Search

This study aims to compare the levels of intrinsic protein disorder within the human lens and zonule proteomes and investigate the role of aging as a potential influencing factor on disorder levels. A cross-sectional proteomic analysis was employed, utilizing a dataset of 1466 proteins derived from the lens and zonule proteomes previously published by Wang et al. and De Maria et al. Bioinformatics tools, including a composition profiler and a rapid intrinsic disorder analysis online tool, were used to conduct a comparative analysis of protein disorder. Statistical tests such as ANOVA, Tukey's HSD, and chi-squared tests were applied to evaluate differences between groups. The study revealed distinct amino acid compositions for each proteome, showing a direct correlation between aging and increased protein disorder in the zonular proteomes, whereas the lens proteomes exhibited the opposite trend. Findings suggest that age-related changes in intrinsic protein disorder within the lens and zonule proteomes may be linked to structural transformations in these tissues. Understanding how protein disorder evolves with age could enhance knowledge of the molecular basis for age-related conditions such as cataracts and pseudoexfoliation, potentially leading to better therapeutic strategies., Competing Interests: Compliance with ethical standards Conflict of interest The authors declare no competing interests., (© 2024. The Author(s).)

Protein S (PROS1) has recently been identified as a ligand for the TAM receptor MERTK, influencing immune response and cell survival. The PROS1-MERTK interaction plays a role in cancer progression, promoting immune evasion and metastasis in multiple cancers by fostering a tumor-supportive microenvironment. Despite its importance, limited structural insights into this interaction underscore the need for computational studies to explore their binding dynamics, potentially guiding targeted therapies. In this study, we investigated the PROS1-MERTK interaction using advanced computational analyses to support immunotherapy research. High-resolution structural models from ColabFold, an AlphaFold2 adaptation, provided a baseline structure, allowing us to examine the PROS1-MERTK interface with ChimeraX and map residue interactions through Van der Waals criteria. Molecular dynamics (MD) simulations were conducted in GROMACS over 100 ns to assess stability and conformational changes using RMSD, RMSF, and radius of gyration (Rg). The PROS1-MERTK interface was predicted to contain a heterogeneous mix of amino acid contacts, with lysine and leucine as frequent participants. MD simulations demonstrated prominent early structural shifts, stabilizing after approximately 50 ns with small conformational shifts occurring as the simulation completed. In addition, there are various regions in each protein that are predicted to have greater conformational fluctuations as compared to others, which may represent attractive areas to target to halt the progression of the interaction. These insights deepen our understanding of the PROS1-MERTK interaction role in immune modulation and tumor progression, unveiling potential targets for cancer immunotherapy., Competing Interests: Compliance with Ethical Standards Conflict of Interest The authors declare no competing interests. Ethics Approval This is an observational study. The University of Miami Research Ethics Committee has confirmed that no ethical approval is required., (© 2024. The Author(s).)

Purpose: The human cornea is essential for vision, providing structural integrity and refractive power to the eye. Recent advancements have deepened our understanding of the corneal molecular composition, yet the role of intrinsically disordered proteins within the cornea is unexplored., Methods: We analyzed 3,250 corneal proteins identified by Dyrlund et al, focusing on the epithelium, stroma, and endothelium layers. We performed a bioinformatics analysis to characterize the amino acid composition, the propensity for intrinsic protein disorder, and the distribution of protein types in 3 corneal layer proteome., Results: Our study demonstrates that each corneal layer exhibited unique patterns in amino acid composition related to protein disorder. Order-promoting amino acids were generally depleted except for leucine, whereas disorder-promoting amino acids like arginine and glutamic acid were enriched across all layers. Significant variations were observed in the levels of intrinsic disorder among the different corneal layers, with substantial proportions of highly disordered proteins present in each. Analysis of protein class type in each layers revealed that no significant differences were detected in the distribution of protein classifications across the layers, suggesting a consistent population of the protein types across all corneal layers., Conclusions: Our findings reveal a sophisticated landscape of protein structures where intrinsic disorder varies across layers, suggesting an adaptation of the corneal proteome to the unique physiological demands of each layer. These structural variations may reflect the intricate requirements for corneal transparency, biomechanical stability, and environmental responsiveness., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: This study evaluates a large language model, Generative Pre-trained Transformer 4 with vision, for diagnosing vitreoretinal diseases in real-world ophthalmology settings., Methods: A retrospective cross-sectional study at Bascom Palmer Eye Clinic, analyzing patient data from January 2010 to March 2023, assesses Generative Pre-trained Transformer 4 with vision's performance on retinal image analysis and International Classification of Diseases 10th revision coding across 2 patient groups: simpler cases (Group A) and complex cases (Group B) requiring more in-depth analysis. Diagnostic accuracy was assessed through open-ended questions and multiple-choice questions independently verified by three retina specialists., Results: In 256 eyes from 143 patients, Generative Pre-trained Transformer 4-V demonstrated a 13.7% accuracy for open-ended questions and 31.3% for multiple-choice questions, with International Classification of Diseases 10th revision code accuracies at 5.5% and 31.3%, respectively. Accurately diagnosed posterior vitreous detachment, nonexudative age-related macular degeneration, and retinal detachment. International Classification of Diseases 10th revision coding was most accurate for nonexudative age-related macular degeneration, central retinal vein occlusion, and macular hole in OEQs, and for posterior vitreous detachment, nonexudative age-related macular degeneration, and retinal detachment in multiple-choice questions. No significant difference in diagnostic or coding accuracy was found in Groups A and B., Conclusion: Generative Pre-trained Transformer 4 with vision has potential in clinical care and record keeping, particularly with standardized questions. Its effectiveness in open-ended scenarios is limited, indicating a significant limitation in providing complex medical advice.

The vitreous is a vital component of the eye, occupying a substantial portion of its volume and maintaining its structure. This study delves into the presence and significance of intrinsically disordered proteins (IDPs) within the vitreous, utilizing a dataset of 1240 vitreous proteins previously discovered in the vitreous proteome by Murthy et al.in five healthy subjects. The results indicate that 26.9 % of vitreous proteins are highly disordered, 68.8 % possess moderate disorder, and only 4.3 % are highly ordered. A complex interaction network among these proteins suggests their biological importance, and approximately 25 % may undergo liquid-liquid phase separation (LLPS). These findings offer new perspectives on the vitreous' molecular composition and behavior, potentially impacting our understanding of eye-related diseases, physiological changes such as vitreous syneresis. Further research is needed to translate these insights into clinical applications, although the intrinsic protein disorder and its association with LLPS appears to play a role in vitreous proteome function., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Using comprehensive plasma lipidomic profiling from men with metastatic castration-resistant prostate cancer (mCRPC), we have previously identified a poor-prognostic lipid profile associated with shorter overall survival (OS). In order to translate this biomarker into the clinic, these men must be identifiable via a clinically accessible, regulatory-compliant assay., Methods: A single regulatory-compliant liquid chromatography-mass spectrometry assay of candidate lipids was developed and tested on a mCRPC Discovery cohort of 105 men. Various risk-score Cox regression prognostic models of OS were built using the Discovery cohort. The model with the highest concordance index (PCPro) was chosen for validation and tested on an independent Validation cohort of 183 men., Results: PCPro, the lipid biomarker, contains Cer(d18:1/18:0), Cer(d18:1/24:0), Cer(d18:1/24:1), triglycerides and total cholesterol. Within the Discovery and Validation cohorts, men who were PCPro positive had significantly shorter OS compared to those who were PCPro negative (Discovery: median OS 12.0 months vs 24.2 months, hazard ratio (HR) 3.75 [95% confidence interval (CI) 2.29-6.15], p < 0.001, Validation: median OS 13.0 months vs 25.7 months, HR = 2.13 [95% CI 1.46-3.12], p < 0.001)., Conclusions: We have developed PCPro, a lipid biomarker assay capable of prospectively identifying men with mCRPC with a poor prognosis. Prospective clinical trials are required to determine if men who are PCPro positive will benefit from therapeutic agents targeting lipid metabolism., (© 2023. The Author(s).)

Purpose: We sought to delineate a multisystem disorder caused by recessive cysteine-rich with epidermal growth factor-like domains 1 (CRELD1) gene variants., Methods: The impact of CRELD1 variants was characterized through an international collaboration utilizing next-generation DNA sequencing, gene knockdown, and protein overexpression in Xenopus tropicalis, and in vitro analysis of patient immune cells., Results: Biallelic variants in CRELD1 were found in 18 participants from 14 families. Affected individuals displayed an array of phenotypes involving developmental delay, early-onset epilepsy, and hypotonia, with about half demonstrating cardiac arrhythmias and some experiencing recurrent infections. Most harbored a frameshift in trans with a missense allele, with 1 recurrent variant, p.(Cys192Tyr), identified in 10 families. X tropicalis tadpoles with creld1 knockdown displayed developmental defects along with increased susceptibility to induced seizures compared with controls. Additionally, human CRELD1 harboring missense variants from affected individuals had reduced protein function, indicated by a diminished ability to induce craniofacial defects when overexpressed in X tropicalis. Finally, baseline analyses of peripheral blood mononuclear cells showed similar proportions of immune cell subtypes in patients compared with healthy donors., Conclusion: This patient cohort, combined with experimental data, provide evidence of a multisystem clinical syndrome mediated by recessive variants in CRELD1., Competing Interests: Conflict of Interest Two authors report part ownership of startup companies unrelated to this work: Qiyas Higher Health (Saquib A. Lakhani) and Victory Genomics (Saquib A. Lakhani and Mustafa K. Khokha). Kirsty McWalter is an employee of GeneDx. Kimberly Nugent is currently an employee of Cooper Surgical. Bryan Mak is currently an employee of Genome Medical. All other authors declare no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The Altmetric Attention Score (AAS) aims to determine the impact of research articles throughout the internet and social media outlets. The AAS is a weighted average of the interaction on platforms including Twitter, Facebook, Reddit, and more., Objectives: The aim of this study was to investigate the relationship between the AAS and traditional bibliometrics across plastic surgery journals., Methods: Articles, number of citations (NOC), and H-index information in Annals of Plastic Surgery (APS), Plastic and Reconstructive Surgery (PRS), Plastic and Reconstructive Surgery Global Open (PRS GO), and Aesthetic Surgery Journal (ASJ) from 2017, 2018, and 2019 were queried with the Scopus Online Tool. AAS metrics were collected with the Altmetric Score Calculator Bookmarklet. Descriptive statistics, Spearman rank-correlation analyses, and analyses of variance were performed to measure associations between NOC and AAS., Results: A total of 3612 articles were analyzed. NOC was weakly correlated with AAS in APS, PRS GO, and ASJ, and moderately correlated with AAS in PRS. NOC was weakly correlated with Twitter mentions in APS, PRS GO, and ASJ, and moderately correlated in PRS. NOC was weakly correlated with news outlet reporting. The H-index of the first author showed more significant correlations with the AAS than the H-index of the last author., Conclusions: NOC and H-index of the first author correlated with AAS in the plastic surgery literature, suggesting AAS may be a useful adjunct to traditional bibliometrics when evaluating the impact and reach of peer-reviewed articles., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Aesthetic Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

In this study, we explore the dynamics between innovation, institutional quality, and foreign-aid flows in middle-income countries. Using an appropriate econometric model, we investigate the links between these variables in 79 middle-income countries (MICs) over 2005-2020. The results from our study show that foreign aid, institutional quality, and innovation have strong endogenous relationships. The short-run outcomes show that innovation Granger-causes institutional quality; foreign aid Granger-causes innovation; and quality of institutions Granger-causes foreign aid. The long-run outcomes indicate that institutional quality and innovation significantly affect the flow of foreign aid to the MICs. These results indicate that policy-makers in both foreign aid donor and recipient countries should pursue appropriate policies on foreign aid, quality of institutions, and innovation. For instance, in the short run, planners and evaluators in donor countries can direct their aid to MICs that have persistent challenges in improving their institutions and enhancing their innovative capabilities. In the long run, recipient countries ought to recognize that their institutional quality and innovation have a considerable impact on the inflows of foreign aid to their countries., Competing Interests: Conflict of Interest We declare that authors have no conflict of interest with respect to Funding Source Declaration, Author Agreement, and Permission Note for the submission paper “Does Foreign Aid Affect Innovation and Institutional Quality in Middle-Income Countries?” by Rudra P. Pradhan, Mak B. Arvin, Mahendhiran Nair and Sara E. Bennett to the possible inclusion in ‘Evaluation and Program Planning’., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Purpose: To determine prognostic and predictive clinical outcomes in metastatic hormone-sensitive prostate cancer (mHSPC) and metastatic castrate-resistant prostate cancer (mCRPC) on the basis of a combination of plasma-derived genomic alterations and lipid features in a longitudinal cohort of patients with advanced prostate cancer., Methods: A multifeature classifier was constructed to predict clinical outcomes using plasma-based genomic alterations detected in 120 genes and 772 lipidomic species as informative features in a cohort of 71 patients with mHSPC and 144 patients with mCRPC. Outcomes of interest were collected over 11 years of follow-up. These included in mHSPC state early failure of androgen-deprivation therapy (ADT) and exceptional responders to ADT; early death (poor prognosis) and long-term survivors in mCRPC state. The approach was to build binary classification models that identified discriminative candidates with optimal weights to predict outcomes. To achieve this, we built multi-omic feature-based classifiers using traditional machine learning (ML) methods, including logistic regression with sparse regularization, multi-kernel Gaussian process regression, and support vector machines., Results: The levels of specific ceramides (d18:1/14:0 and d18:1/17:0), and the presence of CHEK2 mutations, AR amplification, and RB1 deletion were identified as the most crucial factors associated with clinical outcomes. Using ML models, the optimal multi-omics feature combination determined resulted in AUC scores of 0.751 for predicting mHSPC survival and 0.638 for predicting ADT failure; and in mCRPC state, 0.687 for prognostication and 0.727 for exceptional survival. The models were observed to be superior than using a limited candidate number of features for developing multi-omic prognostic and predictive signatures., Conclusion: Using a ML approach that incorporates multiple omic features improves the prediction accuracy for metastatic prostate cancer outcomes significantly. Validation of these models will be needed in independent data sets in future.

Despite key advances in the treatment of prostate cancer (PCa), a proportion of men have de novo resistance, and all will develop resistance to current therapeutics over time. Aberrant lipid metabolism has long been associated with prostate carcinogenesis and progression, but more recently there has been an explosion of preclinical and clinical data which is informing new clinical trials. This review explores the epidemiological links between obesity and metabolic syndrome and PCa, the evidence for altered circulating lipids in PCa and their potential role as biomarkers, as well as novel therapeutic strategies for targeting lipids in men with PCa, including therapies widely used in cardiovascular disease such as statins, metformin and lifestyle modification, as well as novel targeted agents such as sphingosine kinase inhibitors, DES1 inhibitors and agents targeting FASN and beta oxidation., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2023.)

Elevated circulating sphingolipids are associated with shorter overall survival and therapeutic resistance in metastatic castration-resistant prostate cancer (mCRPC), suggesting that perturbations in sphingolipid metabolism promotes prostate cancer growth. This study assessed whether addition of simvastatin to standard treatment for mCRPC can modify a poor prognostic circulating lipidomic profile represented by a validated 3-lipid signature (3LS). Men with mCRPC (n = 27) who were not on a lipid-lowering agent, were given simvastatin for 12 weeks (40 mg orally, once daily) with commencement of standard treatment. Lipidomic profiling was performed on their plasma sampled at baseline and after 12 weeks of treatment. Only 11 men had the poor prognostic 3LS at baseline, of whom five (45%) did not retain the 3LS after simvastatin treatment (expected conversion rate with standard treatment = 19%). At baseline, the plasma profiles of men with the 3LS displayed higher levels (p < 0.05) of sphingolipids (ceramides, hexosylceramides and sphingomyelins) than those of men without the 3LS. These plasma sphingolipids were reduced after statin treatment in men who lost the 3LS (mean decrease: 23−52%, p < 0.05), but not in men with persistent 3LS, and were independent of changes to plasma cholesterol, LDL-C or triacylglycerol. In conclusion, simvastatin in addition to standard treatment can modify the poor prognostic circulating lipidomic profile in mCRPC into a more favourable profile at twice the expected conversion rate.

Background: Specific subvariants of uveal melanoma (UM) are associated with increased rates of metastasis compared to other subvariants. BRCA1 (BReast CAncer gene 1)-associated protein-1 (BAP1) is encoded by a gene that has been linked to aggressive behavior in UM. Methods: We evaluated BAP1 for the presence of intrinsically disordered protein regions (IDPRs) and its protein−protein interactions (PPI). We evaluated specific sequence-based features of the BAP1 protein using a set of bioinformatic databases, predictors, and algorithms. Results: We show that BAP1’s structure contains extensive IDPRs as it is highly enriched in proline residues (the most disordered amino acid; p-value < 0.05), the average percent of predicted disordered residues (PPDR) was 57.34%, and contains 9 disorder-based binding sites (ie. molecular recognition features (MoRFs)). BAP1’s intrinsic disorder allows it to engage in a complex PPI network with at least 49 partners (p-value < 1.0 × 10−16). Conclusion: These findings show that BAP1 contains IDPRs and an intricate PPI network. Mutations in UM that are associated with the BAP1 gene may alter the function of the IDPRs embedded into its structure. These findings develop the understanding of UM and may provide a target for potential novel therapies to treat this aggressive neoplasm.

Objective: To determine the efficacy and safety of intermittent docetaxel chemotherapy guided by circulating methylated glutathione S-transferase Pi-1 ( mGSTP1 ) in men with metastatic castration-resistant prostate cancer (CRPC)., Patients and Methods: GUIDE (NCT04918810) is a randomised, two-arm, non-comparative phase-2 trial recruiting 120 patients at six Australian centres. Patients with Prostate Cancer Working Group-3 defined metastatic CRPC who are commencing docetaxel 75 mg/m 2 q3w will be pre-screened for detectable mGSTP1 at baseline ± following two cycles of treatment. Those with detectable plasma mGSTP1 at baseline that becomes undetectable after two cycles of chemotherapy will be eligible for GUIDE. Prior to Cycle 4 of docetaxel, these patients are randomised 2:1 to one of two treatment arms: Arm A (cease docetaxel and reinstitute if mGSTP1 becomes detectable) or Arm B (continue docetaxel 75 mg/m 2 q3w in accordance with clinician's usual practice). The primary endpoint is radiographic progression-free survival. Secondary endpoints include time on treatment holidays, safety, patient-reported outcomes, overall survival, health resource use, and cost associated with treatment. Enrolment commenced November 2021., Results and Conclusion: The results of this trial will generate data on the clinical utility of mGSTP1 as a novel biomarker to guide treatment de-escalation in metastatic CRPC., Competing Interests: Conflict of interest statement: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2022.)

Background: Both changes in circulating lipids represented by a validated poor prognostic 3-lipid signature (3LS) and somatic tumour genetic aberrations are individually associated with worse clinical outcomes in men with metastatic castration-resistant prostate cancer (mCRPC). A key question is how the lipid environment and the cancer genome are interrelated in order to exploit this therapeutically. We assessed the association between the poor prognostic 3-lipid signature (3LS), somatic genetic aberrations and clinical outcomes in mCRPC., Methods: We performed plasma lipidomic analysis and cell-free DNA (cfDNA) sequencing on 106 men with mCRPC commencing docetaxel, cabazitaxel, abiraterone or enzalutamide (discovery cohort) and 94 men with mCRPC commencing docetaxel (validation cohort). Differences in lipid levels between men ± somatic genetic aberrations were assessed with t-tests. Associations between the 3LS and genetic aberrations with overall survival (OS) were examined using Kaplan-Meier methods and Cox proportional hazard models., Results: The 3LS was associated with shorter OS in the discovery (hazard ratio [HR] 2.15, 95% confidence interval [CI] 1.4-3.3, p < 0.001) and validation cohorts (HR 2.32, 95% CI 1.59-3.38, p < 0.001). Elevated plasma sphingolipids were associated with AR, TP53, RB1 and PI3K aberrations (p < 0.05). Men with both the 3LS and aberrations in AR, TP53, RB1 or PI3K had shorter OS than men with neither in both cohorts (p ≤ 0.001). The presence of 3LS and/or genetic aberration was independently associated with shorter OS for men with AR, TP53, RB1 and PI3K aberrations (p < 0.02). Furthermore, aggressive-variant prostate cancer (AVPC), defined as 2 or more aberrations in TP53, RB1 and/or PTEN, was associated with elevated sphingolipids. The combination of AVPC and 3LS predicted for a median survival of ~12 months. The relatively small sample size of the cohorts limits clinical applicability and warrants future studies., Conclusions: Elevated circulating sphingolipids were associated with AR, TP53, RB1, PI3K and AVPC aberrations in mCRPC, and the combination of lipid and genetic abnormalities conferred a worse prognosis. These findings suggest that certain genotypes in mCRPC may benefit from metabolic therapies., (© 2022. The Author(s).)

Mutations in the titin (TTN) gene are among the most common genomic aberrations in ocular surface squamous neoplasia (OSSN), the most common cancer of the external eye. Further, TTN mutations are associated with resistance to standard therapy with topical interferon alpha-2b (IFN-α2b). However, it remains unclear how TTN mutations drive OSSN pathogenesis and treatment resistance. TTN encodes the largest protein in the human body and its best understood function is as a myofibril scaffold in striated muscle. However, recent evidence indicates that TTN has additional functions in non-muscle cells and in cancer. Here, we performed a disorder-based bioinformatics analysis which revealed that intrinsically disordered protein regions are abundant in TTN and provide mechanistic insights into its function as a nuclear protein in epithelial cells. Specific mutations found in OSSN are predicted to affect its intrinsically disordered protein regions (IDPRs), promoting chromosomal instability, oncogenesis, and altered response to IFN-α2b treatment., (Copyright © 2021. Published by Elsevier B.V.)

In recent years, there has been tremendous enthusiasm with respect to detailing the genetic basis of many neoplasms, including conjunctival melanoma (CM). We aim to analyze five proteins associated with CM, namely BRAF, NRAS, c-KIT, NF1, and PTEN. We evaluated each protein for its intrinsically disordered protein regions (IDPRs) and its protein-protein interactions (PPI) with the Predictor of Natural Disordered Protein Regions (PONDR ® ) and the Search Tool for the Retrieval of Interacting Genes (STRING ® ). Our PONDR ® analysis found high levels of IDPRs in all five proteins with mutations linked to CM. The highest levels of IDPRs were in BRAF (45.95%), followed by PTEN (31.76%), NF1 (22.19%), c-KIT (21.82%), and NRAS (14.81%). Our STRING analysis found that each of these five proteins had more predicted interactions then expected ( p -value < 1.0 × 10 -16 ). Our analysis demonstrates that the mutations linked to CM likely affected IDPRs and possibly altered their highly complex PPIs. Quantifying IDPRs in BRAF, NRAS, c-KIT, NF1, and PTEN and understanding these protein regions are important processes as IDPRs can be possible drug targets for novel targeted therapies for treating CM.

Background: Intrinsic resistance to androgen receptor signalling inhibitors (ARSI) occurs in 20-30% of men with metastatic castration-resistant prostate cancer (mCRPC). Ceramide metabolism may have a role in ARSI resistance. Our study's aim is to investigate the association of the ceramide-sphingosine-1-phosphate (ceramide-S1P) signalling axis with ARSI resistance in mCRPC., Methods: Lipidomic analysis (∼700 lipids) was performed on plasma collected from 132 men with mCRPC, before commencing enzalutamide or abiraterone. AR gene aberrations in 77 of these men were identified by deep sequencing of circulating tumour DNA. Associations between circulating lipids, radiological progression-free survival (rPFS) and overall survival (OS) were examined by Cox regression. Inhibition of ceramide-S1P signalling with sphingosine kinase (SPHK) inhibitors (PF-543 and ABC294640) on enzalutamide efficacy was investigated with in vitro assays, and transcriptomic and lipidomic analyses of prostate cancer (PC) cell lines (LNCaP, C42B, 22Rv1)., Findings: Men with elevated circulating ceramide levels had shorter rPFS (HR=2·3, 95% CI=1·5-3·6, p = 0·0004) and shorter OS (HR=2·3, 95% CI=1·4-36, p = 0·0005). The combined presence of an AR aberration with elevated ceramide levels conferred a worse prognosis than the presence of only one or none of these characteristics (median rPFS time = 3·9 vs 8·3 vs 17·7 months; median OS time = 8·9 vs 19·8 vs 34·4 months). SPHK inhibitors enhanced enzalutamide efficacy in PC cell lines. Transcriptomic and lipidomic analyses indicated that enzalutamide combined with SPHK inhibition enhanced PC cell death by SREBP-induced lipotoxicity., Interpretation: Ceramide-S1P signalling promotes ARSI resistance, which can be reversed with SPHK inhibitors., Funding: None., Competing Interests: Declaration of Competing Interest E.M.K.: Honoraria – Janssen, Ipsen, Astellas Pharma, Research Review; Consulting or Advisory Role – Astellas Pharma, Janssen, Ipsen; Research Funding – Astellas Pharma, AstraZeneca; Travel & accommodation – Astellas Pharma, Pfizer, Ipsen, Roche.B.T.: Grants and personal fees – Amgen, AstraZeneca, Astellas, BMS, Janssen, Pfizer, MSD, Ipsen, Bayer; Personal fees – IQVIA, Sanofi, Tolmar, Novartis, Roche.A.Z.: Advisory Role – Astellas; Honoraria – Astellas; Grants and personal fees – Astra Zeneca, Pfizer; Personal fees – Merck Sharp & Dome, Bayer, Mundipharma, Janssen.I.D.D.: Institutional funding – Pfizer, ANZUP Cancer Trials Group, Bayer, Astellas, Janssen, Movember Foundation, Merck Sharp & Dome; Unremunerated chair of ANZUP Cancer Trials Group.T.S.: Travel – Astra Zeneca.D.R.S.: Grants – Regeneron, Amgen, Arrowhead, Espirion, Novartis; Personal fees – Amgen, Sanofi.A.A.: Consultant – Astellas, Janssen, Novartis; Speakers Bureau – Astellas, Janssen, Novartis, Amgen, Ipsen, Bristol Myers Squibb; Merck Serono, Bayer; Honoraria – Astellas, Novartis, Sanofi, AstraZeneca, Tolmar, Telix, Merck Serono; Janssen, Bristol Myers Squibb, Ipsen, Bayer, Pfizer, Amgen, Noxopharm, Merck Sharpe Dome; Scientific Advisory Board – Astellas, Novartis, Sanofi, AstraZeneca, Tolmar, Pfizer, Telix, Merck Serono; Janssen, Bristol Myers Squibb, Ipsen, Bayer, Merck Sharpe Dome, Amgen, Noxopharm; Travel & accommodation – Astellas, Merck Serono, Amgen, Novartis, Janssen, Tolmar, Pfizer; Investigator research funding – Astellas, Merck Serono, Astra Zeneca; Institutional research funding – Bristol Myers Squibb, Astra Zeneca, Aptevo Therapeutics, Glaxo Smith Kline, Pfizer, MedImmune, Astellas, SYNthorx, Bionomics, Sanofi Aventis, Novartis, Ipsen.A.M.J.: Insitutional funding – Pfizer, Astellas.L.G.H.: Research funding – Astellas; Travel sponsorship – Janssen, Pfizer; Honoraria – Imagion Biosystems. All other authors have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Dysregulated lipid metabolism is associated with more aggressive pathology and poorer prognosis in prostate cancer (PC). The primary aim of the study is to assess the relationship between the plasma lipidome and clinical outcomes in localised and metastatic PC. The secondary aim is to validate a prognostic circulating 3-lipid signature specific to metastatic castration-resistant PC (mCRPC)., Patients and Methods: Comprehensive lipidomic analysis was performed on pre-treatment plasma samples from men with localised PC (N = 389), metastatic hormone-sensitive PC (mHSPC)(N = 44), or mCRPC (validation cohort, N = 137). Clinical outcomes from our previously published mCRPC cohort (N = 159) that was used to derive the prognostic circulating 3-lipid signature, were updated. Associations between circulating lipids and clinical outcomes were examined by Cox regression and latent class analysis., Results: Circulating lipid profiles featuring elevated levels of ceramide species were associated with metastatic relapse in localised PC (HR 5.80, 95% CI 3.04-11.1, P = 1 × 10 -6 ), earlier testosterone suppression failure in mHSPC (HR 3.70, 95% CI 1.37-10.0, P = 0.01), and shorter overall survival in mCRPC (HR 2.54, 95% CI 1.73-3.72, P = 1 × 10 -6 ). The prognostic significance of circulating lipid profiles in localised PC was independent of standard clinicopathological and metabolic factors (P < 0.0002). The 3-lipid signature was verified in the mCRPC validation cohort (HR 2.39, 95% CI 1.63-3.51, P = 1 × 10 -5 )., Conclusions: Elevated circulating ceramide species are associated with poorer clinical outcomes across the natural history of PC. These clinically actionable lipid profiles could be therapeutically targeted in prospective clinical trials to potentially improve PC outcomes., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Associated particle imaging (API) is a non-destructive nuclear technique for the 3D determination of isotopic distributions. By detecting the alpha particle associated with the emitted neutron in the deuterium-tritium fusion reaction with a position- and time-resolving detector, the direction of the 14.1 MeV neutron and its time of emission can be determined. Employing this method, isotope characteristic gamma rays emitted in inelastic neutron scattering events can be correlated with the neutron interaction location. An API system consisting of a sealed-type neutron generator, gamma detectors, and a position-sensitive alpha detector was designed, constructed, and characterized. The system was tested with common soil elements and shown to be sensitive to 12 C, 16 O, 28 Si, 27 Al, and 56 Fe. New aspects of our approach are the use of a yttrium-aluminum-perovskite scintillator, using a sapphire window instead of a fiber-optic faceplate for light transport to the photomultiplier, and the all-digital data acquisition system. We present a description of the system with simulations and experimental results that show a position resolution on the alpha detector of 1 mm, a depth resolution using a LaBr 3 detector of 6.2 cm, and an angular resolution of 4.5°. Additionally, we present single-element gamma response measurements for the elements mentioned above together with a comparison to Monte Carlo simulations (MCNP6).

Glutamine is a critical nutrient in cancer; however, its contribution to purine metabolism in prostate cancer has not previously been determined. Guanosine monophosphate synthetase (GMPS) acts in the de novo purine biosynthesis pathway, utilizing a glutamine amide to synthesize the guanine nucleotide. This study demonstrates that GMPS mRNA expression correlates with Gleason score in prostate cancer samples, while high GMPS expression was associated with decreased rates of overall and disease/progression-free survival. Pharmacological inhibition or knockdown of GMPS significantly decreased cell growth in both LNCaP and PC-3 prostate cancer cells. We utilized [ 15 N-(amide)]glutamine and [U- 13 C 5 ]glutamine metabolomics to dissect the pathways involved and despite similar growth inhibition by GMPS knockdown, we show unique metabolic effects across each cell line. Using a PC-3 xenograft mouse model, tumor growth was also significantly decreased after GMPS knockdown, highlighting the importance of glutamine metabolism and providing support for GMPS as a therapeutic target in prostate cancer. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd., (© 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

Purpose: To identify the approximately 12% with inherited cancer predisposition, all men with metastatic prostate cancer (mPC) should be offered germline genetic testing. This guides treatment choices and impacts cancer prevention in the family. Limited genetic services globally present a barrier to testing. This study tested a potential solution, "mainstreaming," where counseling and testing are performed by the patient's oncologist., Patients and Methods: Men with mPC at three Australian sites were offered germline genetic testing at their medical oncology appointment. Panel testing ( ATM , BRCA1 , BRCA2 , BRIP1 , CHEK2 , EPCAM , FANCA , HOXB13 , MLH1 , MSH2 , MSH6 , NBN , PALB2 , PMS2 , RAD51D , and TP53 ) was performed on saliva/blood (Invitae, San Francisco, CA). Primary outcomes were clinician and patient satisfaction. Secondary outcomes included mutation rates and resource allocation., Results: Of 66 men offered testing, 63 (95%) accepted. Four pathogenic variants were identified (two BRCA2 , one NBN , and one MSH6 ). Fifty patients and nine clinicians completed questionnaires. Satisfaction was high. All patients were pleased to have had testing overall, 98% (46 of 47) to have had testing at their usual oncology appointment, and all to receive results from their usual specialist, rather than a separate genetics appointment. A total of 88% (7 of 8) of clinicians felt confident, and all were satisfied with mainstreaming. Mainstreaming was resource efficient, requiring 87% fewer genetic consultations than traditional genetic counseling., Conclusion: This study demonstrates that mainstreaming of men with mPC is feasible, resource efficient, and satisfactory for clinicians and patients. Widespread implementation as standard of care would facilitate timely access to genetic testing for men with mPC.

The past few decades show that incidences of melanoma are on the rise. The risk associated with this disease is an interplay between genetic and host factors and sun exposure. While scientific progress in the treatment of melanoma is remarkable, additional research is needed to improve patient outcomes and to better understand the heterogenous nature of this disease. Fortunately, as the clinical community enters the era of "big data" and personalized medicine, the rise of bioinformatics that stems from recent advances in high throughout profiling of biological information offers potential for innovative treatment options. This study aims to provide an example of the usefulness of bioinformatics and disorder-based proteomics to identify the molecular pathway in melanoma, garner information on selected proteins from this pathway and uncover their intrinsically disordered proteins regions (IDPRs) and investigate functionality implicated in these IDPRs. The present study provides a new look at the melanoma heterogeneity and suggests that, in addition to the well-established genetic heterogeneity of melanoma, there is another level of heterogeneity that lies within the conformational ensembles that stem from intrinsic disorder in melanoma-related proteins. The hope is that these insights will inspire future drug discovery campaigns., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Programmed cell death (PCD) is an integral component of both developmental and pathological features of an organism. Recently, ferroptosis, a new form of PCD that is dependent on reactive oxygen species and iron, has been described. As with apoptosis, necroptosis, and autophagy, ferroptosis is associated with a large set of proteins assembled in protein-protein interaction (PPI) networks, interactability of which is driven by the presence of intrinsically disordered proteins (IDPs) and IDP regions (IDPRs). Previous investigations have identified the prevalence and functionality of IDPs/IDPRs in non-ferroptosis PCD. The intrinsic disorder in protein structures is used to increase the regulatory powers of these processes. As uncontrolled PCD is associated with the onset of various pathological traits, uncovering the association between intrinsic disorder and ferroptosis-related proteins is crucial. To understand this association, 31 human ferroptosis-related proteins were analyzed via a multi-dimensional array of bioinformatics and computational techniques. In addition, a disorder meta-predictor (PONDR® FIT) was implored to look at the evolutionary conservation of intrinsic disorder in these proteins. This study presents evidence that IDPs and IDPRs are prevalent in ferroptosis. The intrinsic disorder found in ferroptosis has far-reaching functional implications related to ferroptosis-related PPIs and molecular interactions., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Surface bound guidance cues and gradients are vital for directing cellular processes during development and repair. In vivo, these cues are often presented within a soft extracellular matrix with elastic moduli E < 10 kPa, but in vitro haptotaxis experiments have been conducted primarily on hard substrates with elastic moduli in the MPa to GPa range. Here, a technique is presented for patterning haptotactic proteins with nanometer resolution on soft substrates with physiological elasticity. A new nanocontact printing process was developed that circumvented the use of plasma activation that was found to alter the mechanical properties of the substrate. A dissolvable poly(vinyl alcohol) film was first patterned by lift-off nanocontact printing, and in turn printed onto the soft substrate, followed by dissolution of the film in water. An array of 100 unique digital nanodot gradients (DNGs), consisting of millions of 200 × 200 nm 2 protein nanodots, was patterned in less than 5 min with with <5% average deviation from the original gradient design. DNGs of netrin-1, a known protein guidance cue, were patterned, and the unpatterned surface was backfilled with a reference surface consisting of 75% polyethylene glycol grafted with polylysine and 25% poly-d-lysine. Haptotaxis of C2C12 myoblasts demonstrated the functionality of the DNGs patterned on soft substrates. In addition, high densities of netrin-1 were observed to induce cell spreading, while live imaging of sinusoidal control gradients highlighted cell migration and navigation by "inching". The nanopatterning technique developed here paves the way for studying haptotactic responses to diverse digital nanodot patterns on surfaces covering the full range of physiological elasticity, and is expected to be applicable to the study of both culture and primary cells, such as neutrophils and neurons.

A lack of knowledge about mental health and stigma of the mentally ill are barriers to the treatment of mental disorders. To reduce these barriers, anti-stigma campaigns using a knowledge contact approach were launched to raise public mental health knowledge by education and to reduce stigma by encouraging contact with individuals with mental disorders. The current study attempted to investigate the outcome of a knowledge contact-based programme in adolescents and adults in the Hong Kong Chinese population. Matched background individuals served as controls. Results from the 149 adolescents and 98 adults who participated in our programme showed that they had superior mental health literacy to the control group. Although both adolescents and adults showed a positive outcome on most measures of stigma, the former showed positive outcome on more measures of stigma than the latter. Our results support the initiative of using a knowledge contact-based anti-stigma campaign in Chinese societies. The results of this study provide preliminary data that will help inform and guide future research and development of effective mental health awareness programmes specific to people of various age-groups in the Chinese community.

Language teacher's composition rating process has become an issue of growing concern in writing research over the past three decades. It is evident that a substantial number of composition rating research have employed concurrent think-aloud protocol analysis (TAPA) as a major method of qualitative data collection and data analysis. For the previous studies that adopted the method of TAPA in exploring the composition marking process, they were mostly confined to the study on L1/L2 English language education and not much has been done specifically on L1 Chinese language education. None of the previous studies employing TAPA were conducted with a computer marking platform. In the past, researchers generally videotaped and recorded teacher participants' think-aloud protocol during the composition marking process. However, the presence of the camera put a certain amount of psychological pressure on the participant and affected his/her performance in the rating task. To address these research gaps, a camera-free, tablet-based composition marking system is developed allowing writing researchers to examine the composition marking behavior of Chinese writing teachers with the method of TAPA conducted in a tablet-assisted marking environment. The system is able to eliminate the psychological pressure on the teacher participants as in video recording and to record their process of marking compositions systematically for later analysis.

There has been no study evaluating whether primary care services are sufficiently oriented towards the older population in Hong Kong, particularly those with increasing frailty. Since primary care is a key first interface in promotion and maintenance of health in older people, an assessment of the age-friendliness of service provisions is of critical importance in optimizing the health of aging populations. The age-friendliness of primary care services for older people was assessed using focus groups of elderly people and also of service providers who care for them. Discussion content was based on the WHO guidelines for age-friendly primary care in the following areas: Information, education and training, community-based health care management systems, and the physical environment. Desirable improvements were identified in all domains. The findings underscore the need for wider dissemination of health care needs of older people in the primary care setting.

Entecavir switch is one of the treatment options for lamivudine-resistant hepatitis B (HBV) patients in Asia. This study examined the outcome of patients with different baseline resistance genotypes in a cohort study. In this study, 14 patients with chronic HBV were treated with entecavir 1 mg/day for 5 years. Enrolment criteria include: documented lamivudine resistant mutations, treatment with adefovir 10 mg/day for at least 24 weeks, and Child-Pugh score <7. Most had previous failed adefovir therapy and compensated cirrhosis of the liver. Clinical outcomes, liver biochemistries, and HBV DNA were monitored regularly. Patients with virologic breakthrough were rescued with add-on adefovir. At the end of the treatment period, the mean HBV DNA fell from 5.92 × 10(6) (baseline) to 3.67 × 10(1)  IU/ml. The presence of a HBV polymerase rtM204V mutation at the baseline was found to be the major risk factor for adverse outcomes. Compared to the patients with the rtM204I mutant, patients with the rtM204V mutant had increased risk of virologic breakthrough (80% vs. 0%, P = 0.010) requiring add-on adefovir, slower virologic responses (log rank test, P = 0.0011), failure to reach undetectable HBV DNA levels (60% vs. 0%, P = 0.045), and higher risk of entecavir-resistance (60% vs. 0%, P = 0.045). All the patients with rtM204I and rtA181 mutants had undetectable HBV DNA from 18th month. In summary, lamivudine-resistant HBV patients with the rtM204V mutation have the highest risk of developing entecavir resistance, and entecavir monotherapy should be avoided. Those with the rtM204I and rtA181V mutations may have lower risks, but regular surveillance for viral breakthrough is required., (Copyright © 2012 Wiley Periodicals, Inc.)

Aim: This is a preliminary study to identify older people service needs in Hong Kong from the users' and service providers' perspective., Background: As the Hong Kong population is ageing rapidly, it is important to identify the needs for care of older people. Although a wide variety of medical and social services have been provided to meet the needs of older people, there has been little evaluation from the users' or service providers' perspective regarding what the needs are and how well current service provisions match their needs. In recent years the importance of patient-centred care has been emphasised, where patient's expectation of care has been given a central role in guiding and improving the provision of health. However few studies have been carried out with respect to services for older people., Design: To identify the service needs, a focus group study was conducted. Both service providers and older people were interviewed. This preliminary study used a qualitative research method to identify older people's service needs, generating rich information which could be used to inform older people care service development., Method: Data were collected by conducting eight focus group discussions. The focus group interviews were audio-taped. Interviews were then transcribed and themes were identified., Results: The study identified several areas for improvement in services for older people, covering adequacy, accessibility and affordability of medical services, coordination of health and social care, quality of long-term care, negative perceptions and training needs. Some themes such as service adequacy and negative staff attitudes occurred in both older people and health professional focus groups. The themes of fast access, continuity of care and smooth transition, affordability, provision of information of available health and social services appear to be universal as these have also been identified in similar studies in other countries., Conclusion: In addition to other objective outcomes, such as duration of stay in hospital or re-admission rates after hospital discharges, changes in service provisions towards improvement should be evaluated from the users as well as professional care providers' perspectives., Relevance to Clinical Practice: Areas of improvement in service delivery include timely access, continuity, affordability, better coordination of health and social care, quality of care particularly in the long-term residential care setting and healthcare professionals' communication and caring skills and attitude., (© 2011 Blackwell Publishing Ltd.)

Goals: To determine the clinical outcome of chronic hepatitis B cirrhotics on antiviral therapy., Background: The long-term outcome of hepatitis B cirrhotics on therapy remains to be characterized., Methods: A large clinic cohort of chronic hepatitis B cirrhotic patients were enrolled in a treatment program of lamivudine ± adefovir therapy. Patients were analyzed for clinical outcomes, and predictors of these outcomes were evaluated by multivariate analysis. Clinical outcomes of ascites, encephalopathy, hepatocellular carcinoma (HCC), and progression in Child-Pugh score, Model for End-stage Liver Disease score, and mortality were assessed. Data were analyzed by Kaplan-Meier graphs, log-rank test, and Cox regression., Results: Of 143 chronic hepatitis B cirrhotics, 19.6% had decompensated cirrhosis. At 5 years, the mean survival was 83.6%, development of ascites, HCC, encephalopathy, and deterioration in Child-Pugh score were 7.0%, 15.9%, 10.8%, and 16.9%, respectively. The overall progression of liver-related complications was 32.8% at 5 years. Multivariate analysis showed that ascites, albumin ≤28 g/L, Child-Pugh score ≥7.9, Model for End-stage Liver Disease score ≥10.9 were significantly associated with liver-related complications. Low albumin and low hepatitis B virus DNA were independent factors for liver-associated mortality. Lamivudine resistance did not affect mortality or liver disease progression. When stratified by Child-Pugh status, the mean survival of those with Child C cirrhosis was worse than Child A and B cirrhosis (P<0.001, log-rank test). Early deaths (≤12 mo) were due to liver failure or sepsis, whereas deaths ≥12 mo were mainly due to HCC., Conclusion: Decompensated chronic hepatitis B cirrhotics may suffer early mortality despite antiviral treatment, and therefore should be considered for early liver transplantation.

Aims and Objectives: Few surveys have been carried out documenting the quality of life for non-cancer patients in general district hospitals reaching the final trajectory towards death. We carried out a survey of 80 patients facing the final stages of their chronic illness as well as their carers and hospital staff., Background: With increasing life expectancy, a large majority of patients are older, where palliative care principles for patients with cancer are equally applicable. Few surveys have been carried out documenting the quality of life for non-cancer patients in general district hospitals reaching the final trajectory towards death in terms of patients' and carers' perspective, compared with the more extensive literature for patients with cancer., Design: Survey., Methods: Assessment tools include symptom check list, geriatric depression scale, Chinese Death Anxiety Inventory and the McGill Quality of Life Questionnaire for patients; SF-12 and the Chinese cost of care index for informal carers; and the Chinese Maslach Bumout and Death Anxiety Inventories for hospital staff., Results: Lower-limb weakness (92·5%), fatigue (86·2%), oedema (85%), dysphagia (58·2%) and pain (48·8%) were the most common symptoms in this group of patients. The mean Chinese Caregiver Stress Index score was 45·93 (SD 6·45) (maximum score = 80). For staff, the mean SF-12 physical component score was lower than the Hong Kong population average., Conclusion: The findings suggest that there is room for improvement in the quality of end-of-life care. Relevance to clinical practice.  Patients in the final stages of many chronic illnesses have high prevalence of symptoms comparable to those of patients with cancer. Raising awareness and improving training for all health care professionals, formulating guidelines and care pathways and incorporating quality of care as key performance indicators are measures to improve the quality of end-of-life care., (© 2011 Blackwell Publishing Ltd.)

Objectives: To examine how Chinese people in Hong Kong view health care prioritization and to compare the findings with those from a United Kingdom survey., Methods: A cross-sectional opinion survey was conducted in Hong Kong and 1512 participants were interviewed., Results: Data show that the highest rankings were accorded to "treatment for children" and "high technology services." Services for the elderly, whether in the community or in hospitals, and including end-of-life care, were ranked among the lowest. This view was also shared by healthcare professionals. Compared with the UK findings, there are stark contrasts in the low ranking of end-of-life care and the high ranking of high technology services among the HK population., Conclusions: It is evident that most people would give priority to the young over the old in distributing a given amount of healthcare services. To meet the needs of ageing societies and to meet the needs of all users equitably, health care policy needs to acknowledge constraints and the needs for prioritization. Both the public and professionals should engage with policy makers in formulating a policy based on cost benefit considerations as well as overall societal view of prioritization that is not based on age alone., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Objectives: The burden of suffering among patients with end-stage chronic diseases may be greater than those of cancer patients, as a result of longer duration of illness trajectory and high prevalence of symptoms, yet they may be less likely to receive palliative care services. To improve the quality of care of these patients, we carried out a continuous quality improvement initiative among medical and nursing staff of a convalescent facility., Design: Evaluation of a quality improvement initiative., Setting: Nonacute institution in Hong Kong SAR, China., Participants: The participants were patients with advanced chronic diseases not opting for active treatment., Intervention: The intervention was a continuous quality improvement process carried out over a 3-month period, consisting of service reengineering, provision of guidelines and educational material, and interactive sessions to achieve culture change among staff. Evaluation before and after the intervention included patient symptoms checklist and quality-of-life measures for patients; quality-of-life and cost-of-care index for family members; quality-of-life and carer burden for staff; and use of various health care services., Results: There were 80 and 89 participants in the pre- and post-intervention phase. The initiative resulted in shorter duration of stay, fewer investigations, fewer transfers back to the affiliated acute care hospital, and more follow-up by the outreach team, with no significant difference in mortality after adjusting for age and comorbidity. Symptoms of pain and cough were reduced, while there was a trend toward more constipation but less dizziness. Family members' satisfaction improved., Conclusions: It is possible to improve quality-of-life care for elderly patients with end-stage chronic diseases by staff education, and culture and system change, not only without additional resources, but likely savings were achieved in terms of reduced use of health care resources., (Copyright © 2011 American Medical Directors Association. Published by Elsevier Inc. All rights reserved.)

Unlabelled: The relationship between stages of chronic hepatitis B liver disease and health-related quality of life (HRQoL) is an important aspect of the overall management of hepatitis B virus (HBV) infection, yet is not well characterized. Consequently we sought to examine HRQoL in HBV patients, stratified by disease severity, compared with normal controls and hypertensive patients, using the Short Form 36 Health Survey (SF-36) and the EQ-5D self-report questionnaire. Univariate and multivariate analyses were then performed. A total of 432 HBV (156 asymptomatic carriers, 142 chronic hepatitis B, 66 compensated cirrhosis, 24 decompensated cirrhosis, 22 hepatocellular carcinoma, and 22 post-liver transplant) patients, 93 hypertensive patients, and 108 normal controls participated in the study. Multivariate analysis showed that normal controls and asymptomatic carriers had similar SF-36 scores, which were better than those for hypertensive patients, but with development of chronic hepatitis B and compensated cirrhosis, showed a significant decrease in general health and the mental dimension, whereas those with advanced liver disease (decompensated cirrhosis and hepatocellular carcinoma) had significantly lower scores in all components (P < 0.05), indicating that the physical component deteriorates only with advanced liver disease. Similar results were obtained with EQ5D. Post-liver transplant patients had similar HRQoL to patients with decompensated cirrhosis and hepatocellular carcinoma, although there was a trend toward improvement., Conclusion: Our results showed that HRQoL in asymptomatic carriers is comparable to those of normal controls and better than hypertensive patients, but deteriorates with disease progression, initially in general health and mental dimensions, but with advanced disease all dimensions are affected.

Introduction: Hepatitis B virus (HBV) infection is endemic in Asia. Good public knowledge on disease transmission is one way of controlling spread of HBV. We aimed to study the general knowledge on HBV among the general public in Singapore, which is moderately prevalent with HBV., Materials and Methods: Before conducting a public education seminar on liver diseases, a 16-point questionnaire survey was conducted among the participants. Misperceptions (if any) were identified, and factors associated with knowledge score were analysed by multivariate analysis., Results: One hundred and ninety-two subjects completed the questionnaire. The mean age was 52 years, 78 (41%) were male, 183 (95%) were Chinese, 17 (9%) were known hepatitis B carriers and 73 (38%) had completed college education. The mean knowledge score was 10.7 (out of a maximum of 16). Most misperceptions were in the category of HBV transmission. At multivariate analysis, having college education was the only independent factor associated with a high knowledge score., Conclusion: Although HBV infection is moderately prevalent in Singapore, many misperceptions existed among the general public, especially on the mode of transmission. Better education was related to better knowledge of HBV. Further public education should be targeted to clear the misperceptions identified, and be specifically targeted to the less educated.

Background and Aim: In contrast to chronic hepatitis C (CHC), few studies had been performed in assessing non-invasive models for predicting significant fibrosis or cirrhosis in chronic hepatitis B (CHB) patients. We aimed to evaluate non-invasive markers for diagnosing significant fibrosis/cirrhosis in patients with CHB, and to evaluate accuracy of models from CHC in CHB patients., Patients and Methods: Liver biopsies from consecutive treatment-naïve CHB patients were evaluated histologically by a pathologist blindly, using the Ishak score. Patients were divided randomly into a training (65%) and a validation sets (35%). Markers of fibrosis were evaluated by univariate followed by multivariate analysis in the training set. Area under receiver operating characteristics curve (AUROC) was assessed and validated in the training set. AUROC of aspartate aminotransferase (AST), AST/alanine aminotransferase (ALT) ratio, and AST-platelets ratio index (APRI) (derived from studies from CHC) in diagnosing significant fibrosis/cirrhosis were also assessed., Results: Two-hundred and eighteen CHB patients were evaluated: 83% male, 86% Chinese, 47% having significant fibrosis, 19% having cirrhosis. Platelets were the only factor significantly associated with significant fibrosis and cirrhosis at multivariate analysis but the AUROC was only modest at 0.63 and 0.73, respectively. Models derived from studies from CHC were even less accurate., Conclusion: Models with non-invasive markers in predicting histology from CHC patients were unsuitable for CHB patients. No variables consisting of simple and readily available markers were able to predict cirrhosis accurately in patients with CHB.

Aim: To identify the misperceptions among CHB patients, as well as to determine the factors associated with better knowledge., Methods: A telephone interview was conducted on 192 adult CHB patients, who earlier responded to an advertisement for free screening. The questionnaire included items about socio-demographic factors and a 14-item quiz on knowledge of general aspects, transmission, and management of HBV infection., Results: The mean knowledge score on HBV was 10.4/14. Common misperceptions included availability of treatment for HBV infection and early liver cancer, as well as on transmission. Having completed tertiary education was the only independent factor associated with a high knowledge score, after controlling other demographic factors., Conclusion: More educational efforts should be focused on patients' misperceptions and target the less educated HBV carriers.

Background: Regular surveillance is recommended for patients with chronic hepatitis B, to select candidates for anti-viral therapy and detect early complications. However, factors that determine compliance are not well studied., Aim: To determine the utility of the Health Belief Model in explaining non-compliance, among a group of chronic hepatitis B patients for screening., Methods: A total of 192 chronic hepatitis B patients who responded to advertisement for free screening took part in a telephonic interview study. Subjects were asked about the five constructs of the Health Belief Model, and factors associated with recent screening were analysed., Results: The mean age of the subjects was 42.1 +/- 0.7 years; 77% white male, and 97% Chinese. About 108 patients (56%) had recent screening. At multivariate analysis, only the ability to remember date of follow-up (OR: 4.37; 95% CI: 2.07-9.17) and the perception of having to wait a long time for venepuncture (OR: 0.38; 95% CI: 0.19-0.79) were significantly associated with recent screening., Conclusion: Future public health measures should include improving the logistics of follow-up procedures and providing reminders for screening to improve compliance.

Mechanical forces can induce differentiation of fibroblasts into myofibroblasts, a process which requires activation of the MAP kinase p38. Currently, the identification of other phospho-kinases involved in myofibroblast differentiation has not been explored. We applied static tensile forces to rat cardiac fibroblasts via collagen-coated magnetite beads and examined activation of protein phospho-kinases by the Kinexus phospho-antibody screening system. Of 75 candidate protein kinases screened, 39 were detected and, of these, 31 phospho-kinases were analyzed. Following force application, 12 out of 31 phospho-kinases exhibited increases of phosphorylation including PKR (>4-fold), MKK3 (3-fold), MKK6 ( approximately 2-fold), and p38 ( approximately 2-fold). In several types of mechanically sensitive, contractile fibroblasts including rat cardiac, human gingival, and Rat-2 fibroblasts, tensile forces increased eIF-2alpha phosphorylation, a downstream effector of PKR. We conclude that phospho-antibody screening is an efficient method for discovery of novel mechanical force-induced phospho-kinases and force can activate eIF-2alpha phospho-kinases in fibroblasts.

Introduction: Carriers of hepatitis B virus (HBV) are at risk of developing long-term complications. Regular surveillance helps detect treatable chronic hepatitis, cirrhosis and liver cancer, and is recommended by practice guidelines in the United States, Europe and Singapore. However, there have been few studies evaluating the follow-up of HBV carriers. This study seeks to determine the proportion of HBV carriers on regular follow-up in Singapore and the impact on hepatitis B disease., Methods: An advertisement was taken in local newspapers advertising for free screening to HBV carriers. 387 persons answered the advertisement. The screening comprised history-taking, physical examination, blood tests (liver panel, alphafoetoprotein, hepatitis B surface antigen (Ag) and hepatitis B eAg) and ultrasonography of liver. Further evaluation was conducted if the screening results were abnormal., Results: Of the 387 HBV carriers, 346 (89 percent) were male and 375 (97 percent) were Chinese. Their mean age was 39 years (range 20-60 years) and 36 percent were positive for HBeAg. 247 (64 percent) were not on regular screening over the past 12 months. 19 (5.4 percent) patients were diagnosed to have complications, namely: 13 had HBeAg-positive chronic hepatitis, two had HBeAg-negative chronic hepatitis, one had early liver cancer who recovered well after a curative resection and three had compensated cirrhosis., Conclusion: Our screening programme diagnosed 5.4 percent of complications among 387 asymptomatic HBV carriers. However, 64 percent of the study subjects were not screened regularly and may pose an important public health threat if they develop long-term complications. Further studies are needed to evaluate and improve patient compliance for screening.

Isolated sulphite oxidase deficiency (ISOD) is a very rare hereditary metabolic disorder. Imaging findings of the neonatal form of ISOD, including multicystic leukoencephalopathy with brain atrophy, resemble those of severe ischemic changes of the brain. We report the case of a ten-month-old boy who exhibited neonatal seizures on the 24th day after birth. Excessive quantities of sulphite and S-sulphocysteine in the urine and normal blood uric acid were noted. These findings were consistent with those of ISOD. Point mutations were found in two alleles of the sulphite oxidase (SUOX) gene. One of the mutations was a 1029 C > G mutation, which resulted in an amino acid substitution of tyrosine to a stop code (Y343 X); and the other was a 479 G > A mutation, which resulted in an amino acid substitution of arginine to glutamine (R160 Q). Y343 X is a novel SUOX gene mutation. A review of the literature, including data from this report, showed that 3 of 6 cases had typical imaging findings characterized by initial cerebral edema followed by dramatic multicystic leukoencephalopathy. We emphasize that neonatal ISOD should be included in the differential diagnosis of neonates with unexplained hypoxic-ischemic changes on neuroimaging studies.

The matrix metalloproteinases (MMPs) are a family of endoproteinases that degrade various components of the extracellular matrix and have been implicated in the pathogenesis of multiple sclerosis. To determine whether up-regulation of MMP-3, or stromelysin-1, was a causative factor during the development of demyelination, we have examined the expression of MMP-3 mRNA and protein in brain tissue of a spontaneously demyelinating mouse model overexpressing DM20 (ND4 line) prior to and during the progression of disease. Stromelysin-1, but not other MMP mRNA was elevated approximately 10-fold in transgenic mice between 5 days and 1 month of age, more than 2 months before the onset of disease, and was coordinately expressed with the DM20 transgene. Stromelysin-1 protein levels were also up-regulated as was tissue inhibitor of metalloproteinase-1 (TIMP-1), an in vivo regulator of stromelysin-1 mRNA. When we crossed our ND4 mice with a line of transgenic mice overexpressing TIMP-1 in brain, clinical signs in these mice were attenuated, and the level of stromelysin-1 protein was reduced. Thus, in this transgenic model of demyelinating disease up-regulation of DM20, MMP-3, and TIMP-1 represent important changes in the chemical pathogenesis in brain, which precede the onset of disease.

Treatment with paclitaxel by four intraperitoneal injections (20 mg/kg) 1 week apart attenuated clinical signs in a spontaneously demyelinating model, if given with onset of clinical signs. If given at 2 months of age (1 month prior to clinical signs), disease was almost completely prevented The astrogliosis, prominent in our model, was reversed by paditaxel as determined by astrocyte counts and quantitation of GFAP. Electron microscopic examination of affected regions at 2.5 months demonstrated that the myelin was generally normal. By 4 months of age, demyelination was common in the superior cerebellar peduncle, maximal at 6 months, but continued to 8 months. In addition to myelin vacuolation and nude axons, the presence of many thin myelin sheaths suggested remyelination or partial demyelination. Although no evidence of oligodendrocyte loss was seen, nuclear changes were observed. To substantiate that remyelination was occurring, we measured MBP (18.5 kDa), MBP-exon II, Golli-MBP, TP8, Golli-MBP-J37, platelet-derived growth factor alpha (PDGFR alpha) and sonic hedgehog (SHH). Of these TP8, PDGFR alpha and SHH were up-regulated in the untreated transgenic. After paditaxel treatment, MBP-Exon II, TP8, PDGFR alpha and SHH were further up-regulated. We concluded that some of the effects of paditaxel were to stimulate proteins involved in early myelinating events possibly via a signal transduction mechanism.

Lesch-Nyhan syndrome is an X-linked recessive disorder involving the purine metabolism, with resultant hyperuricemia, choreoathetosis, self-mutilation, and profound neurologic dysfunction. A deficiency of the enzyme hypoxanthine guanine phosphoribosyl-transferase is responsible for the disease. The human HPRT gene is located at Xq26-27 and consists of 57 base pairs. At least 2,000 mutations throughout the HPRT gene coding region from exon 1-9 have been reported. Four patients from three Chinese families were diagnosed with Lesch-Nyhan syndrome according to the clinical and laboratory findings. DNA studies revealed the first family (Patients 1 and 2) had a missense mutation in exon 3 of the HPRT encoding region. This novel mutation occurs in the hot spot of the HPRT gene. The second family (Patient 3) was found to have a missense mutation in exon 8 of the HPRT gene. The third family (Patient 4) carried a mutation in the splicing region of intron 4 of the HPRT gene. All three mutations were de novo.