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A novel synthetic analogue of ω-3 17,18-epoxyeicosatetraenoic acid activates TNF receptor-1/ASK1/JNK signaling to promote apoptosis in human breast cancer cells

Dyari HRE, Rawling T, Chen Y, Sudarmana W, Bourget K, Dwyer JM, et al.

FASEB J, 2017 12;31(12):5246-5257.
PMID: 28798154 DOI: 10.1096/fj.201700033R

A saturated analog of the cytochrome P450-mediated ω-3-17,18-epoxide of ω-3-eicosapentaenoic acid (C20E) activated apoptosis in human triple-negative MDA-MB-231 breast cancer cells. This study evaluated the apoptotic mechanism of C20E. Increased cytosolic cytochrome c expression and altered expression of pro- and antiapoptotic B-cell lymphoma-2 proteins indicated activation of the mitochondrial pathway. Caspase-3 activation by C20E was prevented by pharmacological inhibition and silencing of the JNK and p38 MAP kinases (MAPK), upstream MAPK kinases MKK4 and MKK7, and the upstream MAPK kinase kinase apoptosis signal-regulating kinase 1 (ASK1). Silencing of the death receptor TNF receptor 1 (TNFR1), but not Fas, DR4, or DR5, and the adapters TRADD and TNF receptor-associated factor 2, but not Fas-associated death domain, prevented C20E-mediated apoptosis. B-cell lymphoma-2 homology 3-interacting domain death agonist (Bid) cleavage by JNK/p38 MAPK linked the extrinsic and mitochondrial pathways of apoptosis. In further studies, an antibody against the extracellular domain of TNFR1 prevented apoptosis by TNF-α but not C20E. These findings suggest that C20E acts intracellularly at TNFR1 to activate ASK1-MKK4/7-JNK/p38 MAPK signaling and to promote Bid-dependent mitochondrial disruption and apoptosis. Inin vivostudies, tumors isolated from C20E-treated nu/nu mice carrying MDA-MB-231 xenografts showed increased TUNEL staining and decreased Ki67 staining, reflecting increased apoptosis and decreased proliferation, respectively. ω-3-Epoxy fatty acids like C20E could be incorporated into treatments for triple-negative breast cancers.-Dyari, H. R. E., Rawling, T., Chen, Y., Sudarmana, W., Bourget, K., Dwyer, J. M., Allison, S. E., Murray, M. A novel synthetic analogue of ω-3 17,18-epoxyeicosatetraenoic acid activates TNF receptor-1/ASK1/JNK signaling to promote apoptosis in human breast cancer cells.
Physicochemical properties and anti-diabetic ability of polysaccharides from a thinned peach fruit

Zhou L, Song Y, Jiang Y, Wei Y, Jiang S, Chen Y, et al.

Food Funct, 2023 Oct 02;14(19):8876-8892.
PMID: 37698234 DOI: 10.1039/d3fo03041e

Thinned peach fruit is a by-product with abundant yields. However, it is barely utilized. This study aimed to study the physicochemical properties and anti-diabetic ability of polysaccharides (PPSs) from a thinned peach fruit to investigate its application potential. Fourier transform infrared spectroscopy (FT-IR) and scanning electron microscopy (SEM) characterizations were performed together with tests to determine rheology properties, monosaccharide composition, and molecular weight of the obtained polysaccharide. Moreover, the antioxidant activity, α-amylase inhibitory activity, binding abilities to bile salts, and effects on type 2 diabetic mice were analyzed. The results indicated that PPS consisted of two components with molecular weights of 287.38 kDa and 12.02 kDa, accounting for 89.83% and 10.17% of the composition, respectively. The dominant monosaccharides were galactose, galacturonic acid, and arabinose, exhibiting α-configurations. The concentration was positively related to the viscosity of PPS. As the temperature was increased from 25 °C to 37 °C and the pH from 2.0 to 7.0, the viscosity decreased. The IC50 values for scavenging DPPH and ABTS were around 0.22 and 1.47 mg mL-1. Also, PPS could inhibit α-amylase ability and bind bile salts. The administration of PPS significantly inhibited emaciation, organ damage, improved oral glucose tolerance and insulin resistance, enhanced the content of short-chain fatty acids (SCFAs), and regulated blood lipid profiles and the composition and structure of colon microbiota in type-2 diabetic mice. These results provide new evidence for the potential of PPS as a bioactive ingredient with anti-diabetic properties for use in the food industry.
Inhibitory effect of the extract from Sonchus olearleu on the formation of carcinogenic heterocyclic aromatic amines during the pork cooking

Teng H, Chen Y, Lin X, Lv Q, Chai TT, Wong FC, et al.

Food Chem Toxicol, 2019 Jul;129:138-143.
PMID: 31034934 DOI: 10.1016/j.fct.2019.04.043

The aim of this study was to assess the inhibitory effects of Sonchus olearleu extract on the generation of heterocyclic amines in roasted pork patties cooked by pan-frying. All samples were cooked for two different durations (45 min and 105 min) under 200 °C and 230 °C. 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-ami- no-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2-amino-3,4,8-trimethylimidazo[4,5-f]quinox-aline (4,8-DiMeIQx), harman, and norharman were detected and quantified. In patties cooked at 230 °C for 105 min, S. olearleu extract (0.5%) significantly inhibited the formation of IQ, harman, and norharman by 39%, 67%, and 63%, respectively. In contrast to IQ, the levels of harman and norharman were significantly reduced by the extracts tested. However, no such effects were observed for MeIQx and 4, 8-DiMeIQx. Notably, the inhibitory effect on heterocyclic amines is significantly correlated with the antioxidant potential and total phenolic content of S. olearleu extract.
Epinecidin-1, a marine antifungal peptide, inhibits Botrytis cinerea and delays gray mold in postharvest peaches

Fan L, Wei Y, Chen Y, Jiang S, Xu F, Zhang C, et al.

Food Chem, 2023 Mar 01;403:134419.
PMID: 36191421 DOI: 10.1016/j.foodchem.2022.134419

This study investigatedthe mechanism of epinecidin-1 against Botrytis cinerea, in vitro, and its effectiveness at inhibiting gray mold on postharvest peach fruit. We found that in vitro, epinecidin-1 had significantly greater antifungal activity against B. cinerea than either clavanin-A or mytimycin, two other marine derived antimicrobial peptides that we tested. Its antifungal activity was heat-resistant (15 min at 40-100 °C) and tolerant to lower concentrations of cations (<100 mM Na+, K+; <10 mM Ca2+). Epinecidin-1 interacted directly with B. cinerea genomic DNA, and that in mycelia, epinecidin-1 exposure induced accumulation of intracellular ROS and increased the permeability of cell membranes resulting in leakage of nucleic acids and aberrant cell morphology. Meanwhile, 200 μM of epinecidin-1 had a significant inhibitory effect on gray mold injected into peach fruit. These results suggested that epinecidin-1 showed promise as a potential method for controlling postharvest gray mold in peaches.
Melatonin treatment delays postharvest senescence of broccoli with regulation of carotenoid metabolism

Lou J, Wu C, Wang H, Cao S, Wei Y, Chen Y, et al.

Food Chem, 2023 May 15;408:135185.
PMID: 36525725 DOI: 10.1016/j.foodchem.2022.135185

The effect of melatonin treatment on the carotenoid metabolism in broccoli florets during storage was explored. The results indicated that 100 µmol/L of melatonin maintained the sensory quality of broccoli florets, which retarded the increase of the L* value and the decrease of the H value. Melatonin treatment increased the activities of tryptophan decarboxylase (TDC), tryptamine 5-hydroxylase (T5H), serotonin N-acetyltransferase (SNAT) and N-acetylserotonin methyltransferase (ASMT), leading to the enrichment of endogenous melatonin content in broccoli florets. Meanwhile, the treatment inhibited the concentrations of β-carotene, β-cryptoxanthin, zeaxanthin and lutein, which was beneficial in delaying the yellowing of broccoli. In addition, a series of carotenoid biosynthetic genes such as BoPSY, BoPDS, BoZDS, BoLCYβ and BoZEP was also suppressed by melatonin. Further analysis revealed that the lower carotenoid content and the down-regulated BoNCED expression in treated broccoli resulted in less accumulation of abscisic acid precursors, inhibiting abscisic acid production during the yellowing process.
Fulltext Multi-feature fusion learning for Alzheimer's disease prediction using EEG signals in resting state

Chen Y, Wang H, Zhang D, Zhang L, Tao L

Front Neurosci, 2023;17:1272834.
PMID: 37822349 DOI: 10.3389/fnins.2023.1272834

INTRODUCTION: Diagnosing Alzheimer's disease (AD) lesions via visual examination of Electroencephalography (EEG) signals poses a considerable challenge. This has prompted the exploration of deep learning techniques, such as Convolutional Neural Networks (CNNs) and Visual Transformers (ViTs), for AD prediction. However, the classification performance of CNN-based methods has often been deemed inadequate. This is primarily attributed to CNNs struggling with extracting meaningful lesion signals from the complex and noisy EEG data.
METHODS: In contrast, ViTs have demonstrated proficiency in capturing global signal patterns. In light of these observations, we propose a novel approach to enhance AD risk assessment. Our proposition involves a hybrid architecture, merging the strengths of CNNs and ViTs to compensate for their respective feature extraction limitations. Our proposed Dual-Branch Feature Fusion Network (DBN) leverages both CNN and ViT components to acquire texture features and global semantic information from EEG signals. These elements are pivotal in capturing dynamic electrical signal changes in the cerebral cortex. Additionally, we introduce Spatial Attention (SA) and Channel Attention (CA) blocks within the network architecture. These attention mechanisms bolster the model's capacity to discern abnormal EEG signal patterns from the amalgamated features. To make well-informed predictions, we employ a two-factor decision-making mechanism. Specifically, we conduct correlation analysis on predicted EEG signals from the same subject to establish consistency.
RESULTS: This is then combined with results from the Clinical Neuropsychological Scale (MMSE) assessment to comprehensively evaluate the subject's susceptibility to AD. Our experimental validation on the publicly available OpenNeuro database underscores the efficacy of our approach. Notably, our proposed method attains an impressive 80.23% classification accuracy in distinguishing between AD, Frontotemporal dementia (FTD), and Normal Control (NC) subjects.
DISCUSSION: This outcome outperforms prevailing state-of-the-art methodologies in EEG-based AD prediction. Furthermore, our methodology enables the visualization of salient regions within pathological images, providing invaluable insights for interpreting and analyzing AD predictions.
Fulltext Decreased expression of alpha-2-HS glycoprotein in the sera of rats treated with Eurycoma longifolia extract

Chen Y, Phang WM, Mu AK, Chan CK, Low BS, Sasidharan S, et al.

Front Pharmacol, 2015;6:211.
PMID: 26441666 DOI: 10.3389/fphar.2015.00211

Eurycoma longifolia is a Malaysian native herb that has been widely used as an aphrodisiac and a remedy for andropause. Although the physiological effects of the plant extract were predicted as a result of the alterations in protein expression, the key protein(s) involved in these alterations are still unclear. In the present study, we have investigated the effect of standardized E. longifolia extract on serum protein expression up to 28 days following oral administration in rats. Serum protein profiles were analyzed by 2-dimensional electrophoresis, and altered proteins were identified via mass spectrometry. We observed that alpha-2-HS glycoprotein (AHS) was significantly decreased in the serum of experimentally treated rats compared to pre-treated animals. Moreover, reduction in AHS was confirmed using competitive enzyme-linked immunosorbent assay. AHS expression is known to be associated with insulin resistance and diabetes. Our data indicated that serum AHS was reduced in rats treated with standardized E. longifolia extract, and therefore form a prelude for further investigation into the effects of this natural extract in animal models involving infertility and diabetes.
Fulltext Standardized Polyalthia longifolia leaf extract induces the apoptotic HeLa cells death via microRNA regulation: identification, validation, and therapeutic potential

Vijayarathna S, Oon CE, Al-Zahrani M, Abualreesh MH, Chen Y, Kanwar JR, et al.

Front Pharmacol, 2023;14:1198425.
PMID: 37693900 DOI: 10.3389/fphar.2023.1198425

Polyalthia longifolia var. angustifolia Thw. (Annonaceae), is a famous traditional medicinal plant in Asia. Ample data specifies that the medicinal plant P. longifolia has anticancer activity; however, the detailed mechanisms of action still need to be well studied. Recent studies have revealed the cytotoxicity potential of P. longifolia leaf against HeLa cells. Therefore, the current study was conducted to examine the regulation of miRNAs in HeLa cancer cells treated with the standardized P. longifolia methanolic leaf extract (PLME). The regulation of miRNAs in HeLa cancer cells treated with the standardized PLME extract was studied through Illumina, Hi-Seq. 2000 platform of Next-Generation Sequencing (NGS) and various in silico bioinformatics tools. The PLME treatment regulated a subset of miRNAs in HeLa cells. Interestingly, the PLME treatment against HeLa cancer cells identified 10 upregulated and 43 downregulated (p < 0.05) miRNAs associated with apoptosis induction. Gene ontology (GO) term analysis indicated that PLME induces cell death in HeLa cells by inducing the pro-apoptotic genes. Moreover, the downregulated oncomiRs modulated by PLME treatment in HeLa cells were identified, targeting apoptosis-related genes through gene ontology and pathway analysis. The LC-ESI-MS/MS analysis identified the presence of Vidarabine and Anandamide compounds that were previously reported to exhibit anticancer activity. The findings of this study obviously linked the cell cytotoxicity effect of PLME treatment against the HeLa cells with regulating various miRNAs expression related to apoptosis induction in the HeLa cells. PLME treatment induced apoptotic HeLa cell death mechanism by regulating multiple miRNAs. The identified miRNAs regulated by PLME may provide further insight into the mechanisms that play a critical role in cervical cancer, as well as novel ideas regarding gene therapeutic strategies.
Fulltext Study on the eye movement characteristics of the badminton practitioners of different levels regarding visual attention

Chen Y, Zulnaidi H, Syed Ali SKB

Front Psychol, 2022;13:1026006.
PMID: 36875544 DOI: 10.3389/fpsyg.2022.1026006

Badminton is a highly sophisticated, fierce, and competitive tactical game. It requires the same action of hitting a ball with different landing points. Therefore, the complexity of badminton practitioner's sports decision-making is relatively high. Accordingly, it is extremely important to study the difference between the eye movement characteristics of different levels of badminton athletes and the difference between the eye movement characteristics of different sports levels of amateur athletes. Overall, 15 students from the badminton professional training team of the Physical Education College of the Jiangxi Science and Technology Normal University and 15 students from the common public sports and badminton course were included as experimental participants in the present study. The laboratory experimental test on the virtual sports situation in badminton was conducted using an eye tracker. The eye movement index of both the badminton professionals and the experimental participants was recorded for statistical analysis, and the following results were obtained: (1) In the cognitive decision-masking task, the reaction time of the professional badminton practitioners was faster than that of the amateur practitioners. Similarly, in the intuitive decision-masking task, the reaction time and accuracy of the former were better than those of the latter. (2) The professional badminton practitioners' group was able to process and integrate the searched information in the process of sports attention selection information; although the amateur group was able to search and filter information, they were passive and could not actively process and assimilate the searched information. (3) The professional badminton practitioners could allocate their attention reasonably and process information in the process of attention transfer, while their amateur counterparts were affected easily by external interference factors. The level of motor intelligence of badminton practitioners in the professional group was higher than that of the amateur practitioners. Thus, these two groups of different levels showed attention transfer. (4) The mental skills of the professional group were higher than those of the amateur group.
Effectiveness of adjunct psychotherapy for cancer treatment: a review

Chen Y, Ahmad M

Future Oncol, 2018 Jun;14(15):1487-1496.
PMID: 29767550 DOI: 10.2217/fon-2017-0671

Psychotherapies were offered to alleviate psychological and physical symptoms; however, most psychological interventions were only delivered after cancer treatment. Newly diagnosed cancer patients experienced psychological distress while waiting for treatments. This review paper focused on randomized control trial studies, aimed to investigate the effectiveness of psychological intervention among newly diagnosed cancer patients. Eight randomized control trial papers were found in recent 10 year period through electronic database. A moderate to large effect size was detected on the outcomes, ranging from 0.43 to 0.89. This indicated that psychological-based prehabilitation with standard care yielded better outcomes than standard care alone. Psychological-based prehabilitation provides evidence in its effectiveness to reduce psychological distress, functional impairment, recurrence of cancer, numbers of immune reactivity and sleeping quality; however, inconsistent with longer survival result among cancer patients. In conclusion, psychological-based prehabilitation before cancer treatment is necessary for better treatment outcome, and future research is needed to investigate more directly the outcome.
Uniting the Global Gastroenterology Community to Meet the Challenge of Climate Change and Non-Recyclable Waste

Leddin D, Omary MB, Veitch A, Metz G, Amrani N, Aabakken L, et al.

Gastroenterology, 2021 11;161(5):1354-1360.
PMID: 34629165 DOI: 10.1053/j.gastro.2021.08.001
Fulltext Epithelial-Mesenchymal Transition (EMT) Gene Variants and Epithelial Ovarian Cancer (EOC) Risk

Amankwah EK, Lin HY, Tyrer JP, Lawrenson K, Dennis J, Chornokur G, et al.

Genet Epidemiol, 2015 Dec;39(8):689-97.
PMID: 26399219 DOI: 10.1002/gepi.21921

Epithelial-mesenchymal transition (EMT) is a process whereby epithelial cells assume mesenchymal characteristics to facilitate cancer metastasis. However, EMT also contributes to the initiation and development of primary tumors. Prior studies that explored the hypothesis that EMT gene variants contribute to epithelial ovarian carcinoma (EOC) risk have been based on small sample sizes and none have sought replication in an independent population. We screened 15,816 single-nucleotide polymorphisms (SNPs) in 296 genes in a discovery phase using data from a genome-wide association study of EOC among women of European ancestry (1,947 cases and 2,009 controls) and identified 793 variants in 278 EMT-related genes that were nominally (P < 0.05) associated with invasive EOC. These SNPs were then genotyped in a larger study of 14,525 invasive-cancer patients and 23,447 controls. A P-value <0.05 and a false discovery rate (FDR) <0.2 were considered statistically significant. In the larger dataset, GPC6/GPC5 rs17702471 was associated with the endometrioid subtype among Caucasians (odds ratio (OR) = 1.16, 95% CI = 1.07-1.25, P = 0.0003, FDR = 0.19), whereas F8 rs7053448 (OR = 1.69, 95% CI = 1.27-2.24, P = 0.0003, FDR = 0.12), F8 rs7058826 (OR = 1.69, 95% CI = 1.27-2.24, P = 0.0003, FDR = 0.12), and CAPN13 rs1983383 (OR = 0.79, 95% CI = 0.69-0.90, P = 0.0005, FDR = 0.12) were associated with combined invasive EOC among Asians. In silico functional analyses revealed that GPC6/GPC5 rs17702471 coincided with DNA regulatory elements. These results suggest that EMT gene variants do not appear to play a significant role in the susceptibility to EOC.
Fulltext FineMAV: prioritizing candidate genetic variants driving local adaptations in human populations

Szpak M, Mezzavilla M, Ayub Q, Chen Y, Xue Y, Tyler-Smith C

Genome Biol, 2018 Jan 17;19(1):5.
PMID: 29343290 DOI: 10.1186/s13059-017-1380-2

We present a new method, Fine-Mapping of Adaptive Variation (FineMAV), which combines population differentiation, derived allele frequency, and molecular functionality to prioritize positively selected candidate variants for functional follow-up. We calibrate and test FineMAV using eight experimentally validated "gold standard" positively selected variants and simulations. FineMAV has good sensitivity and a low false discovery rate. Applying FineMAV to the 1000 Genomes Project Phase 3 SNP dataset, we report many novel selected variants, including ones in TGM3 and PRSS53 associated with hair phenotypes that we validate using available independent data. FineMAV is widely applicable to sequence data from both human and other species.
Identification of potential glycoprotein biomarkers in oral squamous cell carcinoma using sweet strategies

Wong YL, Anand R, Yuen KM, Mustafa WMW, Abraham MT, Tay KK, et al.

Glycoconj J, 2021 02;38(1):1-11.
PMID: 33547992 DOI: 10.1007/s10719-021-09973-z

The prevalence of oral squamous cell carcinoma (OSCC) is high in South and Southeast Asia regions. Most OSCC patients are detected at advanced stages low 5-year survival rates. Aberrant expression of glycosylated proteins was found to be associated with malignant transformation and cancer progression. Hence, identification of cancer-associated glycoproteins could be used as potential biomarkers that are beneficial for diagnosis or clinical management of patients. This study aims to identify the differentially expressed glycoproteins using lectin-based glycoproteomics approaches. Serum samples of 40 patients with OSCC, 10 patients with oral potentially malignant disorder (OPMD), and 10 healthy individuals as control group were subjected to two-dimensional gel electrophoresis (2-DE) coupled with lectin Concanavalin A and Jacalin that specifically bind to N- and O-glycosylated proteins, respectively. Five differentially expressed N- and O-glycoproteins with various potential glycosylation sites were identified, namely N-glycosylated α1-antitrypsin (AAT), α2-HS-glycoprotein (AHSG), apolipoprotein A-I (APOA1), and haptoglobin (HP); as well as O-glycosylated AHSG and clusterin (CLU). Among them, AAT and APOA1 were further validated using enzyme-linked immunosorbent assay (ELISA) (n = 120). It was found that AAT and APOA1 are significantly upregulated in OSCC and these glycoproteins are independent risk factors of OSCC. The clinical utility of AAT and APOA1 as potential biomarkers of OSCC is needed for further evaluation.
Uniting the global gastroenterology community to meet the challenge of climate change and non-recyclable waste

Leddin D, Omary MB, Veitch A, Metz G, Amrani N, Aabakken L, et al.

Gut, 2021 11;70(11):2025-2029.
PMID: 34620696 DOI: 10.1136/gutjnl-2021-325789
The impact of digital empowerment on the economic openness of the textile industry in Keqiao based on a sustainable environment

He B, Chen Y, Ismail N, Chen G, Ni L

Heliyon, 2024 Jan 15;10(1):e23812.
PMID: 38223717 DOI: 10.1016/j.heliyon.2023.e23812

Based on the framework theory of industrial digitization, digital industrialization, digital governance and digital value-added in a sustainable environment, this paper systematically studies the relevant elements of governance and value distribution in the sustainable environment of global trade, and its impact on the development path of human beings. This paper explores the way to embed digital technology into the global value chain to realize digital empowerment, measures the competitiveness index of Keqiao's textile industry in the global value chain, analyzes the technical and environmental challenges faced by China's textile industry in the digital age, and proposes the corresponding countermeasures to deal with the impact of global value chain participation and to improve the international competitiveness of China's textile industry.
Flare of Autoimmune Hepatitis Causing Acute on Chronic Liver Failure: Diagnosis and Response to Corticosteroid Therapy

Anand L, Choudhury A, Bihari C, Sharma BC, Kumar M, Maiwall R, et al.

Hepatology, 2019 08;70(2):587-596.
PMID: 30113706 DOI: 10.1002/hep.30205

Autoimmune hepatitis (AIH) is considered less common in the Asia Pacific region. Due to this, AIH flare as a cause of acute on chronic liver failure (ACLF) is often overlooked and treatment delayed. We aimed at the defining clinical and histopathological spectrum and role of steroid therapy in AIH-ACLF. Patients with AIH-ACLF, prospectively recruited and followed between 2012 and 2017, were analyzed from the Asian Pacific Association for the Study of the Liver ACLF Research Consortium (AARC) data base. Diagnosis of AIH was confirmed using International Autoimmune Hepatitis Group score or simplified AIH score with histopathological evidence. Of 2,825 ACLF patients, 82 (2.9%) fulfilled criteria of AIH (age 42.1 ± 18.1 years, 70% female). At baseline, mean bilirubin was 18.6 ± 8.2 mg/dL, Child-Turcotte-Pugh score was 11.7 ± 1.4, and Model for End-Stage Liver Disease (MELD) score was 27.6 ± 6.5. Mean immunoglobulin G was 21.61 ± 7.32 g/dL, and this was elevated ≥1.1 times in 97% of cases; 49% were seronegative. Liver histology was available in 90%, with median histological activity index of 10 (interquartile range, 7-12); 90% with moderate to severe interface activity; 56% showing significant parenchymal necrosis (bridging and confluent necrosis); and cirrhosis in 42%. Twenty-eight (34%) patients received steroid therapy and showed shorter intensive care unit (ICU) stay (median 1.5 versus 4 days, P < 0.001) and improved 90-day survival (75% versus 48.1%, P = 0.02) with comparable incidence of sepsis (P = 0.32) compared to those who did not. Patients of advanced age, more severe liver disease (MELD >27; 83.3% sensitivity, 78.9% specificity, area under the receiver operating characteristic curve 0.86), presence of hepatic encephalopathy, and fibrosis grade ≥F3 had an unfavorable response to corticosteroid therapy. Conclusion: AIH presenting as ACLF is not uncommon in Asian patients; a low threshold for liver biopsy is needed to confirm the diagnosis as nearly half the patients are seronegative; early stratification to steroid therapy or liver transplantation (MELD >27, hepatic encephalopathy in ≥F3) would reduce ICU stay and improve outcomes.
Complications constitute a major risk factor for mortality in hepatitis B virus-related acute-on-chronic liver failure patients: a multi-national study from the Asia-Pacific region

Chen T, Yang Z, Choudhury AK, Al Mahtab M, Li J, Chen Y, et al.

Hepatol Int, 2019 Nov;13(6):695-705.
PMID: 31650510 DOI: 10.1007/s12072-019-09992-x

BACKGROUND AND AIM: Cirrhosis is a controversial determinant of mortality in HBV-related acute-on-chronic liver failure (HBV-ACLF). The present study aimed to explore the effects of cirrhosis and the associated risk factors, especially its complications, on the outcome of HBV-ACLF.
METHODS: A prospective-retrospective cohort of 985 patients was identified from the APASL-ACLF Research Consortium (AARC) database and the Chinese Study Group. Complications of ACLF (ascites, infection, hepatorenal syndrome, hepatic encephalopathy, upper gastrointestinal bleeding) as well as cirrhosis and the current main prognostic models were measured for their predictive ability for 28- or 90-day mortality.
RESULTS: A total of 709 patients with HBV-ACLF as defined by the AARC criteria were enrolled. Among these HBV-ACLF patients, the cirrhotic group showed significantly higher mortality and complications than the non-cirrhotic group. A total of 36.1% and 40.1% of patients met the European Association for the Study of Liver (EASL)-Chronic Liver Failure consortium (CLIF-C) criteria in the non-cirrhotic and cirrhotic groups, respectively; these patients had significantly higher rates of mortality and complications than those who did not satisfy the CLIF-C criteria. Furthermore, among patients who did not meet the CLIF-C criteria, the cirrhotic group exhibited higher mortality and complication rates than the non-cirrhotic group, without significant differences in organ failure. The Tongji prognostic predictor model score (TPPMs), which set the number of complications as one of the determinants, showed comparable or superior ability to the Chinese Group on the Study of Severe Hepatitis B-ACLF score (COSSH-ACLFs), APASL-ACLF Research Consortium score (AARC-ACLFs), CLIF-C organ failure score (CLIF-C OFs), CLIF-C-ACLF score (CLIF-C-ACLFs), Model for End-Stage Liver Disease score (MELDs) and MELD-sodium score (MELD-Nas) in HBV-ACLF patients, especially in cirrhotic HBV--ACLF patients. Patients with two (OR 4.70, 1.88) or three (OR 8.27, 2.65) complications had a significantly higher risk of 28- or 90-day mortality, respectively.
CONCLUSION: The presence of complications is a major risk factor for mortality in HBV-ACLF patients. TPPM possesses high predictive ability in HBV-ACLF patients, especially in cirrhotic HBV-ACLF patients.
Comparative accuracy of prognostic models for short-term mortality in acute-on-chronic liver failure patients: CAP-ACLF

Verma N, Dhiman RK, Singh V, Duseja A, Taneja S, Choudhury A, et al.

Hepatol Int, 2021 Jun;15(3):753-765.
PMID: 34173167 DOI: 10.1007/s12072-021-10175-w

BACKGROUND: Multiple predictive models of mortality exist for acute-on-chronic liver failure (ACLF) patients that often create confusion during decision-making. We studied the natural history and evaluated the performance of prognostic models in ACLF patients.
METHODS: Prospectively collected data of ACLF patients from APASL-ACLF Research Consortium (AARC) was analyzed for 30-day outcomes. The models evaluated at days 0, 4, and 7 of presentation for 30-day mortality were: AARC (model and score), CLIF-C (ACLF score, and OF score), NACSELD-ACLF (model and binary), SOFA, APACHE-II, MELD, MELD-Lactate, and CTP. Evaluation parameters were discrimination (c-indices), calibration [accuracy, sensitivity, specificity, and positive/negative predictive values (PPV/NPV)], Akaike/Bayesian Information Criteria (AIC/BIC), Nagelkerke-R2, relative prediction errors, and odds ratios.
RESULTS: Thirty-day survival of the cohort (n = 2864) was 64.9% and was lowest for final-AARC-grade-III (32.8%) ACLF. Performance parameters of all models were best at day 7 than at day 4 or day 0 (p 12 had the lowest 30-day survival (5.7%).
CONCLUSIONS: APASL-ACLF is often a progressive disease, and models assessed up to day 7 of presentation reliably predict 30-day mortality. Day-7 AARC model is a statistically robust tool for classifying risk of death and accurately predicting 30-day outcomes with relatively lower prediction errors. Day-7 AARC score > 12 may be used as a futility criterion in APASL-ACLF patients.
Fulltext Copy number variation arising from gene conversion on the human Y chromosome

Shi W, Massaia A, Louzada S, Banerjee R, Hallast P, Chen Y, et al.

Hum Genet, 2018 Jan;137(1):73-83.
PMID: 29209947 DOI: 10.1007/s00439-017-1857-9

We describe the variation in copy number of a ~ 10 kb region overlapping the long intergenic noncoding RNA (lincRNA) gene, TTTY22, within the IR3 inverted repeat on the short arm of the human Y chromosome, leading to individuals with 0-3 copies of this region in the general population. Variation of this CNV is common, with 266 individuals having 0 copies, 943 (including the reference sequence) having 1, 23 having 2 copies, and two having 3 copies, and was validated by breakpoint PCR, fibre-FISH, and 10× Genomics Chromium linked-read sequencing in subsets of 1234 individuals from the 1000 Genomes Project. Mapping the changes in copy number to the phylogeny of these Y chromosomes previously established by the Project identified at least 20 mutational events, and investigation of flanking paralogous sequence variants showed that the mutations involved flanking sequences in 18 of these, and could extend over > 30 kb of DNA. While either gene conversion or double crossover between misaligned sister chromatids could formally explain the 0-2 copy events, gene conversion is the more likely mechanism, and these events include the longest non-allelic gene conversion reported thus far. Chromosomes with three copies of this CNV have arisen just once in our data set via another mechanism: duplication of 420 kb that places the third copy 230 kb proximal to the existing proximal copy. Our results establish gene conversion as a previously under-appreciated mechanism of generating copy number changes in humans and reveal the exceptionally large size of the conversion events that can occur.

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