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A new cell culture tube in diagnostic virology for virus isolation

Chua KB, Chua KH, Chua IL, Chen KF

Malays J Pathol, 2004 Jun;26(1):69-71.
PMID: 16190110

Virus isolation and accurate characterization plays a crucial role in the rapid identification of the causative agents of infectious disease outbreaks especially if the causative viruses are novel where no pre-existing diagnostic reagents would be available. A new cell culture tube, named Jui Meng (JM) Cell Culture Tube, was developed to reduce the cost and improve the efficiency and biosafety of work pertaining to virus isolation. The design of the tube is based heavily on the principle of practicability, functionality, biosafety and long-term cost saving for diagnostic laboratory work in virus isolation. It is designed to culture an initial inoculum of one milliliter of culture medium containing 1 x 10(4) to 1 x 10(5) cells/ml.
Genetic markers of an aboriginal Taiwanese population

Chen KH, Cann H, Chen TC, Van West B, Cavalli-Sforza L

Am. J. Phys. Anthropol., 1985 Mar;66(3):327-37.
PMID: 3857010

A group of Taiwan aborigines, the Toroko, was typed for 21 classical genetic loci. This is part of an ongoing program aimed at a comprehensive study of Taiwan aborigines. In this first paper a short summary of historical, archeological, and anthropological data in the literature is made, and results of the present survey are compared with older results from other aborigine tribes. An analysis of other neighboring populations from southeast Asia has also been carried out in order to give a preliminary answer to the question of origin of Taiwanese aborigines. Fifteen populations were studied for 13 loci by tree analysis, principal components, and isolation by distance. Tree analysis and principal component analysis gave results in fairly good agreement and indicate three major population clusters: a northeast cluster (Ainu, Korea, Japan, and Ryukyu); a southeast cluster (south China, Thailand, Vietnam, Philippines, Taiwan, and Toroko); and a third cluster including Malaya and Borneo. The positions of Polynesia, Micronesia, and Melanesia are somewhat peripheral. Analysis of the tree shows some potential cases of convergence, perhaps owing to admixture, and of divergence. The analysis of isolation by distance shows that geographic propinquity is a reasonably good predictor of general similarity in this area.
Progress in gene therapy treatments for prostate cancer

Xue J, Chen K, Hu H, Gopinath SCB

Biotechnol Appl Biochem, 2021 May 14.
PMID: 33988271 DOI: 10.1002/bab.2193

Prostate cancer is one of the predominant cancers affecting men and has been widely reported. In the past, various therapies and drugs have been proposed to treat prostate cancer. Among these treatments, gene therapy has been considered to be an optimal and widely applicable treatment. Furthermore, due to the increased specificity of gene sequence complementation, the targeted delivery of complementary gene sequences may represent a useful treatment in certain instances. Various gene therapies, including tumor-suppressor gene therapy, suicide gene therapy, immunomodulation gene therapy and anti-oncogene therapies, have been established to treat a wide range of diseases, such as cardiac disease, cystic fibrosis, HIV/AIDS, diabetes, hemophilia, and cancers. To this end, several gene therapy clinical trials at various phases are underway. This overview describes the developments and progress in gene therapy, with a special focus being placed on prostate cancer.
Elimination of energy-consuming mechanical stirring: Development of auto-suspending ZnO-based photocatalyst for organic wastewater treatment

Ng KH, Chen K, Cheng CK, Vo DN

J Hazard Mater, 2021 05 05;409:124532.
PMID: 33221078 DOI: 10.1016/j.jhazmat.2020.124532

Powdered-photocatalysis of organic wastewater is widely investigated, unfortunately not industrially implemented due to its high energy requirement. Interestingly, such issue may be alleviated via the elimination of mechanical stirring required. Core-shell ZnO-based photocatalysts were developed herein, subsequently demonstrated efficient photocatalytic activities in the absence of mechanical stirring. Results show that the developed SiO2-cored ZnO photocatalyst are highly crystalline, while significantly smaller than coreless, pure ZnO due to the multi-point crystallization prompted. Additionally, it is also inherited with considerable buoyancy ability from SiO2-core in the absence of mechanical stirring, concurrently rendered with UV-active properties due to its ZnO-shell. Experimentally, 55% of particles of ZnO_0.0025 (0.0025 mol of ZnO-deposition) were found stably suspended for 60 min in liquid substrate, as opposed to the instant-settling of pure ZnO particles. In term of photocatalytic activity, ZnO_0.01 manifested the best methylene blue (MB) degradation with 150 mL/min of O2-bubbling. 67.63% of MB was degraded with photocatalyst loading of 0.2 g/L after 120 min UV-irradiation, simultaneously recorded the highest pseudo-first order reaction constant of 9.636 × 10-3 min-1. As summary, the auto-suspending photocatalysis conceptualized in current study offers a high possibility in reducing energy requirement for photo-treatment of wastewater, hence advocating its industrialization potential in near future.
Current Status and Challenges in Rotigotine Delivery

Md S, Karim S, Saker SR, Gie OA, Hooi LC, Yee PH, et al.

Curr Pharm Des, 2020;26(19):2222-2232.
PMID: 32175832 DOI: 10.2174/1381612826666200316154300

Rotigotine is a non-ergoline, high lipophilic dopamine agonist. It is indicated as the first-line therapy for Parkinson's disease (PD) and Restless Leg Syndrome (RLS). However, the precise mechanism of rotigotine is yet to be known. Rotigotine has similar safety and tolerability to the other oral non-ergolinic dopamine antagonists in clinical trials, which include nausea, dizziness and somnolence. Neupro® was the first marketed transdermal patch formulation having rotigotine. The transdermal delivery system is advantageous as it enables continuous administration of the drug, thus providing steady-state plasma drug concentration for 24-hours. Intranasal administration of rotigotine allows the drug to bypass the blood-brain barrier enabling it to reach the central nervous system within minutes. Rotigotine can also be formulated as an extended-release microsphere for injection. Some challenges remain in other routes of rotigotine administration such as oral, parenteral and pulmonary, whereby resolving these challenges will be beneficial to patients as they are less invasive and comfortable in terms of administration. This review compiles recent work on rotigotine delivery, challenges and its future perspective.
Dietary berberine regulates lipid metabolism in muscle and liver of black sea bream (Acanthopagrus schlegelii) fed normal or high-lipid diets

Wang L, Xu B, Sagada G, Ng WK, Chen K, Zhang J, et al.

Br J Nutr, 2021 Mar 14;125(5):481-493.
PMID: 32718379 DOI: 10.1017/S0007114520003025

The present study investigated the influence of berberine (BBR) supplementation in normal and high-lipid (HL) diets on lipid metabolism and accumulation in black sea bream (Acanthopagrus schlegelii). BBR was supplemented at 50 mg/kg to control (Con, 11·1 % crude lipid) and high-lipid (HL, 20·2 % crude lipid) diets and named as ConB and HLB, respectively. After the 8-week feeding trial, fish body length and specific growth rate were significantly reduced by HL diets (P < 0·05). Muscle and whole-body crude lipid contents were significantly influenced by both BBR supplementation and dietary lipid level. Fish fed the HLB diet had significantly lower serum TAG, LDL-cholesterol contents and alanine aminotransferase activity compared with the HL group. The HL group presented vast lipid accumulation in the liver, and hypertrophied hepatocytes along with large lipid droplets, and translocation of nuclear to the cell periphery. These abnormalities in black sea bream were alleviated in the HLB group. BBR supplementation in the HL diet significantly down-regulated the hepatic expression levels of acetyl-CoA carboxylase α, sterol regulatory element-binding protein-1, 6-phosphogluconate dehydrogenase, glucose 6-phosphate dehydrogenase and pparγ, whereas the lipoprotein lipase, hormone-sensitive lipase and carnitine palmitoyltransferase 1a expression levels were significantly up-regulated. However, the expression levels of these genes showed opposite trends in muscle (except for pparγ). In conclusion, dietary BBR supplementation in the HL diet reduced hepatic lipid accumulation by down-regulating lipogenesis gene expression and up-regulating lipolysis gene expression, and it increased muscle lipid contents with opposite trends of the mechanism observed in the liver.
Efficacy of purified nucleotide supplements on the growth performance and immunity of hybrid striped bass Morone chrysops x Morone saxatilis

de Cruz CR, Yamamoto FY, Ju M, Chen K, Velasquez A, Gatlin DM

Fish Shellfish Immunol, 2020 Mar;98:868-874.
PMID: 31751660 DOI: 10.1016/j.fsi.2019.11.046

Fishmeal is being increasingly replaced in aquatic animal diets with alternative plant protein feedstuffs such as soybean meal which have lower concentrations of nucleotides; therefore, supplemental sources of exogenous nucleotides in diets could become increasingly important. A 9-week feeding trial was conducted with triplicate groups of juvenile hybrid striped bass (average initial body weight ± standard deviation, 5.6 ± 0.1 g) to determine the effects of supplementing single purified nucleotides on the growth performance and immune parameters. The basal diet, which utilized menhaden fishmeal (25%) and soybean meal (75%) as protein sources, contained 44% protein, 10% lipid and an estimated digestible energy level of 3.5 kcal g-1. Single additions of 5'- adenosine monophosphate (AMP), 5'- uridine monophosphate (UMP), 5'- cytidine monophosphate (CMP), 5'- guanosine monophosphate (GMP), and 5'- inosine monophosphate (IMP) disodium salts (Chem-Impex International, Wood Dale, Illinois, USA) were evaluated with each nucleotide added to the basal diet at 0.5% of dry weight at the expense of cellulose. A positive control diet in this trial was a diet containing 5'- AMP from Sigma-Aldrich also supplemented at 0.5% by weight. Results showed significantly (P 0.05) was detected in whole-body proximate composition and protein retention of fish fed any of the dietary treatments. The respiratory burst of whole blood phagocytes also was significantly (P
Fulltext A Trusted Reputation Management Scheme for Cross-Chain Transactions

Chen K, Lee LF, Chiu W, Su C, Yeh KH, Chao HC

Sensors (Basel), 2023 Jun 29;23(13).
PMID: 37447883 DOI: 10.3390/s23136033

Blockchain has become a well-known, secured, decentralized datastore in many domains, including medical, industrial, and especially the financial field. However, to meet the requirements of different fields, platforms that are built on blockchain technology must provide functions and characteristics with a wide variety of options. Although they may share similar technology at the fundamental level, the differences among them make data or transaction exchange challenging. Cross-chain transactions have become a commonly utilized function, while at the same time, some have pointed out its security loopholes. It is evident that a secure transaction scheme is desperately needed. However, what about those nodes that do not behave? It is clear that not only a secure transaction scheme is necessary, but also a system that can gradually eliminate malicious players is of dire need. At the same time, integrating different blockchain systems can be difficult due to their independent architectures, and cross-chain transactions can be at risk if malicious attackers try to control the nodes in the cross-chain system. In this paper, we propose a dynamic reputation management scheme based on the past transaction behaviors of nodes. These behaviors serve as the basis for evaluating a node's reputation to support the decision on malicious behavior and enable the system to intercept it in a timely manner. Furthermore, to establish a reputation index with high precision and flexibility, we integrate Particle Swarm Optimization (PSO) into our proposed scheme. This allows our system to meet the needs of a wide variety of blockchain platforms. Overall, the article highlights the importance of securing cross-chain transactions and proposes a method to prevent misbehavior by evaluating and managing node reputation.
Asymmetric Synthesis of Arboduridine

Yang R, Zhou Z, Jiang H, Kam TS, Chen K, Ma Z

Angew Chem Int Ed Engl, 2024 Jan 15;63(3):e202316016.
PMID: 38038685 DOI: 10.1002/anie.202316016

The first asymmetric total synthesis of the monoterpenoid indole alkaloid arboduridine has been accomplished. The tricyclic A/B/D ring system was constructed by an enantioselective Michael reaction followed by intramolecular nucleophilic addition. Intramolecular α-amination of a ketone forged the piperidine ring, while a Horner-Wadsworth-Emmons (HWE) reaction was used to form the pyrrolidine ring. A reduction cyclization cascade led to formation of the tetrahydrofuran ring.
Southeast Asian mitochondrial DNA analysis reveals genetic continuity of ancient mongoloid migrations

Ballinger SW, Schurr TG, Torroni A, Gan YY, Hodge JA, Hassan K, et al.

Genetics, 1992 Jan;130(1):139-52.
PMID: 1346259

Human mitochondrial DNAs (mtDNAs) from 153 independent samples encompassing seven Asian populations were surveyed for sequence variation using the polymerase chain reaction (PCR), restriction endonuclease analysis and oligonucleotide hybridization. All Asian populations were found to share two ancient AluI/DdeI polymorphisms at nps 10394 and 10397 and to be genetically similar indicating that they share a common ancestry. The greatest mtDNA diversity and the highest frequency of mtDNAs with HpaI/HincII morph 1 were observed in the Vietnamese suggesting a Southern Mongoloid origin of Asians. Remnants of the founding populations of Papua New Guinea (PNG) were found in Malaysia, and a marked frequency cline for the COII/tRNA(Lys) intergenic deletion was observed along coastal Asia. Phylogenetic analysis indicates that both insertion and deletion mutations in the COII/tRNA(Lys) region have occurred more than once.
Childhood adrenocortical carcinoma as a sentinel cancer for detecting families with germline TP53 mutations

Choong SS, Latiff ZA, Mohamed M, Lim LL, Chen KS, Vengidasan L, et al.

Clin Genet, 2012 Dec;82(6):564-8.
PMID: 22233476 DOI: 10.1111/j.1399-0004.2012.01841.x

Li-Fraumeni syndrome (LFS) is a highly penetrant, autosomal dominant disorder where affected individuals carry a 50% risk of developing cancer before 30 years of age. It is most commonly associated with mutations in the tumour suppressor gene, TP53. Adrenocortical carcinoma (ACC) is a very rare paediatric cancer, and up to 80% of affected children are found to carry germline TP53 mutations. Hence, we propose using childhood ACC incidence as selection criteria for referral for TP53 mutation testing, independent of familial cancer history. Under the auspices of the Malaysian Society of Paediatric Haematology-Oncology, four eligible children diagnosed with ACC over a 30-month study period were referred for mutation testing. Three had a germline TP53 mutation. Subsequent TP53 testing in relatives showed two inherited mutations and one de novo mutation. These findings strongly support paediatric ACC as a useful sentinel cancer for initiating a germline TP53/LFS detection programme, particularly in countries where the lack of structured oncogenetic practice precludes the identification of families with LFS features.
Effect of carnosine supplementation on lipid profile, fasting blood glucose, HbA1C and insulin resistance: A systematic review and meta-analysis of long-term randomized controlled trials

Peng W, Mao P, Liu L, Chen K, Zhong Y, Xia W, et al.

Complement Ther Med, 2020 Jan;48:102241.
PMID: 31987255 DOI: 10.1016/j.ctim.2019.102241

OBJECTIVE: Glucose disorders and dyslipidemia are closely associated with obesity and metabolic disease. The purpose of this study was to investigate the effect of Carnosine supplementation on lipid profile, fasting blood glucose, HbA1C and Insulin resistance.
METHOD: MEDLINE/PubMed, Scopus and Web of sciences were investigated to identify relevant articles up to June 2019. The search strategy combined the Medical Subject Heading and Title and/or abstract keywords. The combined effect sizes were calculated as weight mean difference (WMD) using the random-effects model. Between study heterogeneity was evaluated by the Cochran's Q test and I2.
RESULTS: Four RCTs studies investigated Carnosine use versus any control for at least 2 weeks were identified and analyzed. Overall results from the random-effects model on included studies, with 184 participants, indicated that carnosine intervention reduced HbA1C levels in intervention vs control groups (WMD: -0.92 %, 95 % CI: -1.20, -0.63, I2:69 %). Four studies, including a total of 183 participants, reported TG changes as an outcome measure variable, but combined results did not show significant reduction in this outcome (WMD: -14.46 mg/dl, 95 % CI: -29.11, 0.19, I2:94 %). Furthermore, combined results did not show any significant change in HOMA-IR, Cholesterol, fasting blood sugar, or HDL-C.
CONCLUSION: Carnosine supplementation results in a decrease in HbA1C, but elicits no effect on HOMA-IR, Cholesterol, fasting blood sugar, TG and HDL-C. Future studies with a larger sample sizes, varied doses of carnosine, and population-specific sub-groups are warranted to confirm, and enhance, the veracity of our findings.
Fulltext Effect of Silymarin as an Adjunct Therapy in Combination with Sofosbuvir and Ribavirin in Hepatitis C Patients: A Miniature Clinical Trial

Ahmed S, Ullah N, Parveen S, Javed I, Jalil NAC, Murtey MD, et al.

Oxid Med Cell Longev, 2022;2022:9199190.
PMID: 35154575 DOI: 10.1155/2022/9199190

Silymarin is proclaimed to be a blend of flavonolignans or phytochemicals. An era of new generation of direct-acting antivirals (DAAs) has commenced to have facet effect in swaying of the hepatitis C virus (HCV). Nonetheless, this therapy has serious side effects that jeopardize its efficacy. This study is aimed at probing the effects of ribavirin (RBV) and sofosbuvir (SOF) along with silymarin as an adjunct therapy on hematological parameters and markers of obscured oxidative stress. The effect of DAAs along with silymarin was also examined on variable sex hormone level and liver function markers such as alanine aminotransferase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), and bilirubin. The study was followed to determine viral load and viral genotypes. A total of 30 patients were randomly divided into two equal groups comprising the control group (n = 15) and treatment group (n = 15). The control group was solely administered with DAAs (SOF and RBV; 400 mg/800 mg each/day). Conversely, the treatment group was dispensed with DAAs, but with adjunct therapy of silymarin (400 mg/day) along with DAAs (400/800 mg/day) over period of 8 weeks. Sampling of blood was performed at pre- and posttreatment levels for the evaluation of different propound parameters. Our data showed that silymarin adjunct therapy enhances the efficiency of DAAs. A decrease in menace level of liver markers such as ALT, ALP, AST, and bilirubin was observed (p > 0.05). The adjunct therapy concurrently also demonstrated an ameliorative effect on hematological indices and oxidative markers, for instance, SOD, TAS, GSH, GSSG, and MDA (p < 0.05), diminishing latent viral load. The silymarin administration was also found to revamp the fluster level of sex hormones. Our outcomes provide evidence that systematic administration of silymarin effectively remits deviant levels of hematological, serological, hormonal, and antioxidant markers. This demonstrates a possibly unique role of silymarin in mitigating hepatitis C.
Biomass-derived carbon-based and silica-based materials for catalytic and adsorptive applications- An update since 2010

Chen K, Ng KH, Cheng CK, Cheng YW, Chong CC, Vo DN, et al.

Chemosphere, 2022 Jan;287(Pt 2):132222.
PMID: 34826917 DOI: 10.1016/j.chemosphere.2021.132222

Biomass, which defined as plant- or animal-based materials, is intriguing tremendous scientific attentions due to its renewable attribute in serving energy security. Amongst, the plant-based biomasses, particularly those that co-generated in the agriculture activities, are commonly regarded as fuel for burning, which overlooked their hidden potentials for high-end applications. Organically, the plant-based biomass constitutes of lignocellulose components, which can be served as promising precursors for functionalized carbon materials. Meanwhile, its inorganic counterpart made up of various minerals, with Si being the most concerned one. With the advancement of biomass technologies and material synthesis in recent years, numerous attempts were endeavoured to obtain valorised products from biomass. Particularly, syntheses of catalytic and adsorptive materials are actively researched in the field of biomass reutilization. Herein, our work systematically summarized the advancements of biomass-materials for these applications in recent 10 years (2010-2020), with a special focus on the carbon-based and Si-based catalytic/adsorptive materials. Significantly, the deriving steps, inclusive of both pre-treatment and post-treatment of such materials, are incorporated in the discussion, alongside with their significances revealed too. The performance of the as-obtained materials in the respective application is systematically correlated to their physicochemical properties, hence providing valuable insights to the readers. Challenges and promising directions to be explored are raised too at the end of the review, aiming to advocate better-usage of biomass while offering great opportunities to sustain catalysis and adsorption in the industrial scale.
Parkin deficiency promotes liver cancer metastasis by TMEFF1 transcription activation via TGF-β/Smad2/3 pathway

Su Q, Wang JJ, Ren JY, Wu Q, Chen K, Tu KH, et al.

Acta Pharmacol Sin, 2024 Mar 22.
PMID: 38519646 DOI: 10.1038/s41401-024-01254-3

Parkin (PARK2) deficiency is frequently observed in various cancers and potentially promotes tumor progression. Here, we showed that Parkin expression is downregulated in liver cancer tissues, which correlates with poor patient survival. Parkin deficiency in liver cancer cells promotes migration and metastasis as well as changes in EMT and metastasis markers. A negative correlation exists between TMEFF1 and Parkin expression in liver cancer cells and tumor tissues. Parkin deficiency leads to upregulation of TMEFF1 which promotes migration and metastasis. TMEFF1 transcription is activated by Parkin-induced endogenous TGF-β production and subsequent phosphorylation of Smad2/3 and its binding to TMEFF1 promotor. TGF-β inhibitor and TMEFF1 knockdown can reverse shParkin-induced cell migration and changes of EMT markers. Parkin interacts with and promotes the ubiquitin-dependent degradation of HIF-1α/HIF-1β and p53, which accounts for the suppression of TGF-β production. Our data have revealed that Parkin deficiency in cancer leads to the activation of the TGF-β/Smad2/3 pathway, resulting in the expression of TMEFF1 which promotes cell migration, EMT, and metastasis in liver cancer cells.
Fulltext Novel Polymyxin Combination with the Antiretroviral Zidovudine Exerts Synergistic Killing against NDM-Producing Multidrug-Resistant Klebsiella pneumoniae

Lin YW, Abdul Rahim N, Zhao J, Han ML, Yu HH, Wickremasinghe H, et al.

Antimicrob Agents Chemother, 2019 04;63(4).
PMID: 30670431 DOI: 10.1128/AAC.02176-18

Polymyxins are used as a last-line therapy against multidrug-resistant (MDR) New Delhi metallo-β-lactamase (NDM)-producing Klebsiella pneumoniae However, polymyxin resistance can emerge with monotherapy; therefore, novel strategies are urgently needed to minimize the resistance and maintain their clinical utility. This study aimed to investigate the pharmacodynamics of polymyxin B in combination with the antiretroviral drug zidovudine against K. pneumoniae Three isolates were evaluated in static time-kill studies (0 to 64 mg/liter) over 48 h. An in vitro one-compartment pharmacokinetic/pharmacodynamic (PK/PD) model (IVM) was used to simulate humanized dosage regimens of polymyxin B (4 mg/liter as continuous infusion) and zidovudine (as bolus dose thrice daily to achieve maximum concentration of drug in broth [Cmax] of 6 mg/liter) against K. pneumoniae BM1 over 72 h. The antimicrobial synergy of the combination was further evaluated in a murine thigh infection model against K. pneumoniae 02. In the static time-kill studies, polymyxin B monotherapy produced rapid and extensive killing against all three isolates followed by extensive regrowth, whereas zidovudine produced modest killing followed by significant regrowth at 24 h. Polymyxin B in combination with zidovudine significantly enhanced the antimicrobial activity (≥4 log10 CFU/ml) and minimized bacterial regrowth. In the IVM, the combination was synergistic and the total bacterial loads were below the limit of detection for up to 72 h. In the murine thigh infection model, the bacterial burden at 24 h in the combination group was ≥3 log10 CFU/thigh lower than each monotherapy against K. pneumoniae 02. Overall, the polymyxin B-zidovudine combination demonstrates superior antimicrobial efficacy and minimized emergence of resistance to polymyxins.
Fulltext Genome-wide association studies identify susceptibility loci for epithelial ovarian cancer in east Asian women

Lawrenson K, Song F, Hazelett DJ, Kar SP, Tyrer J, Phelan CM, et al.

Gynecol Oncol, 2019 05;153(2):343-355.
PMID: 30898391 DOI: 10.1016/j.ygyno.2019.02.023

OBJECTIVE: Genome-wide association studies (GWASs) for epithelial ovarian cancer (EOC) have focused largely on populations of European ancestry. We aimed to identify common germline variants associated with EOC risk in Asian women.
METHODS: Genotyping was performed as part of the OncoArray project. Samples with >60% Asian ancestry were included in the analysis. Genotyping was performed on 533,631 SNPs in 3238 Asian subjects diagnosed with invasive or borderline EOC and 4083 unaffected controls. After imputation, genotypes were available for 11,595,112 SNPs to identify associations.
RESULTS: At chromosome 6p25.2, SNP rs7748275 was associated with risk of serous EOC (odds ratio [OR] = 1.34, P = 8.7 × 10-9) and high-grade serous EOC (HGSOC) (OR = 1.34, P = 4.3 × 10-9). SNP rs6902488 at 6p25.2 (r2 = 0.97 with rs7748275) lies in an active enhancer and is predicted to impact binding of STAT3, P300 and ELF1. We identified additional risk loci with low Bayesian false discovery probability (BFDP) scores, indicating they are likely to be true risk associations (BFDP <10%). At chromosome 20q11.22, rs74272064 was associated with HGSOC risk (OR = 1.27, P = 9.0 × 10-8). Overall EOC risk was associated with rs10260419 at chromosome 7p21.3 (OR = 1.33, P = 1.2 × 10-7) and rs74917072 at chromosome 2q37.3 (OR = 1.25, P = 4.7 × 10-7). At 2q37.3, expression quantitative trait locus analysis in 404 HGSOC tissues identified ESPNL as a putative candidate susceptibility gene (P = 1.2 × 10-7).
CONCLUSION: While some risk loci were shared between East Asian and European populations, others were population-specific, indicating that the landscape of EOC risk in Asian women has both shared and unique features compared to women of European ancestry.
Genetic risk of extranodal natural killer T-cell lymphoma: a genome-wide association study in multiple populations

Lin GW, Xu C, Chen K, Huang HQ, Chen J, Song B, et al.

Lancet Oncol, 2020 Feb;21(2):306-316.
PMID: 31879220 DOI: 10.1016/S1470-2045(19)30799-5

BACKGROUND: Extranodal natural killer T-cell lymphoma (NKTCL; nasal type) is an aggressive malignancy with a particularly high prevalence in Asian and Latin American populations. Epstein-Barr virus infection has a role in the pathogenesis of NKTCL, and HLA-DPB1 variants are risk factors for the disease. We aimed to identify additional novel genetic variants affecting risk of NKTCL.
METHODS: We did a genome-wide association study of NKTCL in multiple populations from east Asia. We recruited a discovery cohort of 700 cases with NKTCL and 7752 controls without NKTCL of Han Chinese ancestry from 19 centres in southern, central, and northern regions of China, and four independent replication samples including 717 cases and 12 650 controls. Three of these independent samples (451 cases and 5301 controls) were from eight centres in the same regions of southern, central, and northern China, and the fourth (266 cases and 7349 controls) was from 11 centres in Hong Kong, Taiwan, Singapore, and South Korea. All cases had primary NKTCL that was confirmed histopathologically, and matching with controls was based on geographical region and self-reported ancestry. Logistic regression analysis was done independently by geographical regions, followed by fixed-effect meta-analyses, to identify susceptibility loci. Bioinformatic approaches, including expression quantitative trait loci, binding motif and transcriptome analyses, and biological experiments were done to fine-map and explore the functional relevance of genome-wide association loci to the development of NKTCL.
FINDINGS: Genetic data were gathered between Jan 1, 2008, and Jan 23, 2019. Meta-analysis of all samples (a total of 1417 cases and 20 402 controls) identified two novel loci significantly associated with NKTCL: IL18RAP on 2q12.1 (rs13015714; p=2·83 × 10-16; odds ratio 1·39 [95% CI 1·28-1·50]) and HLA-DRB1 on 6p21.3 (rs9271588; 9·35 × 10-26 1·53 [1·41-1·65]). Fine-mapping and experimental analyses showed that rs1420106 at the promoter of IL18RAP was highly correlated with rs13015714, and the rs1420106-A risk variant had an upregulatory effect on IL18RAP expression. Cell growth assays in two NKTCL cell lines (YT and SNK-6 cells) showed that knockdown of IL18RAP inhibited cell proliferation by cell cycle arrest in NKTCL cells. Haplotype association analysis showed that haplotype 47F-67I was associated with reduced risk of NKTCL, whereas 47Y-67L was associated with increased risk of NKTCL. These two positions are component parts of the peptide-binding pocket 7 (P7) of the HLA-DR heterodimer, suggesting that these alterations might account for the association at HLA-DRB1, independent of the previously reported HLA-DPB1 variants.
INTERPRETATION: Our findings provide new insights into the development of NKTCL by showing the importance of inflammation and immune regulation through the IL18-IL18RAP axis and antigen presentation involving HLA-DRB1, which might help to identify potential therapeutic targets. Taken in combination with additional genetic and other risk factors, our results could potentially be used to stratify people at high risk of NKTCL for targeted prevention.
FUNDING: Guangdong Innovative and Entrepreneurial Research Team Program, National Natural Science Foundation of China, National Program for Support of Top-Notch Young Professionals, Chang Jiang Scholars Program, Singapore Ministry of Health's National Medical Research Council, Tanoto Foundation, National Research Foundation Singapore, Chang Gung Memorial Hospital, Recruitment Program for Young Professionals of China, First Affiliated Hospital and Army Medical University, US National Institutes of Health, and US National Cancer Institute.
Fulltext Multi-platform discovery of haplotype-resolved structural variation in human genomes

Chaisson MJP, Sanders AD, Zhao X, Malhotra A, Porubsky D, Rausch T, et al.

Nat Commun, 2019 04 16;10(1):1784.
PMID: 30992455 DOI: 10.1038/s41467-018-08148-z

The incomplete identification of structural variants (SVs) from whole-genome sequencing data limits studies of human genetic diversity and disease association. Here, we apply a suite of long-read, short-read, strand-specific sequencing technologies, optical mapping, and variant discovery algorithms to comprehensively analyze three trios to define the full spectrum of human genetic variation in a haplotype-resolved manner. We identify 818,054 indel variants (<50 bp) and 27,622 SVs (≥50 bp) per genome. We also discover 156 inversions per genome and 58 of the inversions intersect with the critical regions of recurrent microdeletion and microduplication syndromes. Taken together, our SV callsets represent a three to sevenfold increase in SV detection compared to most standard high-throughput sequencing studies, including those from the 1000 Genomes Project. The methods and the dataset presented serve as a gold standard for the scientific community allowing us to make recommendations for maximizing structural variation sensitivity for future genome sequencing studies.
Fulltext Genetic Data from Nearly 63,000 Women of European Descent Predicts DNA Methylation Biomarkers and Epithelial Ovarian Cancer Risk

Yang Y, Wu L, Shu X, Lu Y, Shu XO, Cai Q, et al.

Cancer Res, 2019 Feb 01;79(3):505-517.
PMID: 30559148 DOI: 10.1158/0008-5472.CAN-18-2726

DNA methylation is instrumental for gene regulation. Global changes in the epigenetic landscape have been recognized as a hallmark of cancer. However, the role of DNA methylation in epithelial ovarian cancer (EOC) remains unclear. In this study, high-density genetic and DNA methylation data in white blood cells from the Framingham Heart Study (N = 1,595) were used to build genetic models to predict DNA methylation levels. These prediction models were then applied to the summary statistics of a genome-wide association study (GWAS) of ovarian cancer including 22,406 EOC cases and 40,941 controls to investigate genetically predicted DNA methylation levels in association with EOC risk. Among 62,938 CpG sites investigated, genetically predicted methylation levels at 89 CpG were significantly associated with EOC risk at a Bonferroni-corrected threshold of P < 7.94 × 10-7. Of them, 87 were located at GWAS-identified EOC susceptibility regions and two resided in a genomic region not previously reported to be associated with EOC risk. Integrative analyses of genetic, methylation, and gene expression data identified consistent directions of associations across 12 CpG, five genes, and EOC risk, suggesting that methylation at these 12 CpG may influence EOC risk by regulating expression of these five genes, namely MAPT, HOXB3, ABHD8, ARHGAP27, and SKAP1. We identified novel DNA methylation markers associated with EOC risk and propose that methylation at multiple CpG may affect EOC risk via regulation of gene expression. SIGNIFICANCE: Identification of novel DNA methylation markers associated with EOC risk suggests that methylation at multiple CpG may affect EOC risk through regulation of gene expression.

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