Displaying publications 81 - 100 of 153 in total

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  1. Li L, Shuai L, Sun J, Li C, Yi P, Zhou Z, et al.
    Food Sci Nutr, 2020 Feb;8(2):1284-1294.
    PMID: 32148834 DOI: 10.1002/fsn3.1417
    Mango (Mangifera indica L.) is respiratory climacteric fruit that ripens and decomposes quickly following their harvest. 1-methylcyclopropene (1-MCP) is known to affect the ripening of fruit, delaying the decay of mango stored under ambient conditions. The objective of this study was to clarify the role of 1-MCP in the regulation of ethylene biosynthesis and ethylene receptor gene expression in mango. 1-MCP significantly inhibited the 1-aminocyclopropane-1-carboxylic acid (ACC) content. The activity of ACC oxidase (ACO) increased on days 6, 8, and 10 of storage, whereas delayed ACC synthase (ACS) activity increased after day 4. The two homologous ethylene receptor genes, ETR1 and ERS1 (i.e., MiETR1 and MiERS1), were obtained and deposited in GenBank® (National Center for Biotechnology Information-National Institutes of Health [NCBI-NIH]) (KY002681 and KY002682). The MiETR1 coding sequence was 2,220 bp and encoded 739 amino acids (aa). The MiERS1 coding sequence was 1,890 bp and encoded 629 aa, similar to ERS1 in other fruit. The tertiary structures of MiETR1 and MiERS1 were also predicted. MiERS1 lacks a receiver domain and shares a low homology with MiETR1 (44%). The expression of MiETR1 and MiERS1 mRNA was upregulated as the storage duration extended and reached the peak expression on day 6. Treatment with 1-MCP significantly reduced the expression of MiETR1 on days 4, 6, and 10 and inhibited the expression of MiETR1 on days 2, 4, 6, and 10. These results indicated that MiETR1 and MiERS1 had important functions in ethylene signal transduction. Treatment with 1-MCP might effectively prevent the biosynthesis of ethylene, as well as ethylene-induced ripening and senescence. This study presents an innovative method for prolonging the storage life of mango after their harvest through the regulation of MiETR1 and MiERS1 expression.
  2. Liang X, Wang Q, Jiang Z, Li Z, Zhang M, Yang P, et al.
    J Tradit Chin Med, 2020 08;40(4):690-702.
    PMID: 32744037 DOI: 10.19852/j.cnki.jtcm.2020.04.019
    OBJECTIVE: To analyze clinical studies on correlations between Traditional Chinese Medicine (TCM) body constitution types and diseases published in the past 10 years, and to provide an evidence base to support the use of such correlations for health maintenance and disease prevention.

    METHODS: We searched five databases for the period April 2009 to December 2019: China National Knowledge Infrastructure Database, Wanfang Database, China Science and Technology Journal Database, PubMed and Embase. Three types of observational studies on correlation between constitution types and diseases were included: cross-sectional, case-control and cohort studies. Descriptive statistical methods were employed for data analysis.

    RESULTS: A total of 1639 clinical studies were identified: 1452 (88.59%) cross-sectional studies, 115 (7.02%) case-control studies and 72 (4.39%) cohort studies covering 30 regions of China and five other countries (Malaysia, South Korea, Singapore, Thailand and France). The collection of studies comprised 19 disease categories and 333 different diseases. The 10 most commonly studied diseases were hypertension, diabetes, stroke, coronary atherosclerotic heart disease (CAHD), sleep disorders, neoplasm of the breast, dysmenorrhea, fatty liver disease, chronic viral hepatitis B and dyslipidemia. We found high distributions for each biased constitution type in different patient populations as follows: Qi-deficiency constitution in stroke, diabetes, chronic obstructive pulmonary disease, acquired immunodeficiency syndrome and hypertension; Yang-deficiency constitution in female infertility, osteoporosis, irritable bowel syndrome, gonarthrosis and dysmenorrhea; Yin-deficiency constitution in hypertension, diabetes, constipation, female climacteric states and osteoporosis; phlegm- dampness constitution in hypertension, stroke, fatty liver disease, diabetes and metabolic syndrome; damp-heat constitution in acne, chronic gastritis, chronic viral hepatitis B, human papillomavirus infection and hyperuricemia; blood-stasis constitution in CAHD, endometriosis and stroke; Qi-stagnation constitution in hyperplasia and neoplasms of the breast, insomnia, depression and thyroid nodules; and inherited-special constitution in asthma and allergic rhinitis.

    CONCLUSION: Eight biased TCM constitutions were closely related to specific diseases, and could be used to guide individualized prevention and treatment. More rigorously designed studies are recommended to further verify the constitution-disease relationship.

  3. Wang Z, Li P, Ma K, Chen Y, Yan Z, Penfold J, et al.
    J Colloid Interface Sci, 2021 Mar 15;586:876-890.
    PMID: 33309145 DOI: 10.1016/j.jcis.2020.10.122
    HYPOTHESIS: The α-sulfo alkyl ester, AES, surfactants are a class of anionic surfactants which have potential for improved sustainable performance in a range of applications, and an important feature is their enhanced tolerance to precipitation in the presence of multivalent counterions. It is proposed that their adsorption properties can be adjusted substantially by changing the length of the shorter alkyl chain, that of the alkanol group in the ester.

    EXPERIMENTS: Surface tension and neutron reflectivity have been used to investigate the variation in the adsorption properties with the shorter alkyl chain length (methyl, ethyl and propyl), the impact of NaCl on the adsorption, the tendency to form surface multilayer structures in the presence of AlCl3, and the effects of mixing the methyl ester sulfonate with the ethyl and propyl ester sulfonates on the adsorption.

    FINDINGS: The variations in the critical micelle concentration, CMC, the adsorption isotherms, the saturation adsorption values, and the impact of NaCl illustrate the subtle influence of varying the shorter alkyl chain length of the surfactant. The non-ideal mixing of pairs of AES surfactants with different alkanol group lengths of the ester show that the extent of the non-ideality changes as the difference in the alkanol length increases. The surface multilayer formation observed in the presence of AlCl3 varies in a complex manner with the length of the short chain and for mixtures of surfactants with different chains lengths.

  4. Koschut D, Ray D, Li Z, Giarin E, Groet J, Alić I, et al.
    Oncogene, 2021 01;40(4):746-762.
    PMID: 33247204 DOI: 10.1038/s41388-020-01567-7
    Leukemias are routinely sub-typed for risk/outcome prediction and therapy choice using acquired mutations and chromosomal rearrangements. Down syndrome acute lymphoblastic leukemia (DS-ALL) is characterized by high frequency of CRLF2-rearrangements, JAK2-mutations, or RAS-pathway mutations. Intriguingly, JAK2 and RAS-mutations are mutually exclusive in leukemic sub-clones, causing dichotomy in therapeutic target choices. We prove in a cell model that elevated CRLF2 in combination with constitutionally active JAK2 is sufficient to activate wtRAS. On primary clinical DS-ALL samples, we show that wtRAS-activation is an obligatory consequence of mutated/hyperphosphorylated JAK2. We further prove that CRLF2-ligand TSLP boosts the direct binding of active PTPN11 to wtRAS, providing the molecular mechanism for the wtRAS activation. Pre-inhibition of RAS or PTPN11, but not of PI3K or JAK-signaling, prevented TSLP-induced RAS-GTP boost. Cytotoxicity assays on primary clinical DS-ALL samples demonstrated that, regardless of mutation status, high-risk leukemic cells could only be killed using RAS-inhibitor or PTPN11-inhibitor, but not PI3K/JAK-inhibitors, suggesting a unified treatment target for up to 80% of DS-ALL. Importantly, protein activities-based principal-component-analysis multivariate clusters analyzed for independent outcome prediction using Cox proportional-hazards model showed that protein-activity (but not mutation-status) was independently predictive of outcome, demanding a paradigm-shift in patient-stratification strategy for precision therapy in high-risk ALL.
  5. Janib SM, Gustafson JA, Minea RO, Swenson SD, Liu S, Pastuszka MK, et al.
    Biomacromolecules, 2014 Jul 14;15(7):2347-58.
    PMID: 24871936 DOI: 10.1021/bm401622y
    Recombinant protein therapeutics have increased in number and frequency since the introduction of human insulin, 25 years ago. Presently, proteins and peptides are commonly used in the clinic. However, the incorporation of peptides into clinically approved nanomedicines has been limited. Reasons for this include the challenges of decorating pharmaceutical-grade nanoparticles with proteins by a process that is robust, scalable, and cost-effective. As an alternative to covalent bioconjugation between a protein and nanoparticle, we report that biologically active proteins may themselves mediate the formation of small multimers through steric stabilization by large protein polymers. Unlike multistep purification and bioconjugation, this approach is completed during biosynthesis. As proof-of-principle, the disintegrin protein called vicrostatin (VCN) was fused to an elastin-like polypeptide (A192). A significant fraction of fusion proteins self-assembled into multimers with a hydrodynamic radius of 15.9 nm. The A192-VCN fusion proteins compete specifically for cell-surface integrins on human umbilical vein endothelial cells (HUVECs) and two breast cancer cell lines, MDA-MB-231 and MDA-MB-435. Confocal microscopy revealed that, unlike linear RGD-containing protein polymers, the disintegrin fusion protein undergoes rapid cellular internalization. To explore their potential clinical applications, fusion proteins were characterized using small animal positron emission tomography (microPET). Passive tumor accumulation was observed for control protein polymers; however, the tumor accumulation of A192-VCN was saturable, which is consistent with integrin-mediated binding. The fusion of a protein polymer and disintegrin results in a higher intratumoral contrast compared to free VCN or A192 alone. Given the diversity of disintegrin proteins with specificity for various cell-surface integrins, disintegrin fusions are a new source of biomaterials with potential diagnostic and therapeutic applications.
  6. Tong WK, Dai C, Hu J, Li J, Gao MT, You X, et al.
    Sci Total Environ, 2024 Jan 10;907:168099.
    PMID: 37884130 DOI: 10.1016/j.scitotenv.2023.168099
    Nanobubbles (NBs), given their unique properties, could theoretically be paired with rhamnolipids (RL) to tackle polycyclic aromatic hydrocarbon contamination in groundwater. This approach may overcome the limitations of traditional surfactants, such as high toxicity and low efficiency. In this study, the remediation efficiency of RL, with or without NBs, was assessed through soil column experiments (soil contaminated with phenanthrene). Through the analysis of the two-site non-equilibrium diffusion model, there was a synergistic effect between NBs and RL. The introduction of NBs led to a reduction of up to 24.3 % in the total removal time of phenanthrene. The direct reason for this was that with NBs, the retardation factor of RL was reduced by 1.9 % to 15.4 %, which accelerated the solute replacement of RL. The reasons for this synergy were multifaceted. Detailed analysis reveals that NBs improve RL's colloidal stability, increase its absolute zeta potential, and reduce its soil adsorption capacity by 13.3 %-19.9 %. Furthermore, NBs and their interaction with RL substantially diminish the surface tension, contact angle, and dynamic viscosity of the leaching solution. These changes in surface thermodynamic and rheological properties significantly enhance the migration efficiency of the eluent. The research outcomes facilitate a thorough comprehension of NBs' attributes and their relevant applications, and propose an eco-friendly method to improve the efficiency of surfactant remediation.
  7. Yu S, Kim BK, Wang H, Zhou J, Wan Q, Yu T, et al.
    J Headache Pain, 2022 Nov 21;23(1):146.
    PMID: 36404301 DOI: 10.1186/s10194-022-01514-9
    ABSTACT: BACKGROUND: DRAGON was a phase 3, randomised, double-blind, placebo-controlled study which evaluated the efficacy and safety of erenumab in patients with chronic migraine (CM) from Asia not adequately represented in the global pivotal CM study.

    METHODS: DRAGON study was conducted across 9 Asian countries or regions including mainland China, India, the Republic of Korea, Malaysia, the Philippines, Singapore, Taiwan, Thailand, and Vietnam. Patients (N = 557) with CM (aged 18-65 years) were randomised (1:1) to receive once-monthly subcutaneous erenumab 70 mg or matching placebo for 12 weeks. The primary endpoint was the change in monthly migraine days (MMD) from baseline to the last 4 weeks of the 12-week double-blind treatment phase (DBTP). Secondary endpoints included achievement of ≥ 50% reduction in MMD, change in monthly acute headache medication days, modified migraine disability assessment (mMIDAS), and safety. Study was powered for the primary endpoint of change from baseline in MMD.

    RESULTS: At baseline, the mean (SD) age was 41.7 (± 10.9) years, and 81.5% (n = 454) patients were women. The mean migraine duration was 18.0 (± 11.6) years, and the mean MMD was 19.2 (± 5.4). 97.8% (n = 545) randomised patients completed the DBTP. Overall, demographics and baseline characteristics were balanced between the erenumab and placebo groups except for a slightly higher proportion of women in the placebo group. At Week 12, the adjusted mean change from baseline in MMD was - 8.2 days for erenumab and - 6.6 days for placebo, with a statistically significant difference for erenumab versus placebo (adjusted mean difference vs placebo: - 1.57 [95%CI: - 2.83, - 0.30]; P = 0.015). A greater proportion of patients treated with erenumab achieved ≥ 50% reduction in MMD versus placebo (47.0% vs 36.7%, P = 0.014). At Week 12, greater reductions in monthly acute headache medication days (- 5.34 vs - 4.66) and mMIDAS scores (- 14.67 vs - 12.93) were observed in patients treated with erenumab versus placebo. Safety and tolerability profile of erenumab was comparable to placebo, except the incidence of constipation (8.6% for erenumab vs 3.2% for placebo).

    CONCLUSION: DRAGON study demonstrated the efficacy and safety of erenumab 70 mg in patients with CM from Asia. No new safety signals were observed during the DBTP compared with the previous trials.

    TRIAL REGISTRATION: NCT03867201.

  8. Deschepper P, Vanbergen S, Zhang Y, Li Z, Hassani IM, Patel NA, et al.
    Evol Appl, 2023 Jan;16(1):48-61.
    PMID: 36699130 DOI: 10.1111/eva.13507
    An increasing number of invasive fruit fly pests are colonizing new grounds. With this study, we aimed to uncover the invasion pathways of the oriental fruit fly, Bactrocera dorsalis into the islands of the Indian Ocean. By using genome-wide SNP data and a multipronged approach consisting of PCA, ancestry analysis, phylogenetic inference, and kinship networks, we were able to resolve two independent invasion pathways. A western invasion pathway involved the stepping-stone migration of B. dorsalis from the east African coast into the Comoros, along Mayotte and into Madagascar with a decreasing genetic diversity. The Mascarene islands (Reunion and Mauritius), on the contrary, were colonized directly from Asia and formed a distinct cluster. The low nucleotide diversity suggests that only a few genotypes invaded the Mascarenes. The presence of many long runs of homozygosity (ROH) in the introduced populations is indicative of population bottlenecks, with evidence of a more severe bottleneck for populations along the western migration pathway than on the Mascarene islands. More strict phytosanitary regulations are recommended in order to prevent the further spread of B. dorsalis.
  9. Yang Q, Wu F, Peñuelas J, Sardans J, Peng Y, Wu Q, et al.
    Environ Res, 2024 Dec 01;262(Pt 2):119963.
    PMID: 39251176 DOI: 10.1016/j.envres.2024.119963
    The significance of intermittent streams in nutrient loss within forest ecosystems is becoming increasingly critical due to changes in precipitation patterns associated with global climate change. However, few studies have focused on nutrient export from intermittent streams. We conducted continuous sediment collection from intermittent streams from March 2022 to February 2023 to investigate the export pattern and mechanism of sediment-associated nitrogen (N) from intermittent streams of different forest types (composed forest of Castanopsis carlesii (Cas. carlesii) and Cunninghamia lanceolata (C. lanceolata) forests, compared to Cas. carlesii forests). We measured the N concentrations and calculated the export amounts of four common forms of N associated with sediments: total N (TN), dissolved N (DN), nitrate, and ammonia. Our results showed that (1) the annual average exports of TN, DN, nitrate, and ammonia associated with sediments from intermittent streams from both forest types were 273, 1.62, 0.26, and 0.84 kg ha-1, respectively; (2) N export was significantly higher in composite forests of Cas. carlesii and C. lanceolata, compared to Cas. carlesii forests; (3) stream sediment export amount positively affected N export both in composite forests and Cas. carlesii forests; and (4) N export was also controlled by rainfall amount and stream characteristics. Our study quantified sediment-associated N export from intermittent streams among different subtropical forest types, which will enhance our understanding of N dynamics associated with stream hydrological processes in subtropical forests.
  10. Lu J, Feng Y, Peng X, He Z, Li Z, Jia A, et al.
    Int J Biol Sci, 2026;22(14):7737-7759.
    PMID: 42807847 DOI: 10.7150/ijbs.140281
    In advanced diabetic kidney disease (DKD), tubulointerstitial fibrosis (TIF) is a key histopathological lesion accompanying progressive renal functional decline. However, the tubular mechanisms that drive tubulointerstitial fibrogenesis remain incompletely understood. N-acetyltransferase 10 (NAT10) mediates mRNA N4-acetylcytidine (ac4C) modification, but its role and therapeutic potential in DKD are unknown. We investigated NAT10 regulation and function using cultured tubular cells, diabetic mouse models, patient kidney specimens, and tubule-specific Nat10 knockout mice, together with pharmacological treatment using guanosine diphosphate disodium salt. High glucose or diabetes increased tubular NAT10 abundance in cultured cells, mouse kidneys, and human DKD tissues through activation of NF-κB signaling. Mechanistically, NAT10 in tubular cells stabilized Brd4 and Pfkm mRNAs through ac4C modification, activating the STAT3/TGF-β and lactate/H3K18 lactylation pathways. These pathways synergistically promoted fibroblast activation through NOTCH/SMAD3 signaling and formed a positive feedback loop with NF-κB. Tubule-specific Nat10 deletion reduced Brd4 and Pfkm expression, suppressed the associated signaling cascades, and mitigated kidney fibrosis in the DKD model. Consistently, guanosine diphosphate disodium salt alleviated renal injury and fibrosis in db/db mice. Thus, NAT10 drives tubular fibrosis through ac4C-dependent profibrotic signaling, supporting NAT10 inhibition as a potential therapeutic strategy for DKD.
  11. Liu Q, Wang Y, Huang J, Liu X, Mao C, Wang C, et al.
    ACS Nano, 2025 Apr 08;19(13):13341-13355.
    PMID: 40145746 DOI: 10.1021/acsnano.5c01112
    Conventional periodontitis treatments can be superseded by sonodynamic therapy. In this study, a Zn(OH)F/CaF2 heterojunction was synthesized via a hydrothermal method, which exhibited good biocompatibility and antibacterial properties. The band gap decreased significantly after the formation of the heterojunction, thereby enhancing the internal electron transfer. In addition, after the bacteria contact with the material, the electrons of the electron transport chain turn to Zn(OH)F/CaF2 and affect its steady state. Ultimately, H2O2 in an inflammatory environment was used to react with Zn(OH)F/CaF2 to facilitate electron transfer under the influence of ultrasound, ultimately enhancing the catalytic activity. Zn(OH)F/CaF2 exhibits significant antibacterial efficacy against Porphyromonas gingivalis and Staphylococcus aureus. Trace elements Ca and Zn can promote tissue repair and osteogenic differentiation, resulting in less bone destruction and intact gingival tissue after periodontitis treatment. This sonodynamic therapy provides a rapid antibacterial, effective, and deep therapeutic method for treating periodontitis.
  12. Yeoh AEJ, Lu Y, Chin WHN, Chiew EKH, Lim EH, Li Z, et al.
    J Clin Oncol, 2018 09 10;36(26):2726-2735.
    PMID: 30044693 DOI: 10.1200/JCO.2018.78.3050
    Purpose Although IKZF1 deletion ( IKZF1del) confers a higher risk of relapse in childhood B-cell acute lymphoblastic leukemia (B-ALL), it is uncertain whether treatment intensification will reverse this risk and improve outcomes. The Malaysia-Singapore ALL 2010 study (MS2010) prospectively upgraded the risk assignment of patients with IKZF1del to the next highest level and added imatinib to the treatment of all patients with BCR- ABL1 fusion. Patients and Methods In total, 823 patients with B-ALL treated in the Malyasia-Singapore ALL 2003 study (MS2003; n = 507) and MS2010 (n = 316) were screened for IKZF1del using the multiplex ligation-dependent probe amplification assay. The impact of IKZF1del on the 5-year cumulative incidence of relapse (CIR) was compared between the two studies. Results Patient characteristics were similar in both cohorts, including IKZF1del frequencies (59 of 410 [14.4%] v 50 of 275 [18.2%]; P = .2). In MS2003, where IKZF1del was not used in risk assignment, IKZF1del conferred a significantly higher 5-year CIR (30.4% v 8.1%; P = 8.7 × 10-7), particularly in the intermediate-risk group who lacked high-risk features (25.0% v 7.5%; P = .01). For patients with BCR-ABL1-negative disease, IKZF1del conferred a higher 5-year CIR (20.5% v 8.0%; P = .01). In MS2010, the 5-year CIR of patients with IKZF1del significantly decreased to 13.5% ( P = .05) and no longer showed a significant difference in patients with BCR-ABL1-negative disease (11.4% v 4.4%; P = .09). The 5-year overall survival for patients with IKZF1del improved from 69.6% in MS2003 to 91.6% in MS2010 ( P = .007). Conclusion Intensifying therapy for childhood B-ALL with IKZF1del significantly reduced the risk of relapse and improved overall survival. Incorporating IKZF1del screening significantly improved treatment outcomes in contemporary ALL therapy.
  13. Rey-Iglesia A, Gopalakrishan S, Carøe C, Alquezar-Planas DE, Ahlmann Nielsen A, Röder T, et al.
    Mol Ecol Resour, 2019 Mar;19(2):512-525.
    PMID: 30575257 DOI: 10.1111/1755-0998.12984
    In recent years, the availability of reduced representation library (RRL) methods has catalysed an expansion of genome-scale studies to characterize both model and non-model organisms. Most of these methods rely on the use of restriction enzymes to obtain DNA sequences at a genome-wide level. These approaches have been widely used to sequence thousands of markers across individuals for many organisms at a reasonable cost, revolutionizing the field of population genomics. However, there are still some limitations associated with these methods, in particular the high molecular weight DNA required as starting material, the reduced number of common loci among investigated samples, and the short length of the sequenced site-associated DNA. Here, we present MobiSeq, a RRL protocol exploiting simple laboratory techniques, that generates genomic data based on PCR targeted enrichment of transposable elements and the sequencing of the associated flanking region. We validate its performance across 103 DNA extracts derived from three mammalian species: grey wolf (Canis lupus), red deer complex (Cervus sp.) and brown rat (Rattus norvegicus). MobiSeq enables the sequencing of hundreds of thousands loci across the genome and performs SNP discovery with relatively low rates of clonality. Given the ease and flexibility of MobiSeq protocol, the method has the potential to be implemented for marker discovery and population genomics across a wide range of organisms-enabling the exploration of diverse evolutionary and conservation questions.
  14. Lau CS, Chia F, Dans L, Harrison A, Hsieh TY, Jain R, et al.
    Int J Rheum Dis, 2019 Mar;22(3):357-375.
    PMID: 30809944 DOI: 10.1111/1756-185X.13513
    AIM: To update recommendations based on current best evidence concerning the treatment of rheumatoid arthritis (RA), focusing particularly on the role of targeted therapies, to inform clinicians on new developments that will impact their current practice.

    MATERIALS AND METHODS: A search of relevant literature from 2014 to 2016 concerning targeted therapies in RA was conducted. The RA Update Working Group evaluated the evidence and proposed updated recommendations using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach, to describe the quality of evidence and strength of recommendations. Recommendations were finalized through consensus using the Delphi technique.

    RESULTS: This update provides 16 RA treatment recommendations based on current best evidence and expert clinical opinion. Recommendations 1-3 deal with the use of conventional synthetic disease-modifying antirheumatic drugs. The next three recommendations (4-6) cover the need for screening and management of infections and comorbid conditions prior to starting targeted therapy, while the following seven recommendations focus on use of these agents. We address choice of targeted therapy, switch, tapering and discontinuation. The last three recommendations elaborate on targeted therapy for RA in special situations such as pregnancy, cancer, and major surgery.

    CONCLUSION: Rheumatoid arthritis remains a significant health problem in the Asia-Pacific region. Patients with RA can benefit from the availability of effective targeted therapies, and these updated recommendations provide clinicians with guidance on their use.

  15. Li Z, Jiang N, Lim EH, Chin WHN, Lu Y, Chiew KH, et al.
    Leukemia, 2020 09;34(9):2418-2429.
    PMID: 32099036 DOI: 10.1038/s41375-020-0774-4
    Identifying patient-specific clonal IGH/TCR junctional sequences is critical for minimal residual disease (MRD) monitoring. Conventionally these junctional sequences are identified using laborious Sanger sequencing of excised heteroduplex bands. We found that the IGH is highly expressed in our diagnostic B-cell acute lymphoblastic leukemia (B-ALL) samples using RNA-Seq. Therefore, we used RNA-Seq to identify IGH disease clone sequences in 258 childhood B-ALL samples for MRD monitoring. The amount of background IGH rearrangements uncovered by RNA-Seq followed the Zipf's law with IGH disease clones easily identified as outliers. Four hundred and ninety-seven IGH disease clones (median 2, range 0-7 clones/patient) are identified in 90.3% of patients. High hyperdiploid patients have the most IGH disease clones (median 3) while DUX4 subtype has the least (median 1) due to the rearrangements involving the IGH locus. In all, 90.8% of IGH disease clones found by Sanger sequencing are also identified by RNA-Seq. In addition, RNA-Seq identified 43% more IGH disease clones. In 69 patients lacking sensitive IGH targets, targeted NGS IGH MRD showed high correlation (R = 0.93; P = 1.3 × 10-14), better relapse prediction than conventional RQ-PCR MRD using non-IGH targets. In conclusion, RNA-Seq can identify patient-specific clonal IGH junctional sequences for MRD monitoring, adding to its usefulness for molecular diagnosis in childhood B-ALL.
  16. Jiang N, Wang L, Xiang X, Li Z, Chiew EKH, Koo YM, et al.
    Br J Clin Pharmacol, 2021 Apr;87(4):1990-1999.
    PMID: 33037681 DOI: 10.1111/bcp.14596
    AIMS: Vincristine (VCR) is a key drug in the successful multidrug chemotherapy for childhood acute lymphoblastic leukaemia (ALL). However, it remains unclear how VCR pharmacokinetics affects its antileukaemic efficacy. The objective of this study is to explore the VCR pharmacokinetic parameters and intracellular VCR levels in an up-front window of Ma-Spore ALL 2010 (MS2010) study.

    METHODS: We randomised 429 children with newly diagnosed ALL to 15-minute vs 3-hour infusion for the first dose of VCR to study if prolonging the first dose of VCR infusion improved response. In a subgroup of 115 B-ALL and 20 T-ALL patients, we performed VCR plasma (n = 135 patients) and intracellular (n = 66 patients) pharmacokinetic studies. The correlations between pharmacokinetic parameters and intracellular VCR levels with early treatment response, final outcome and ABCB1 genotypes were analysed.

    RESULTS: There was no significant difference between 15-minute and 3-hour infusion schedules in median Day 8 peripheral or bone marrow blast response. Plasma VCR pharmacokinetic parameters did not predict outcome. However, in B-ALL, Day 33 minimal residual disease (MRD) negative patients and patients in continuous complete remission had significantly higher median intracellular VCR24h levels (P = .03 and P = .04, respectively). The median VCR24h intracellular levels were similar among the common genetic subtypes of ALL (P = .4). Patients homozygous for wild-type ABCB1 2677GG had significantly higher median intracellular VCR24h (P = .04) than 2677TT.

    CONCLUSION: We showed that in childhood B-ALL, the intracellular VCR24h levels in lymphoblasts affected treatment outcomes. The intracellular VCR24h level was independent of leukaemia subtype but dependent on host ABCB1 G2677T genotype.

  17. Ni Chin WH, Li Z, Jiang N, Lim EH, Suang Lim JY, Lu Y, et al.
    J Mol Diagn, 2021 10;23(10):1359-1372.
    PMID: 34365011 DOI: 10.1016/j.jmoldx.2021.07.013
    Despite the immense genetic heterogeneity of B-lymphoblastic leukemia [or precursor B-cell acute lymphoblastic leukemia (B-ALL)], RNA sequencing (RNA-Seq) could comprehensively interrogate its genetic drivers, assigning a specific molecular subtype in >90% of patients. However, study groups have only started to use RNA-Seq. For broader clinical use, technical, quality control, and appropriate performance validation are needed. We describe the development and validation of an RNA-Seq workflow for subtype classification, TPMT/NUDT15/TP53 variant discovery, and immunoglobulin heavy chain (IGH) disease clone identification for Malaysia-Singapore acute lymphoblastic leukemia (ALL) 2020. We validated this workflow in 377 patients in our preceding Malaysia-Singapore ALL 2003/Malaysia-Singapore ALL 2010 studies and proposed the quality control measures for RNA quality, library size, sequencing, and data analysis using the International Organization for Standardization 15189 quality and competence standard for medical laboratories. Compared with conventional methods, we achieved >95% accuracy in oncogene fusion identification, digital karyotyping, and TPMT and NUDT15 variant discovery. We found seven pathogenic TP53 mutations, confirmed with Sanger sequencing, which conferred a poorer outcome. Applying this workflow prospectively to the first 21 patients in Malaysia-Singapore ALL 2020, we identified the genetic drivers and IGH disease clones in >90% of patients with concordant TPMT, NUDT15, and TP53 variants using PCR-based methods. The median turnaround time was 12 days, which was clinically actionable. In conclusion, RNA-Seq workflow could be used clinically in management of B-cell ALL patients.
  18. Li Z, Lee SHR, Chin WHN, Lu Y, Jiang N, Lim EH, et al.
    Blood Adv, 2021 12 14;5(23):5226-5238.
    PMID: 34547766 DOI: 10.1182/bloodadvances.2021004895
    Among the recently described subtypes in childhood B-lymphoblastic leukemia (B-ALL) were DUX4- and PAX5-altered (PAX5alt). By using whole transcriptome RNA sequencing in 377 children with B-ALL from the Malaysia-Singapore ALL 2003 (MS2003) and Malaysia-Singapore ALL 2010 (MS2010) studies, we found that, after hyperdiploid and ETV6-RUNX1, the third and fourth most common subtypes were DUX4 (n = 51; 14%) and PAX5alt (n = 36; 10%). DUX4 also formed the largest genetic subtype among patients with poor day-33 minimal residual disease (MRD; n = 12 of 44). But despite the poor MRD, outcome of DUX4 B-ALL was excellent (5-year cumulative risk of relapse [CIR], 8.9%; 95% confidence interval [CI], 2.8%-19.5% and 5-year overall survival, 97.8%; 95% CI, 85.3%-99.7%). In MS2003, 21% of patients with DUX4 B-ALL had poor peripheral blood response to prednisolone at day 8, higher than other subtypes (8%; P = .03). In MS2010, with vincristine at day 1, no day-8 poor peripheral blood response was observed in the DUX4 subtype (P = .03). The PAX5alt group had an intermediate risk of relapse (5-year CIR, 18.1%) but when IKZF1 was not deleted, outcome was excellent with no relapse among 23 patients. Compared with MS2003, outcome of PAX5alt B-ALL with IKZF1 codeletion was improved by treatment intensification in MS2010 (5-year CIR, 80.0% vs 0%; P = .05). In conclusion, despite its poor initial response, DUX4 B-ALL had a favorable overall outcome, and the prognosis of PAX5alt was strongly dependent on IKZF1 codeletion.
  19. Collister D, Mbuagbaw L, Guyatt G, Devereaux PJ, Tennankore KK, Reis G, et al.
    Contemp Clin Trials, 2021 08;107:106466.
    PMID: 34098039 DOI: 10.1016/j.cct.2021.106466
    BACKGROUND/AIMS: To examine how measuring adherence at 3 weeks by self-report and pill counts compares to measurements at 7 weeks in a pre-randomization run-in period.

    METHODS: Study within a trial of an international parallel group randomized controlled trial (RCT) that compares spironolactone to placebo. Adults receiving dialysis enter an 8-week active run-in period with spironolactone. Adherence was assessed by both self-report and pill counts in a subgroup of participants at both 3 weeks and 7 weeks.

    RESULTS: 332 participants entered the run-in period of which 166 had complete data. By self-report, 146/166 (94.0%) and 153/166 (92.2%) had at least 80% adherence at 3 and 7 weeks respectively (kappa = 0.27 (95% C.I. 0.16 to 0.38). By pill counts, the mean (SD) adherence was 96.5% (16.1%) and 92.4% (18.2%) at 3 and 7 weeks respectively (r = 0.32) with a mean (SD) difference of 3.1% (17.8%) and a 95% limit of agreement from -31.7% to +37.9%. The proportion of adherent participants by self-report and pill counts at 3 weeks agreed in 87.4% of participants (McNemar's p-value 0.58, kappa 0.11, p = 0.02) and at 7 weeks agreed in 92.2% (McNemar's p-value 0.82, kappa 0.47, p 

  20. Wang C, Zhang Y, Lim LG, Cao W, Zhang W, Wan X, et al.
    Sci Rep, 2023 Jul 10;13(1):11141.
    PMID: 37429942 DOI: 10.1038/s41598-023-38057-1
    Living in high expressed emotion (EE) environments tends to increase the relapse rate in schizophrenia (SZ). At present, the neural substrates responsible for high EE in SZ remain poorly understood. Functional near-infrared spectroscopy (fNIRS) may be of great use to quantitatively assess cortical hemodynamics and elucidate the pathophysiology of psychiatric disorders. In this study, we designed novel low- (positivity and warmth) and high-EE (criticism, negative emotion, and hostility) stimulations, in the form of audio, to investigate cortical hemodynamics. We used fNIRS to measure hemodynamic signals while participants listened to the recorded audio. Healthy controls (HCs, [Formula: see text]) showed increased hemodynamic activation in the major language centers across EE stimulations, with stronger activation in Wernicke's area during the processing of negative emotional language. Compared to HCs, people with SZ ([Formula: see text]) exhibited smaller hemodynamic activation in the major language centers across EE stimulations. In addition, people with SZ showed weaker or insignificant hemodynamic deactivation in the medial prefrontal cortex. Notably, hemodynamic activation in SZ was found to be negatively correlated with the negative syndrome scale score at high EE. Our findings suggest that the neural mechanisms in SZ are altered and disrupted, especially during negative emotional language processing. This supports the feasibility of using the designed EE stimulations to assess people who are vulnerable to high-EE environments, such as SZ. Furthermore, our findings provide preliminary evidence for future research on functional neuroimaging biomarkers for people with psychiatric disorders.
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