Search

The self-face advantage (SFA) is reflected through a faster recognition of a self-face compared with familiar and unfamiliar faces. Nevertheless, as Westerners and East Asians tend to present differences in self-concept styles, it is possible that the SFA is modulated by culture. The present study explored this possibility using a visual search task. British Caucasians and Malaysian Chinese participants were asked to search for frontal view images of self, friend, and unfamiliar faces among an array of unfamiliar faces. Regardless of race, participants were more accurate and faster in searching for the own face and friend’s face compared with an unfamiliar face, with no differences in the search between the own and friend’s face, and these findings could not be accounted by the cultural differences in self-concept (i.e., operationalised by scores from the Independent and Interdependent Self-Concept Scale and the Horizontal and Vertical Individualism and Collectivism Scale). Altogether our results suggest that culture does not modulate the SFA and that this effect is better explained by a familiar face advantage.

Urban overheating, driven by global climate change and urban development, is a major contemporary challenge which substantially impacts urban livability and sustainability. Overheating represents a...

Introduction/Background* Inflammatory myofibroblastic tumours (IMT) are rare spindle cell neoplasms of indeterminate malignant potential, commonly found in the lungs, but also originating from various organs ranging from head and neck, gastrointestinal to the genitourinary system. IMTs of the female gynaecological tract are rare and may mimic benign leiomyoma in both clinical presentation and appearance on imaging. We describe a case of uterine IMT, diagnosed after a laparoscopic myomectomy with in-bag morcellation. Methodology Result(s)* A 37-year-old woman was on follow-up for uterine mass on pelvic ultrasound, slowly enlarging to 3.3cm, presumed to be a fibroid. Although she did not have significant pressure symptoms or menorrhagia, she requested for removal and underwent laparoscopic myomectomy with morcellation-in-bag. Intra-operatively, a 6cm mass was seen on the uterine posterior wall, macroscopically and morphologically consistent with that of benign leiomyoma. However, immunohistochemistry and molecular sequencing were positive for ALK-1 hence a diagnosis of IMT was made. Diffuse staining for desmin, H-caldesmon and ER was also noted. Following a multi-disciplinary tumour board, consensus was for a CT scan of the thorax, abdomen and pelvis(which showed no extra-uterine spread) and for regular surveillance scans. A review of the literature shows no universal consensus as to optimal treatment of uterine IMT. Majority of cases have been treated with surgical excision – open, laparoscopic or hysteroscopic. While most cases have a benign course with no recurrence/relapse, local recurrences are a known complication. Given controversies in recent years over power morcellation potentially leading to dissemination of undiagnosed uterine leiomyosarcomas, morcellation-in-bag has become standard practice for all laparoscopic myomectomies or hysterectomies requiring morcellation. There is little data regarding outcomes of other types of uterine tumours, or IMT specifically, with regards to outcomes following morcellation. The only two documented cases in the literature specifically involving morcellation resulted in local recurrences requiring further treatment. Conclusion* We present a case of uterine IMT diagnosed following laparoscopic myomectomy and in-bag morcellation. While the patient has no sign of extrauterine spread at present, further follow-up will be required to monitor for any progression or recurrence. Outcomes following morcellation or specific other treatment options will need to be further studied.

Background Achilles tendinopathy is one of the most common overuse injuries in running, and forefoot pronation, seen in flatfeet participants, has been proposed to cause additional loading across the Achilles tendon. Foot orthoses are one of the common and effective conservative treatment prescribed for Achilles tendinopathy, it works by correcting the biomechanical malalignment and reducing tendon load. Previous studies have shown reduction of Achilles Tendon load (ATL) during running by using customized arch support orthosis (CASO) or an orthotic heel lift (HL). However, there are still little biomechanical evidence and comparative studies to guide orthotic prescriptions for Achilles tendinopathy management. Therefore, this study seeks to investigate the two currently employed orthotic treatment options for Achilles tendinopathy: CASO and HL for the reduction of ATL and Achilles tendon loading rate (ATLR) in recreational runners with flatfeet. Methods Twelve participants were recruited and run along the runway in the laboratory for three conditions: (1) without orthoses, (2) with CASO (3) with HL. Kinematic and kinetic data were recorded by 3D motion capturing system and force platform. Ankle joint moments and ATL were computed and compared within the three conditions. Results Participants who ran with CASO (p = 0.001, d = 0.43) or HL (p = 0.001, d = 0.48) associated with a significant reduction in ATL when compared to without orthotics while there was no significant difference between the two types of orthoses, the mean peak ATL of CASO was slightly lower than HL. Regarding the ATLR, both orthoses, CASO (p = 0.003, d = 0.93) and HL (p = 0.004, d = 0.78), exhibited significant lower value than the control but similarly, no significant difference was noted between them in which the use of CASO yielded a slightly lower loading rate than that of HL. Conclusions Both CASO and HL were able to cause a significant reduction in peak ATL and ATLR comparing to without orthotics condition. There were subtle but no statistically significant differences in the biomechanical effects between the two types of orthoses. The findings help to quantify the effect of CASO and HL on load reduction of Achilles tendon and suggests that foot orthoses may serve to prevent the incidence of Achilles tendon pathologies. Trial registration NCT04003870 on clinicaltrials.gov 1 July 2019.

Background: Achilles tendinopathy is one of the most common overuse injuries in running, and forefoot pronation, seen in flatfeet participants, has been proposed to cause additional loading across the Achilles tendon. Foot orthoses are one of the common and effective conservative treatment prescribed for Achilles tendinopathy, it works by correcting the biomechanical malalignment and reducing tendon load. Previous studies have shown reduction of Achilles Tendon load (ATL) during running by using customized arch support orthosis (CASO) or an orthotic heel lift (HL). However, there are still little biomechanical evidence and comparative studies to guide orthotic prescriptions for Achilles tendinopathy management. Therefore, this study seeks to investigate the two currently employed orthotic treatment options for Achilles tendinopathy: CASO and HL for the reduction of ATL and Achilles tendon loading rate (ATLR) in recreational runners with flatfeet. Methods: 12 participants were recruited and run along the runway in the laboratory for three conditions: (1) without orthoses, (2) with CASO (3) with HL. Kinematic and kinetic data were recorded by 3D motion capturing system and force platform. Ankle joint moments and ATL were computed and compared within the three conditions. Results: Participants who ran with CASO (p=0.001, d=0.43) or HL (p=0.001, d=0.48) associated with a significant reduction in ATL when compared to without orthotics. There was no difference between the two types of orthoses, the mean peak ATL of CASO was slightly lower than HL. Regarding the ATLR, both orthoses, CASO (p=0.003, d= 0.93) and HL (p=0.004, d= 0.78), exhibited significant lower value than the control but similarly, no significant difference was noted between them in which the use of CASO yielded a slightly lower loading rate than that of HL. Conclusions: Both CASO and HL were able to cause a significant reduction in peak ATL and ATLR comparing to without orthotics condition. There were subtle but no statistically significant differences in the biomechanical effects between the two types of orthoses. The findings help to quantify the effect of CASO and HL on load reduction of Achilles tendon and suggests that foot orthoses may serve to prevent the incidence of Achilles tendon pathologies.

Introduction: Achilles tendinopathy is one of the most common overuse injuries in running,and forefoot pronation, seen in flatfeet subjects, has been proposed to cause additional loading across the Achilles tendon. Foot orthoses are one of the common and effective conservative treatment prescribed for Achilles tendinopathy, it works by correcting the biomechanical malalignment and reducing tendon load Previous studies have shown reduction of Achilles Tendon load (ATL) during running by using customized arch support orthosis (CASO) or an orthotic heel lift (HL). However, there are still little biomechanical evidence and comparative studies to guide orthotic prescriptions for Achilles tendinopathy management. Therefore, this study seeks to investigate the two currently employed orthotic treatment options for Achilles tendinopathy: CASO and HL for the reduction of ATL and Achilles tendon loading rate (ATLR) in recreational runners with flatfeet. Methods: 12 subjects were recruited and run along the runway in the laboratory for three conditions: (1) without orthoses, (2) with CASO (3) with HL. Kinematic and kinetic data were recorded by 3D motion capturing system and force platform. Ankle joint moments and ATL were computed and compared within the three conditions. Results: Subjects who ran with CASO (p=0.001, d=0.43) or HL (p=0.001, d=0.48) associated with a significant reduction in ATL when compared to without orthotics while there was no significant difference between the two types of orthoses, the mean peak ATL of CASO was slightly lower than HL. Regarding the ATLR, both orthoses, CASO (p=0.003, d= 0.93) and HL (p=0.004, d= 0.78), exhibited significant lower value than the control but similarly, no significant difference was noted between them in which the use of CASO yielded a slightly lower loading rate than that of HL. Conclusions: Both CASO and HL were able to cause a significant reduction in peak ATL and ATLR comparing to without orthotics condition. There were subtle differences in the biomechanical effects between the two types of orthoses. The findings help to quantify the effect of CASO and HL on load reduction of Achilles tendon and suggests that foot orthoses may serve to prevent the incidence of Achilles tendon pathologies. Trial: NCT04003870_clinicaltrials.gov, retrospectively_registered

Objective Previous genome-wide association studies (GWAS), which were mainly based on single-variant analysis, have identified many systemic lupus erythematosus (SLE) susceptibility loci. However, the genetic architecture of this complex disease is far from being understood. The aim of this study was to investigate whether using a gene-based analysis may help to identify novel loci, by considering global evidence of association from a gene or a genomic region rather than focusing on evidence for individual variants. Methods Based on the results of a meta-analysis of 2 GWAS of SLE conducted in 2 Asian cohorts, we performed an in-depth gene-based analysis followed by replication in a total of 4,626 patients and 7,466 control subjects of Asian ancestry. Differential allelic expression was measured by pyrosequencing. Results More than one-half of the reported SLE susceptibility loci showed evidence of independent effects, and this finding is important for understanding the mechanisms of association and explaining disease heritability. ANXA6 was detected as a novel SLE susceptibility gene, with several single-nucleotide polymorphisms (SNPs) contributing independently to the association with disease. The risk allele of rs11960458 correlated significantly with increased expression of ANXA6 in peripheral blood mononuclear cells from heterozygous healthy control subjects. Several other associated SNPs may also regulate ANXA6 expression, according to data obtained from public databases. Higher expression of ANXA6 in patients with SLE was also reported previously. Conclusion Our study demonstrated the merit of using gene-based analysis to identify novel susceptibility loci, especially those with independent effects, and also demonstrated the widespread presence of loci with independent effects in SLE susceptibility genes.

7nm platform technology that takes full advantage of EUV lithography was developed, where EUV was straightforwardly used for single patterning of MOL and BEOL, not just as a means for cutting of SADP/SAQP. The combination of 27nm fin pitch (FP) and 54nm contacted poly pitch (CPP) as well as the high density SRAM cell size of 0.0262 um2 is the smallest in the reported FinFET platform. Further scaling is secured with special constructs and the 3rd generation single diffusion break. Full working of 256M bit SRAM and large-scale logic test chip was demonstrated with guaranteed reliability.

Objective: Some studies have evaluated the prognostic indicators associated with acute paraquat (PQ) poisoning. In this study, we externally validated the Yamaguchi index, which showed a good prognostic relevance in predicting the outcome of PQ poisoning. Methods: A retrospective analysis of 297 patients was performed. The Yamaguchi index was calculated using the following equation: Eq1 = (K+ × HCO3−)/(Creatinine × 0.088)(mEq/L) against time from PQ ingestion ( T). The patients were divided into three groups: group A: Eq1 > 1500 − 399 × log T, group B: 930 − 399 × log T < Eq1 ≤ 1500 − 399 × log T, and group C: Eq1 ≤ 930 − 399 × log T). Results: The overall mortality rate was 65.3% (194 of 297). The mortality rates of the three groups stratified by the Yamaguchi index were 7.1% (2 of 28), 22.4% (15 of 67), and 87.6% (177 of 202). The area under the receiver–operating characteristic curve for predicting mortality from the external validation of the Yamaguchi index was 0.842 (95% confidence interval: 0.795–0.882). Conclusion: The Yamaguchi index is a reliable prognostic factor and could be helpful in predicting mortality due to PQ poisoning.

Genetic interaction has been considered as a hallmark of the genetic architecture of systemic lupus erythematosus (SLE). Based on two independent genome-wide association studies (GWAS) on Chinese populations, we performed a genome-wide search for genetic interactions contributing to SLE susceptibility.The study involved a total of 1 659 cases and 3 398 controls in the discovery stage and 2 612 cases and 3 441 controls in three cohorts for replication. Logistic regression and multifactor dimensionality reduction were used to search for genetic interaction.Interaction of CD80 (rs2222631) and ALOX5AP (rs12876893) was found to be significantly associated with SLE (OR_int=1.16, P_int_all=7.7E-04 at false discovery rate0.05). Single nuclear polymorphism rs2222631 was found associated with SLE with genome-wide significance (P_all=4.5E-08, OR=0.86) and is independent of rs6804441 in CD80, whose association was reported previously. Significant correlation was observed between expression of these two genes in healthy controls and SLE cases, together with differential expression of these genes between cases and controls, observed from individuals from the Hong Kong cohort. Genetic interactions between BLK (rs13277113) and DDX6 (rs4639966), and between TNFSF4 (rs844648) and PXK (rs6445975) were also observed in both GWAS data sets.Our study represents the first genome-wide evaluation of epistasis interactions on SLE and the findings suggest interactions and independent variants may help partially explain missing heritability for complex diseases.

Background IgG4 related disease (IgG4RD) is a spectrum of immune mediated disease with multiple organs involvement characterized by organ enlargement, function loss or obstructive symptoms (1, 2). Objectives In this retrospective study, clinical, serological and histological features of IgG4RD patients over the past ten years from four regional hopsitals were reviewed. Methods Four regional hospitals participated with study period from 1/1/2006 to 30/6/2016. IgG4RD patients were classifed into definite, probable and possible IgG4RD according to Japanese Comprehensive Diagnostic Criteria for IgG4RD (3). Statistical analysis: Association between the individual categorical covariates and the different organ involvement were analyzed by Fisher9s exact test. Results 108 patients were included. There were 81 male patients and 27 female patients and the male to female ratio is 3:1. The mean age of diagnosis was 62.8 year old. 57 patients were diagnosed as definite IgG4RD (53%), 14 patients as probable IgG4RD (13%) and 37 patients as possible IgG4RD (34%). Salivary glands involvement was the commonest, (M=45.7% vs F=33.3%), followed by pancreas (M=28.4% vs F=18.5%) and biliary system in male (M=24.7% vs F=11.1%) and orbital in female (M=23.5% vs F=18.5%). 53% patients also had multi organ involvement. 104 patients had serum IgG4 level checked and it was raised in 94 patients (90.4%). 77 patients (74.0%) had IgG4 level above twice upper limit of normal. IgG4 level was normal in 10 patients. 98% and 86.3% patients with multi organ involvement had IgG4 level >135mg/dL (p=0.016) and >270mg/dL (p=0.007) respectively. In the hepatobiliary group (n=36), 30 patients had blood checked for Ca19.9 level and it was raised in 17 patients (56.7%), with the highest level 14127 U/ml. 71 histological reports were available. Lymphoplasmacytic infiltration was a consistent features in all specimens (100%). Eosinophilic infiltration was seen in 19 specimen (27%). Fibrosis was seen in 44 specimens (63%). Sialadenitis and dacryoadenitis were associated with dense fibrosis. Obliterative phlebitis was seen in 7 specimens (10%). IgG4/IgG ratio was reported in 61 specimens. 53 specimens had IgG4/IgG ratio greater than 40% per high power field which accounted for 86.9% of the specimens. Conclusions Most patients were male with the peak diagnosis at age 50 to 70. Salivary gland and pancreas were the most common organ involved. Most patients had a raised IgG4 level and most histological specimens showed a raised IgG4/IgG ratio on immunostaining. IgG4 level twice the upper limit of normal was quite specific for the disease and was associated with multi organ involvement. References Pieringer H, et al. IgG4- related disease: an orphan disease with many faces. Orphanet journal of rare diseases. 2014;9:110. Haitao Du YW et al. IgG4-related disease and the curreny status of diagnostic approaches. EXCLI. 2012;11:651–8. Umehara H, et al. Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011. Modern Rheumatology. 2012;22(1):21–30. Disclosure of Interest None declared

Background Currently most consensus suggests treating IgG4 related disease (IgG4RD) with prednisolone 0.6mg/kg/day tapering over 6 months while some experts prefer continuation of steroid up to 3 years (1–3). Objectives In this retrospective study, the treatment modality, response and relapse risk of IgG4RD patients over the past ten years from four regional hospitals in Hong Kong were analyzed. Methods Four regional hospitals participated with study period from 1/1/2006 to 30/6/2016. Patients were diagnosed IgG4RD according to the Japanese Comprehensive Diagnostic Criteria for IgG4RD. Treatment response at 6 months was recorded as complete, partial or non-remission based on the patient9s and physician9s perspective. Relapse was defined as disease progression either clinically or radiologically. Statistical analysis: The association between treatment response and steroid dosage was analyzed by multivariate logistic regression. Risk factors for relapse were analyzed by multivariate cox regression and the hazard ratio was reported. Results 37 cases had surgical excision and disease recurred in 5 cases (relapse rate =13.5%). 87 patients (81%) received steroid treatment. The mean starting prednisolone was 33.5mg daily, with a mean duration of 95.2 weeks. At 6 months, 5 patients (6%) had no response, 34 patients (41%) had partial remission and 44 patients (53%) had complete remission. 29 patients also received other immunosuppressants, including azathioprine (n=25), mycophenolate mofetil (MMF) (n=6), cyclosporine A (n=4), mercaptopurine (n=2) and rituximab (n=1). The overall response rate for azathioprine and MMF was 64% and 67% respectively. In the final multiple logistic regression, an initial prednisolone 30mg daily or above was associated with a higher complete remission at 6 months (OR=3.4, p=0.079) and the effect was more seen in patients with salivary and orbital involvement (OR=6.8, p=0.10) 18 patients relapsed after steroid was stopped and 6 patients relapsed while on prednisolone 2.5–7.5mg daily. The one year, two year and three year relapse rate were 13.3%, 24.1% and 26.5% respectively. In the final multivariate cox regression, the presence of maintenance steroid was associated with a lower relapse risk (Hazard ratio=0.121, p=0.000) while serum IgG4 level above twice upper limit of normal (Hazard ratio=5.283, p=0.029) and hepatobiliary involvement (Hazard ratio=2.164, p=0.095) were associated with a higher relapse risk. Conclusions Most patients (94%) had good response to steroid. Patients with hepatobiliary involvement and serum IgG4 level above twice upper limit of normal were at higher relapse risk and a low dose, maintenance prednisolone for longer period is recommended. References Kleger A, et al. IgG4-related autoimmune diseases: Polymorphous presentation complicates diagnosis and treatment. Deutsches Arzteblatt international. 2015;112(8):128–35. Ghazale A, et al. Immunoglobulin G4-associated cholangitis: clinical profile and response to therapy. Gastroenterology. 2008;134(3):706–15. Kamisawa T, et al. Standard steroid treatment for autoimmune pancreatitis. Gut. 2009;58(11):1504–7. Disclosure of Interest None declared

Summary T-helper cells that produce IL-17 (Th17 cells) are a subset of CD4+ T-cells with pathological roles in autoimmune diseases including systemic lupus erythematosus (SLE), and ETS1 is a negative regulator of Th17 cell differentiation. Our previous work on genome-wide association study (GWAS) identified two variants in the ETS1 gene (rs10893872 and rs1128334) as being associated with SLE. However, like many other risk alleles for complex diseases, little is known on how these genetic variants might affect disease pathogenesis. In this study, we examined serum IL-17 levels from 283 SLE cases and observed a significant correlation between risk variants in ETS1 and serum IL-17 concentration in patients, which suggests a potential mechanistic link between these variants and the disease. Furthermore, we found that the two variants act synergistically in influencing IL-17 production, with evidence of significant genetic interaction between them as well as higher correlation between the haplotype formed by the risk alleles and IL-17 level in patient serum. In addition, the correlation between ETS1 variants and IL-17 level seems to be more significant in SLE patients manifesting renal involvement, dsDNA autoantibody production or early-onset.

Objective This study aims to identify the existence of, and relationship between autoantibody clusters and clinical subsets in Chinese SLE patients. Methods Data from 1928 SLE patients from Hong Kong were analysed. Using cluster analysis, patients were grouped by autoantibodies into clusters. The frequencies of various clinical manifestations were then compared between each cluster. Separate association analyses between individual autoantibodies and clinical manifestations as well as between clinical manifestations were also performed without any prior clustering. Results Three separate autoantibody clusters were identified, each with significantly different clinical manifestations. Cluster 1 was characterized by anti-dsDNA and the greatest prevalence of renal disorder but the lowest frequencies of other clinical manifestations. Cluster 2 was represented by the predominance of anti-Smith, anti-RNP and aPL, with greater prevalence of malar rash, oral ulcers, arthritis and serositis. Cluster 3 was characterized by anti-Ro and anti-La with greater prevalence of discoid rash, photosensitivity and haematological involvement. Individual association analysis also revealed similar findings. Patients of clusters 2 and 3 were more closely related, while cluster 1 was more distinct, associated with renal disorder only and negatively associated or not associated with other manifestations. Conclusion We conclude that autoantibody clustering and clinical subsets exist in SLE patients of our locality. These clusters may be viewed as a bipolar spectrum of related autoantibody and clinical manifestations. At one end are patients with over-representation of anti-dsDNA and renal disorder, while at the other end are two distinct autoantibody clusters (anti-Sm/anti-RNP/aPL and anti-Ro/anti-La) with overlapping of other clinical manifestations.

Public stigma is an important barrier to the recovery of patients with psychosis. The current study aimed to investigate the change in stigma towards psychosis and knowledge about psychosis between 2009 and 2014 among the Chinese population in Hong Kong, with a specific focus on gender role. Random telephone survey of general population in Hong Kong was conducted in 2009 and 2014. Stigma was measured with the revised Link’s Perceived Discrimination-Devaluation Scale (LPDDS). Logistic regression was used to explore the effect of time on the change of knowledge of psychosis, and linear regression was used to explore the effect of time on the change of stigma. Change of knowledge and stigma based on gender was specifically explored. In total, 1016 and 1018 subjects completed the survey in 2009 and 2014, respectively. Significantly, more people agreed with medication treatment for psychosis and fewer people had misunderstanding about psychosis. However, there was no significant change in stigma levels. Males were found to have a significant deterioration of stigma (B = 0.099, SE = 0.033, β = 0.100, p = 0.003) but not females. Significantly, more males endorsed medication treatment for psychosis (χ 2 = 5.850, df = 1, p = 0.016) but no change for females (χ 2 = 1.401, df = 1, p = 0.238). Results of this study suggested that there was an improvement in the biological understanding of psychosis but no change of public stigma within the Hong Kong Chinese population. The specific role of gender in relation to stigma and level of knowledge about psychosis indicates that this should be a consideration in designing future anti-stigma campaigns.

Objective: Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease with complex genetic inheritance. CD247 (CD3Z, TCRZ) plays a vital role in antigen recognition and signal transduction in antigen-specific immune responses, and is known to be involved in SLE pathogenesis. Weak disease association was reported for genetic variants in this gene in Caucasian studies for SLE, Crohn's disease and systemic sclerosis, but its role as a genetic risk factor was never firmly established. Methods: In this study, using a collection of 612 SLE patients and 2193 controls of Chinese ethnicity living in Hong Kong in a genome-wide study, single nucleotide polymorphisms (SNPs) in and around CD247 were identified as being associated with SLE. The two most significant SNPs in this locus were selected for further replication using TaqMan genotyping assay in 3339 Asian patients from Hong Kong, Mainland China, and Thailand, as well as 4737 ethnically and geographically matched controls. Results: The association of CD247 with SLE in Asian populations was confirmed (rs704853: odds ratio [OR] = 0. 81, p = 2.47 × 10−7; rs858543: OR = 1.10, p = 0.0048). Patient-only analysis suggested that rs704853 is also linked to oral ulcers, hematologic disorders and anti-double-stranded DNA (dsDNA) antibody production. Conclusion: A significant association between variants in CD247 and SLE was demonstrated in Asian populations. Understanding the involvement of CD247 in SLE may shed new light on disease mechanisms and development of new treatment paradigms.

UHRF1BP1 encodes a highly conserved protein with unknown function. Previously, a coding variant in this gene was found to be associated with systemic lupus erythematosus (SLE) in populations of European ancestry (rs11755393, R454Q, P=2.22 x 10⁻⁸, odds ratio=1.17). In this study, by a combination of genome-wide study and replication involving a total of 1230 patients and 3144 controls, we confirmed the association of this coding variant to SLE in Hong Kong Chinese. We also identified another coding variant in this gene that independently contributes to SLE susceptibility (rs13205210, M1098T, P=4.44 x 10⁻⁹, odds ratio=1.49). Cross-population confirmation establishes the involvement of this locus in SLE and indicates that distinct alleles are contributing to disease susceptibility.

ITGAM was recently found to be associated with systemic lupus erythematosus (SLE) in populations of not only European ancestry, but also in Hispanic- and African-Americans, Mexicans and Colombians. The risk alleles in the gene, however, were found to be monomorphic in two Asian populations examined: Japanese and Korean. In this study, using a collection of 910 SLE patients and 2360 controls from Chinese living in Hong Kong, analyzed by both genome-wide association and direct sequencing, we confirmed the association of the same risk alleles in ITGAM with the disease. These findings were further replicated in the Thai population with 278 patients and 383 ethnicity- and geography-matched controls. Subphenotype stratification analyses showed significantly more involvement of the gene in patients with renal nephritis and neurological disorders. Although our results support a pivotal role by rs1143679 (R77H) in disease association, our data also suggests an additional contribution from rs1143683, another non-synonymous polymorphism in this gene (A858V). Therefore, despite the low-allele frequencies of the risk alleles of the gene in our two Asian populations, ITGAM was confirmed to be a risk factor related to disease susceptibility and probably severe manifestations of SLE. © 2009 The Author(s)., published_or_final_version

In this study, we compared the association of several newly discovered susceptibility genes for systemic lupus erythematosus (SLE) between populations of European origin and two Asian populations. Using 910 SLE patients and 1440 healthy controls from Chinese living in Hong Kong, and 278 SLE patients and 383 controls in Thailand, we studied association of STAT4, BLK and PXK with the disease. Our data confirmed association of STAT4 (rs7574865, odds ratio (OR) =1.71, P=3.55 x 10(-23)) and BLK (rs13277113, OR=0.77, P=1.34 x 10(-5)) with SLE. It was showed that rs7574865 of STAT4 is also linked to hematologic disorders and potentially some other subphenotypes of the disease. More than one genetic variant in STAT4 were found to be associated with the disease independently in our populations (rs7601754, OR=0.59, P=1.39 x 10(-9), and P=0.00034 when controlling the effect of rs7574865). With the same set of samples, however, our study did not detect any significant disease association for PXK, a risk factor for populations of European origin (rs6445975, joint P=0.36, OR=1.06, 95% confidence interval: 0.93-1.21). Our study indicates that some of the susceptibility genes for this disease may be population specific.

INTRODUCTION: Systemic lupus erythematosus (SLE) is a heterogeneous disease with a diverse spectrum of clinical symptoms from skin rash to end-organ damage. 22q11.21 has been identified as a susceptibility region for several autoimmune diseases, including SLE. However, the detailed information for SLE association and the underlying functional mechanism(s) are still lacking. METHODS: Through meta-analysis of two genome-wide association studies (GWAS) on Chinese Han populations with a total of 1659 cases and 3398 controls matched geographically, we closely examined this region, especially on the reported single nucleotide polymorphisms (SNPs) associated with different autoimmune diseases and their relationships. We further replicated the most significant association SNP with SLE using 2612 cases and 2323 controls of Asian ancestry. RESULTS: All reported SNPs in this region with different autoimmune diseases were examined in the two GWAS data and meta- analysis result, and supportive evidence of association with SLE was found (meta-analysis P_meta ≤ 7.27E-05), which might require further investigation. SNP rs2298428 was identified as the most significant SNP associated with SLE in this region (P_meta = 2.70E-09). It showed independent effect through both stepwise and conditional logistic regression, and there is no evidence of other independent association signals for SLE in this region. The association of rs2298428 was further replicated in three cohorts from Hong Kong, Anhui and Thailand with a total of 2612 cases and 2323 controls (joint analysis of GWAS and replication result P_all = 1.31E-11, OR = 1.23). SNP rs2298428 was shown to be an eQTL for UBE2L3 gene in different cell types, with the risk allele (T) being correlated with higher expression of UBE2L3. This is consistent with earlier reports on higher expression of UBE2L3 in SLE cases. CONCLUSIONS: Association to distinct autoimmune diseases highlights the significance of this region in autoreactive responses and potentially shared functional mechanisms by these diseases., published_or_final_version

Insulin-like growth factor (IGF) binding protein (IGFBP)-3 has been shown to be a growth inhibitory, apoptosis-inducing molecule by virtue of its ability to bind IGFs, in addition to previously demonstrated IGF-independent effects. The recent discovery of the interaction between nuclear IGFBP-3 and 9-cis retinoic acid receptor-alpha (retinoid X receptor alpha RXRalpha), a nuclear receptor, and its involvement in the regulation of transcriptional signaling and apoptosis represents an important paradigm shift in the understanding of IGFBP function. RXRalpha is required for the apoptosis-inducing effects of IGFBP-3. IGFBP-3 and RXR ligands are additive in inducing apoptosis in cancer cells. IGFBP-3 has direct effects on gene transcription, as RXR response element reporter signaling was enhanced and the all-trans retinoic acid receptor response element reporter signaling was inhibited. Accumulating evidence further confirms IGF-independent functions of this multifunction binding protein. Other binding proteins, in addition to other members of the IGF axis, have now been described in the nucleus and are postulated to have effects on transcriptional events. Investigation into these new interactions will expose new protein partners in the interface between the nuclear receptor and growth factor pathways and reveal new targets to be exploited in the treatment of cancer and other diseases.

Sorafenib is the only FDA-approved tyrosine kinase inhibitor for targeted therapy in advanced HCC. Nevertheless, its efficacy is limited with only a modest improvement in patient outcome, likely due to acquired resistance. In-depth understanding of the molecular mechanism of sorafenib resistance is warranted for the development of novel treatment strategies. Recent studies by us and others have characterized liver tumor-initiating cells (T-ICs) to be a possible source of resistant and recurrent tumors and a plausible target for HCC treatment. Our group has previously identified CD133 to be a functional marker of liver T-ICs and found annexin a3 (ANXA3) to regulate cancer and stem cell-like properties in this subset of cells. Interestingly, our recent observations also found CD133+ liver T-ICs to be more resistant to sorafenib. Sorafenib resistant clones, established in HepG2 and Huh7 cells by continuous exposure to increasing concentrations of sorafenib, displayed enhanced abilities to migrate, invade, self-renew, and initiate tumor formation in immunodeficient mice, as well as higher expression of stemness associated genes. These two sorafenib resistant cell lines and two other sorafenib resistant HCC patient-derived xenografts established in a similar manner were also found to be enriched for CD133 and ANXA3 expression. Sorafenib resistant clones with ANXA3 stably suppressed were re-sensitized to sorafenib treatment and had diminished ability to migrate, invade, self-renew and initiate tumor growth in vivo, further substantiating the role of ANXA3 in mediating sorafenib resistance in HCC. Mechanistically, an activated PKC/ERK/FRA2 signaling axis was found to be responsible for driving this phenomenon. Clinically, ANXA3 expression was also found to have prognostic value as a higher ANXA3 expression in HCC patients who have received sorafenib treatment was correlated with poor overall survival. The combinatorial use of a homemade ANXA3 neutralizing antibody and sorafenib on HCC patient derived xenografts is now being investigated as a potential new treatment regimen for combating sorafenib resistance in HCC. Citation Format: Man Tong, Steve Luk, Noelia Che, Jin Ding, Terence KW Lee, Stephanie Ma. Targeting ANXA3 in combination with sorafenib for the treatment of hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3146. doi:10.1158/1538-7445.AM2017-3146

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease that affects mainly females. What role the X chromosome plays in the disease has always been an intriguing question. In this study, we examined the genetic variants on the X chromosome through meta-analysis of two genome-wide association studies (GWAS) on SLE on Chinese Han populations. Prominent association signals from the meta-analysis were replicated in 4 additional Asian cohorts, with a total of 5373 cases and 9166 matched controls. We identified a novel variant in PRPS2 on Xp22.3 as associated with SLE with genome-wide significance (rs7062536, OR = 0.84, P = 1.00E-08). Association of the L1CAM-MECP2 region with SLE was reported previously. In this study, we identified independent contributors in this region in NAA10 (rs2071128, OR = 0.81, P = 2.19E-13) and TMEM187 (rs17422, OR = 0.75, P = 1.47E-15), in addition to replicating the association from IRAK1-MECP2 region (rs1059702, OR = 0.71, P = 2.40E-18) in Asian cohorts. The X-linked susceptibility variants showed higher effect size in males than that in females, similar to results from a genome-wide survey of associated SNPs on the autosomes. These results suggest that susceptibility genes identified on the X chromosome, while contributing to disease predisposition, might not contribute significantly to the female predominance of this prototype autoimmune disease.

Hydration pertains simplistically to body water volume. Functionally, however, hydration is one aspect of fluid regulation that is far more complex, as it involves the homeostatic regulation of total body fluid volume, composition and distribution. Deliberate or pathological alteration of these regulated factors can be disabling or fatal, whereas they are impacted by exercise and by all environmental stressors (e.g. heat, immersion, gravity) both acutely and chronically. For example, dehydration during exercising and environmental heat stress reduces water volume more than electrolyte content, causing hyperosmotic hypohydration. If exercise continues for many hours with access to food and water, composition returns to normal but extracellular volume increases well above baseline (if exercising upright and at low altitude). Repeating bouts of exercise or heat stress does likewise. Dehydration due to physical activity or environmental heat is a routine fluid-regulatory stress. How to gauge such dehydration and — more importantly—what to do about it, are contested heavily within sports medicine and nutrition. Drinking to limit changes in body mass is commonly advocated (to maintain ≤2% reduction), rather than relying on behavioural cues (mainly thirst) because the latter has been deemed too insensitive. This review, as part of the series on moving in extreme environments, critiques the validity, problems and merits of externally versus autonomously controlled fluid-regulatory behaviours, both acutely and chronically. Our contention is that externally advocated hydration policies (especially based on change in body mass with exercise in healthy individuals) have limited merit and are extrapolated and imposed too widely upon society, at the expense of autonomy. More research is warranted to examine whether ad libitum versus avid drinking is beneficial, detrimental or neither in: acute settings; adapting for obligatory dehydration (e.g. elite endurance competition in the heat), and; development of chronic diseases that are associated with an extreme lack of environmental stress.

Background: There is limited information on the effects of sports drinks on cognitive function after exercise in the heat. We aimed to investigate the effects of ingesting a commercially available carbohydrate-electrolyte (CHO) solution on cognitive performance following exercise-induced hyperthermia. Methods: Twelve participants completed three practices of cognitive tests, one full familiarisation and two experimental trials in an environmental chamber (dry bulb temperature: 30.2 ± 0.3°C, relative humidity: 70 ± 3%). The experimental trials consisted of five cognitive tests (symbol digit matching, search and memory, digit span, choice reaction time and psychomotor vigilance test) performed before and after a 75-min run on a treadmill at 70% VO2 max. One ml/kg body mass of a 6.8% CHO solution or placebo was consumed at the start, every 15 min during exercise and between cognitive tests after exercise. Core temperature, heart rate, blood glucose concentrations, subjective ratings and cognitive performance were assessed (symbol digit matching, search and memory, digit span, choice reaction time and psychomotor vigilance). Results: Participants were hyperthermic at the end of the run (placebo: 39.5 ± 0.4°C, CHO: 39.6 ± 0.5°C; Mean ± SD; p = 0.37). The change in blood glucose was higher with CHO ingestion (1.6, 0.7 to 4.5 mmol/L) (median, range) than with placebo ingestion (0.9, -0.1 to 4.7 mmol/L; p < 0.05). CHO ingestion reduced the maximum span of digits memorized, in contrast to an increase in maximum span with placebo ingestion (p < 0.05). CHO solution had no effect on other cognitive tests (p > 0.05). Conclusions: These results suggest that CHO solution ingestion may impair short-term memory following exertional heat stress. Published version