP EXPERIMENTAL DESIGN: We compared two analytical methods, μTAS and liquid chromatography-parallel reaction monitoring mass spectrometry (LC-PRM MS), for the measurement of fucosylated AFP in serum to evaluate the usefulness of the results. For this purpose, serum samples were used (cirrhosis, n = 105; HCC, n = 105), and we have discussed the analytical performance of these two methods RESULTS: We observed a correlation (R2 = 0.84) between LC-PRM MS and μTAS using samples where fucosylated levels were measured by both methods. The fucosylated level of AFP by LC-PRM MS better differentiated between cirrhosis and HCC patients than those by μTAS (AUC = 0.910 vs. 0.861), particularly in subgroups with a level of total AFP

The electrochemical conversion of CO2 can include renewable surplus electricity storage and CO2 utilisation. This review focuses on the microbial CO2 electrobiorefinery based on microbial electrosynthesis (MES) which merges electrochemical and microbial conversion to produce biofuels and higher-value chemicals. In this review, recent developments are discussed about bioelectrochemical conversion of CO2 into biofuels and chemicals in MES via microbial CO2-fixation and electricity utilisation reactions. In addition, this review examines technical approaches to overcome the current limitations of MES including the following: engineering of the biocathode, application of electron mediators, and reactor optimisation, among others. An in-depth discussion of strategies for the CO2 electrobiorefinery is presented, including the integration of the biocathode with inorganic catalysts, screening of novel electroactive microorganisms, and metabolic engineering to improve target productivity from CO2.

Although tuberculosis is largely a curable disease, it remains a major cause of morbidity and mortality worldwide. Although the standard 6-month treatment regimen is highly effective for drug-susceptible tuberculosis, the use of multiple drugs over long periods of time can cause frequent adverse drug reactions. In addition, some patients with drug-susceptible tuberculosis do not respond adequately to treatment and develop treatment failure and drug resistance. Response to tuberculosis treatment could be affected by multiple factors associated with the host-pathogen interaction including genetic factors and the nutritional status of the host. These factors should be considered for effective tuberculosis control. Therefore, therapeutic drug monitoring (TDM), which is individualized drug dosing guided by serum drug concentrations during treatment, and pharmacogenetics-based personalized dosing guidelines of anti-tuberculosis drugs could reduce the incidence of adverse drug reactions and increase the likelihood of successful treatment outcomes. Moreover, assessment and management of comorbid conditions including nutritional status could improve anti-tuberculosis treatment response.

Polycyclic aromatic hydrocarbons (PAHs) are commonly present xenobiotics in natural and contaminated soils. We studied three (phenanthrene, naphthalene, and biphenyl) xenobiotics, catabolism, and associated proteins in Sphingobium chungbukense DJ77 by two-dimensional gel electrophoresis (2-DE) analysis. Comparative analysis of the growth-dependent 2-DE results revealed that the intensity of 10 protein spots changed identically upon exposure to the three xenobiotics. Among the upregulated proteins, five protein spots, which were putative dehydrogenase, dioxygenase, and hydrolase and involved in the catabolic pathway of xenobiotic degradation, were induced. Identification of these major multifunctional proteins allowed us to map the multiple catabolic pathway for phenanthrene, naphthalene, and biphenyl degradation. A part of the initial diverse catabolism was converged into the catechol degradation branch. Detection of intermediates from 2,3-dihydroxy-biphenyl degradation to pyruvate and acetyl-CoA production by LC/MS analysis showed that ring-cleavage products of PAHs entered the tricarboxylic acid cycle, and were mineralized in S. chungbukense DJ77. These results suggest that S. chungbukense DJ77 completely degrades a broad range of PAHs via a multiple catabolic pathway.

Background A newborn screening (NBS) program has been utilized to detect asymptomatic newborns with inherited metabolic diseases (IMDs). There have been some bottlenecks such as false-positives and imprecision in the current NBS tests. To overcome these issues, we developed a multigene panel for IMD testing and investigated the utility of our integrated screening model in a routine NBS environment. We also evaluated the genetic epidemiologic characteristics of IMDs in a Korean population. Methods In total, 269 dried blood spots with positive results from current NBS tests were collected from 120,700 consecutive newborns. We screened 97 genes related to NBS in Korea and detected IMDs, using an integrated screening model based on biochemical tests and next-generation sequencing (NGS) called NewbornSeq. Haplotype analysis was conducted to detect founder effects. Results The overall positive rate of IMDs was 20%. We identified 10 additional newborns with preventable IMDs that would not have been detected prior to the implementation of our NGS-based platform NewbornSeq. The incidence of IMDs was approximately 1 in 2,235 births. Haplotype analysis demonstrated founder effects in p.Y138X in DUOXA2, p.R885Q in DUOX2, p.Y439C in PCCB, p.R285Pfs*2 in SLC25A13, and p.R224Q in GALT. Conclusions Through a population-based study in the NBS environment, we highlight the screening and epidemiological implications of NGS. The integrated screening model will effectively contribute to public health by enabling faster and more accurate IMD detection through NBS. This study suggested founder mutations as an explanation for recurrent IMD-causing mutations in the Korean population.

The aim of this study was to evaluate serum cytokines and natural antimicrobial peptide profiles in pulmonary tuberculosis, and compare them with levels in controls without tuberculosis, to explore the associations between these biomarkers and response to antituberculosis treatment. Serum levels of 10 biomarkers were measured using a Luminex bead array platform. Tuberculosis biosignatures were identified from the discovery cohort (n=148) and were validated in the independent cohort (n=148). Association between biosignatures and clinical outcome was investigated with negative conversion in follow-up sputum culture after 2months of treatment. Serum concentrations of eotaxin, MIP-1α, sIL-2Rα, and lipocalin 2 were significantly different between pulmonary tuberculosis patients and controls (P0.05). Serum concentrations of eotaxin and sIL-2Rα were higher in pulmonary tuberculosis patients than in controls, while those of MIP-1α and lipocalin 2 were lower (P0.05). Eotaxin concentrations were significantly higher in good responders to treatment (P0.05), indicating this immunomolecule may serve as a positive predictor for therapy response in pulmonary tuberculosis. The magnitude serum eotaxin, MIP-1α, sIL-2Rα, and lipocalin 2 are important indicators for pulmonary tuberculosis. These biomarkers alone or combinatorial detections have potential applicability in monitoring tuberculosis patients during antituberculosis treatment.Cytokines and endogenous antimicrobial peptides represent an important part of immune system and the identification of a pattern of differentially expressed those biomarkers (a "biosignature") could help to differentiate tuberculosis infection from the non-infected state which might eventually assist case identification and accelerate access to treatment. In this direction, cytokine analysis including multiple serum biomarkers to evaluate biosignatures of pulmonary tuberculosis would provide basic knowledge to aid understanding of the pathophysiology of tuberculosis infection and for the development of future diagnostic methods, treatments, and monitoring for pulmonary tuberculosis.

Background After adrenalectomy, urinary fractionated metanephrine concentrations are expected to be reduced. However, there are few studies suggesting cut-offs for adrenalectomy patients. Methods Urinary metanephrine and normetanephrine concentrations in adrenalectomy patients and two controls were compared and hormonal concentrations were evaluated via time intervals after surgery. Results The median urinary metanephrine level after unilateral adrenalectomy was lower than that of the non-pheochromocytoma controls but comparable to healthy controls. Urinary normetanephrine concentrations did not differ between adrenalectomy patients and non-pheochromocytoma controls, although both group had levels higher than those of healthy controls. The median urinary normetanephrine level in the immediate postoperative period was higher than in the later period. Conclusions Urinary metanephrine concentrations were lower after adrenalectomy, but urinary normetanephrine concentrations were not changed compared with the non-pheochromocytoma controls. However, urinary normetanephrine concentrations in the patient group were higher than levels in the heathy controls.

Preemptive and multi-variant genotyping is suggested to improve the safety of patient drug therapy. The number of South Koreans who would benefit from this approach is unknown. We aimed to quantify the number of patients who may experience serious adverse drug events (ADEs) due to high-risk pharmacogenetic variants and who may benefit from preemptive genotyping. The health claims dataset of the Korean Health Insurance Review and Assessment service for 3 % of the South Korean population for year 2011 was used to calculate the number of patients exposed to 84 drugs covered by National Health Insurance with pharmacogenomic biomarkers. The product of ADE risk-conferring genotype prevalence, ADE prevalence rates, and genotype effect sizes in South Koreans or East Asians derived from published literature and the 1000 Genomes Project, and the drug exposure data were solved to estimate the number of South Koreans in whom preemptive genotyping may prevent serious ADEs. Among 1,341,077 patients in the dataset with prescriptions, 47.4 % were prescribed a drug whose response was affected by genetic variants and 31.9 % were prescribed at least one drug with serious ADEs modulated by these variants. Without genetic testing, the number of South Korean patients predicted to experience serious ADEs due to their higher ADE risk genotypes was estimated at 729. Extrapolating this to the total South Korean population indicated that approximately 24,300 patients in 2011 might have benefitted from preemptive genotyping. This study quantified the number of South Korean patients predicted to have serious ADEs and demonstrated the need for preemptive genotyping to assist safer drug therapy in South Korea.

In Korea, an amendment to the Child Welfare Act was made in 2008 that required a national study estimating the occurrence rate of child abuse and neglect every 5 years. The present study reports the major findings of the first national study conducted after the 2008 amendment. The aim of the study is to estimate the prevalence of child physical and psychological maltreatment (CPPM) in Korea and to explore the basic characteristics associated with such incidents. Household surveys were administered to caregivers and focal children who were school age and older. We estimated the prevalence of CPPM using the Parent–child Conflict Tactic Scale, which was developed by Straus et al. (1998). The occurrence rate of CPPM was 25.3 % in Korea, with instances differing by household income, poverty status, and size of the region. Children who experienced physical and psychological maltreatment were more likely to witness the abuse of their siblings and domestic violence. The implications of the findings are discussed and recommendations made for further research.

Today, bioplastics are recognised as sustainable alternatives and one of the solutions to the crisis of petro-based plastics. The next-generation polymer poly(ethylene 2,5-furandicarboxlate) (PEF) has gained great popularity since it is associated with significant reduction of energy use and GHG emissions, as well as with superior barrier properties. This drop-in polymer is a promising 100% bio-based alternative to its petro-based counterpart poly(ethylene terephthalate) (PET). PEF can be effectively synthesised by polymerisation between 2,5-furandicarboxylic acid (FDCA) and ethylene glycol (EG), which represent biomass-derived building blocks. These bio-building blocks are an important commodity and platform chemicals that can be used for a variety of applications, including the synthesis of PEF. This review covers recent progress in the production of novel bio-building blocks for the preparation of PEF. Among various synthesis methods, we reviewed the catalytic conversion of biomass-derived hydroxylmethylfurfural (HMF) into FDCA and the biological route from biomass feedstock into EG. In addition, we covered recent progress in the synthesis of HMF from biomass since a reliable supply of HMF is important for the synthesis of FDCA. Finally, research goals and challenges for future development of bio-building blocks production were proposed.