Ts1Cje mouse model for Down syndrome research

Intellectual disabilities, hypotonia and cranio-facial dysmorphism are the cardinal characteristics of Down syndrome (DS) individuals. To varying extent, DS individuals also exhibit other developmental problems such as heart defects, vision impairments, hearing loss, hypothyroidism, dental problems and gastrointestinal defects. They are also at a higher risk for certain disorders such as early onset neurodegeneration and childhood leukaemia. For many decades, scientists have been trying to elucidate how additional full or partial set of chromosome 21 may responsible for these developmental disabilities or disorders. To date, many investigations are based on molecular, cellular and behavioural analyses of mouse models exhibiting similar characteristics observed in DS individuals. Among various models, Ts1Cje, in particular, is suitable for dissecting the effect of additional genetic materials on learning and memory impairment as well as muscle weakness in DS. Ts1Cje has partial triplication of the mouse chromosome 16, which is syntenic to chromosome 21 in human. This talk will focus on the genetics of Ts1Cje mouse model for DS and discuss how much do we know about the model and the degree of resemblance between Ts1Cje and human DS individuals in term of neuropathology of Down syndrome

Expression profiling of genes involved in the development and function of skeletal muscles in Ts1Cje mouse model of down syndrome

Introduction: Down syndrome (DS) is caused by trisomy of human chromosome 21 (HSA21). Motor dysfunction due to hypotonia has limited labour productivity and have significant effects on socio-economic status in DS individuals. Ts1Cje, a mouse model of DS that exhibits muscle weakness was employed, to investigate the expression profile of selected trisomic and disomic genes involved in skeletal muscle structure and function. Methods: Quadriceps and triceps were harvested from the Ts1Cje (C57BL/6) postnatal day 60-70 mice and corresponding wild-type littermates. Total RNA extracted from these tissues was subjected for quantitative expression profiling of three trisomic genes (Itsn1, Synj1 and Rcan1) involved in neurotransmission and six disomic genes (Lamc1, Leprel1, Myl6b, Msn, Pgm5 and Tmod1) essential for maintenance of muscle structure and function. Real-time quantitative PCR method was used for the profiling. Results: Differential gene expression in DS is reflected by 1.5-fold or more increase in the level of expression as predicted by the gene dosage imbalance hypothesis. The analysis showed no significant changes in the expression level of trisomic genes (Itsn1, Synj1 and Rcan1). On contrary, disomic genes, Leprel1 and Pgm5, were upregulated for more than 1.5-fold in DS quadriceps whereas Lamc1, Myl6b and Pgm5 were upregulated for more than 1.5 fold in DS triceps as compared to the wild-type group. Conclusions: Our findings suggest that the dysregulation of Lamc1, Leprel1, Myl6b and Pgm5 genes is associated to muscle weakness seen in Ts1Cje and may play a role in molecular pathogenesis of muscle weakness in DS

Breast cancer associated mutations reported among Malaysian Malay, Chinese and Indian patients

Breast cancer among women has reached an alarming stage compared to 20 years ago. It was found that single nucleotide polymorphisms (SNPs) play an important role in the development of breast cancer. SNPs may suppress or activate the functional genes, which then leads to an increased survival of cells due to the suppression of tumour suppressor genes or increased activity in detrimental proteins, resulting in cancers. Recently, breast cancer research is given significant attention due to the increasing number of breast cancer patients in Malaysia each year. However, breast cancer researches in Malaysia are mainly focused on well known breast cancer genes such as BRCA1 and BRCA2. There is less emphasis on the other breast cancer contributing genes. This paper was aimed to review the research findings on mutations associated with breast cancer in Malaysian Malay, Malaysian Chinese and Malaysian Indian as it has never been cumulatively reported and to ascertain the common mutations found in these three major Malaysia ethnicity

Association of maternal and cord plasma total, free and bioavailable 25-hyrodroxyvitamin D with neonatal anthropometric measurements at birth: a preliminary study in a private hospital

Introduction: 25-hydroxyvitamin D (25OHD) is the principal biomarker of vitamin D status. In circulation, 25OHD is primarily bound to vitamin D binding protein (VDBP), leaving a small proportion bound to albumin and as free form. Previous studies have suggested that free 25OHD is better correlated with health outcomes. However, in pregnancy where VDBP level is extremely elevated, the correlations between free 25OHD with health outcomes are far from conclusive. Here we show the associations of maternal and cord total, free and bioavailable 25OHD con-currently with neonatal anthropometric measurements in healthy pregnant mothers-neonates pairs. Method: Total 25OHD level was measured by using chemiluminescent immunoassay. Free and bioavailable 25OHD were calculated using published mathematical models. Results: The results showed that birth weight and head circumference were negatively associated with maternal total 25OHD but not significantly associated with free and bioavailable 25OHD. There were no significant associations between cord total, free and bioavailable 25OHD with any of the neonatal anthropometric measurements. Conclusion: The outcomes of this study should encourage further research in a larger sample size. Notably, future research could lead to the establishment of causative relationships and plausible mechanisms between maternal and cord 25OHD with neonatal anthropometric measurements

MicroRNA-based therapy and breast cancer: a comprehensive review of novel therapeutic strategies from diagnosis to treatment

MicroRNAs (miRNA) are 21–23 nucleotide molecules not translated into proteins that bind and target the 3′ untranslated regions of mRNA. These characteristics make them a possible tool for inhibiting protein translation. Different cellular pathways involved in cancer development, such as cellular proliferation, apoptosis, and migration, are regulated by miRNAs. The objective of this review is to discuss various miRNAs involved in breast cancer in detail as well as different therapeutic strategies from the clinic to industry. A comprehensive discussion is provided on various miRNAs involved in breast cancer development, progression, and metastasis as well as the roles, targets, and related therapeutic strategies of different miRNAs associated with breast cancer. miRNAs known to be clinically useful for the diagnosis and prognosis of breast cancer are also discussed. Different strategies and challenges, including nucleic acid-based (miRNA mimics, antagomiRs, and miRNA sponges) and drug-based (drug resistance, drugs/miRNA interaction, nanodelivery, and sensing systems) approaches to suppress specific oncogenes and/or activate target tumor suppressors are discussed. In contrast to other articles written on the same topic, this review focuses on the therapeutic and clinical value of miRNAs as well as their corresponding targets in order to explore how these strategies can overcome breast cancer, which is the second most frequent type of cancer worldwide. This review focuses on promising and validated miRNAs involved in breast cancer. In particular, two miRNAs, miR-21 and miR-34, are discussed as the most promising targets for RNA-based therapy in non-invasive and invasive breast cancer, respectively. Finally, relevant and commercialized therapeutic strategies are highlighted

In silico analysis of mRNA:miR-3099 interaction

Introduction: MicroRNAs (miRNA) are small non-coding RNAs and have crucial role in gene expression and protein synthesis regulation, especially in nervous system and brain development. A novel miR-3099 was found highly express throughout embryogenesis especially in the developing central nervous system. Moreover, miR-3099 was also expressed upon neuronal differentiation in in vitro system suggesting that miR-3099 is a potential regulator during neuronal development. Therefore, objective of this study is to predict target genes of miR-3099 via in-silico analysis. These analyses will predict potential downstream targets for miR-3099 and their relationship to signalling pathways with special focus on neuronal function and brain development. Methods: Four different prediction software, miRDB, miRanda, TargetScan and DIANA micro-T, were employed to identify the candidate target genes of miR-3099. The predicted downstream targeted genes were selected based on the database criteria, prior to BioVenn clustering to identify the common targeted genes. The targeted genes that were predicted by at least three different databases were subjected to DAVID bioinformatics analysis to understand the biological process and function of these targeted genes. Results: Based on the analysis, a total of 1676 predicted genes were targeted by miR-3099. Of these, 73 genes were predicted by three software and 22 genes were predicted by all the four software. Majority of the targeted genes were annotated as involved in positive regulation of transcription activity and were identified as related to neuronal and brain development. Hence, the predicted downstream targets of miR-3099 warrant further investigation to validate the in silico analysis

Ts1Cje mouse model for Down syndrome exhibits motor function deficit; the potential role of MRFS and peripheral nervous system

Introduction: Down syndrome (DS) is a chromosomal abnormality caused by presence of extra-copy of human chromosome 21. Motor dysfunction due to hypotonia is commonly seen in DS individuals and its etiology is still unknown. In this study, we employed the Ts1Cje, a mouse model for DS to investigate the motor performance in vivo and to elucidate the potential molecular mechanism and the role of peripheral nervous system in causing hypotonia. Method: The motor performance of two groups of mice, wild type (WT) and Ts1Cje aged P60-70 was accessed using the different behavioural machineries. Protein and total RNA were extracted from two muscles (quadriceps and triceps). Expression level of the myogenic regulator factors (MRFs) and some selected genes were performed using western blot and RT-qPCR respectively. The sciatic nerve was harvested from the mice and was processed for light and transmission electron microscopic (TEM) studies. Results: The automated grip test result revealed that forelimb strength of the WT mice (86.04±1.7N) was significantly (P<0.0001) better than the Ts1Cje mice (70.91±1.9N). The ability of the mice to survive the hanging position was also compared. The survival time of the WT mice was significantly better (P<0.01) than the Ts1Cje mice. For motor coordination, the WT mice (77.70±1.73S) performed significantly (P<0.01) better than the Ts1Cje mice (70.54±2.39S). There was altered expression of the genes involved in neuromuscular transmission and skeletal muscles structure and function. The expression level of MyoD was higher in Ts1Cje mice (P<0.02). We assessed the degree of sciatic nerve myelination in Ts1Cje mice. Conclusion: The Ts1Cje mice exhibits muscle weakness. The MRFs, gene dosage and peripheral nervous system might contribute to motor dysfunction seen in Ts1Cje mice