Stanniocalcin-1 Reduces Tumor Size in Human Hepatocellular Carcinoma

Growing evidence has revealed high expression levels of stanniocalcin-1 (STC1) in different types of human cancers. Numerous experimental studies using cancer cell lines demonstrated the involvement of STC1 in inflammatory and apoptotic processes; however the role of STC1 in carcinogenesis remains elusive. Hepatocellular carcinoma (HCC) an exemplified model of inflammation-related cancer, represents a paradigm of studying the association between STC1 and tumor development. Therefore, we conducted a statistical analysis on the expression levels of STC1 using clinicopathological data from 216 HCC patients. We found that STC1 was upregulated in the tumor tissues and its expression levels was positively correlated with the levels of interleukin (IL)-6 and IL-8. Intriguingly tumors with greater expression levels of STC1 (tumor/normal >= 2) were significantly smaller than the lower level (tumor/normal<2) samples (p = 0.008). A pharmacological approach was implemented to reveal the functional correlation between STC1 and the ILs in the HCC cell-lines. IL-6 and IL-8 treatment of Hep3B cells induced STC1 expression. Lentiviral-based STC1 over-expression in Hep3B and MHCC-97L cells however showed inhibitory action on the pro-migratory effects of IL-6 and IL-8 and reduced size of tumor spheroids. The inhibitory effect of STC1 on tumor growth was confirmed in vivo using the stable STC1-overexpressing 97L cells on a mouse xenograft model. Genetic analysis of the xenografts derived from the STC1-overexpressing 97L cells, showed upregulation of the pro-apoptotic genes interleukin-12 and NOD-like receptor family, pyrin domain-containing 3. Collectively, the anti-inflammatory and pro-apoptotic functions of STC1 were suggested to relate its inhibitory effect on the growth of HCC cells. This study supports the notion that STC1 may be a potential therapeutic target for inflammatory tumors in HCC patients.published_or_final_versio

With others and for others: accounting for decisions about genetic testing in the Clinic

Poster PresentationWhile there are various factors influencing clients' decisions about genetic testing; testing for the sake of others is not uncommon. This paper focuses on decisions about testing (DOT) when a genetic mutation is identified in a Sudden Arrhythmia Death Syndromes (SADS) patient and it is unclear whether the mutation is the cause of the disease. Family members are then asked to consider genetic testing to ascertain the client’s genetic status and future risk. The paper examines, at the interactional level, how genetic counselors, clients and family members negotiate decisionmaking involving others. The data consists of 23 video-recorded consultations obtained from a Hong Kong hospital. Episodes of decisionmaking about testing are identified and extracted from the transcribed data. By using theme-oriented discourse analysis, the analysis focuses on the discourse strategies that participants employ to foreground the possible benefits when other family members undergo the genetic test. Preliminary findings show a disjuncture of perspectives between genetic counselors and family members in terms of the benefits of testing. While genetic counselors see testing as a means of confirming the diagnosis and managing risk, family members voice concerns about the usefulness of the test for a client's treatment. To mitigate these different perspectives on DOT, participants use a range of discourse strategies, such as contrast, foregrounding, self-and-other construction as a way of emphasizing future scenarios. This study, in sum, elucidates how other-oriented decisions are made in the clinical setting.published_or_final_versio

Silver-Russell syndrome in Hong Kong

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De novo large rare copy-number variations contribute to conotruncal heart disease in Chinese patients

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Homozygous Missense Mutation in ABR Causes Cerebellar Hypoplasia with Early Lethality - A New Condition Identified by Exome Sequencing?

Poster PresentationWe performed whole exome sequencing (WES) in a consanguineous Pakistani family with a recurrent pattern of cerebellar hyposplasia, intra-uterine growth restriction, and various CNS/non-CNS malformations, resulting in early lethality (1 perinatal death and 1 intrauterine death). Karyotype (in the first pregnancy) and oligonucleotide array (in the 2nd affected pregnancy) were normal. Parents declined post-mortem examination. By WES, a novel homozygous missense mutation was identified in the ABR gene (ABR: NM_021962.4:c.G2455T: p.A819S) in both affected pregnancies. Both parents were identified to be heterozygous of the same mutation while the healthy child did not carry any mutation. The mutation is located in a highly conserved region and is predicted to be highly damaging by all the commonly used in silico mutation prediction tools. The protein encoded by ABR gene contains a GTPase-activating protein domain, a domain found in members of the Rho family of GTP-binding proteins. Previous reports showed that OPHN1, mutations in which cause X-linked mental retardation with cerebellar hypoplasia (OMIM300486), also encodes for a regulator of GTPase-activating protein. Both OPHN1 and ABR are highly expressed in the human brain especially in the cerebellum, and both contain a GTPase-activating domain. Rho proteins are important mediators of intracellular signal transduction, which affects cell migration and cell morphogenesis. Other studies have demonstrated a regulatory role of Rho GTPase in differentiation of cerebellar neurons, and that ethanolassociated impairment of Rho GTPase might contribute to brain defects in fetal alcohol syndrome. Further functional studies, including zebrafish morpholino studies, are currently ongoing. WES can be helpful in individual families with undiagnosed lethal MCA syndromes to identify potentially responsible autosomal recessive mutations and may lead to a better understanding of the role of various developmental pathways in human embryogenesis.published_or_final_versio

Diagnostic value of whole-exome sequencing in Chinese pediatric-onset neuromuscular patients

BACKGROUND: Neuromuscular disorders (NMDs) comprise a group of heterogeneous genetic diseases with a broad spectrum of overlapping the clinical presentations that makes diagnosis challenging. Notably, the recent introduction of whole-exome sequencing (WES) is introducing rapid changes on the genetic diagnosis of NMDs. We aimed to investigate the diagnostic value of WES for pediatric-onset NMDs. METHODS: We applied integrated diagnostic approach and performed WES in 50 Chinese subjects (30 males, 20 females) with undiagnosed pediatric-onset NMDs despite previous specific tests. The patients were categorized in four subgroups according to phenotyping and investigation findings. Variants on NMDs gene list and open exome analysis for those with initial negative findings were identified. RESULTS: WES identified causative variants in ACTA1 (n = 2), POMT1, COL6A1 (n = 2), MTMR2, LMNA, SELENON, DNM2, TGFB1, MPZ, IGHMBP2, and LAMA2 in 13 patients. Two subjects have variants of uncertain significance (VUSs) in TTN and SCN11A, unlikely to be pathogenic due to incompatible phenotypes. The mean interval time from symptom onset to genetic diagnosis was 10.4 years (range from 1 month to 33 years). The overall diagnostic yield of WES in our cohort was 26%. Open exome analysis was necessary to identify the pathogenic variant in TGFB1 that caused skeletal dysplasia with neuromuscular presentation. CONCLUSION: Our study shows a clear role of WES in the pathway of integrated diagnostic approach to shorten the diagnostic odyssey in patients with rare NMDs

Genome-Wide DNA Methylation Analysis of Chinese Patients with Systemic Lupus Erythematosus Identified Hypomethylation in Genes Related to the Type I Interferon Pathway

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Identification of mutations in the PI3K-AKT-mTOR signalling pathway in patients with macrocephaly and developmental delay and/or autism

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Mutation in PIK3CA leading to developmental mosaic disorders

Oral Free Paper Session: Oral Presentation 8published_or_final_versio

CFTR founder mutation causes protein trafficking defects in Chinese patients with cystic fibrosis

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