Bioinformatics

Molecular classification of prostate cancer using curated expression signatures

by Hideaki Mizuno

Markert EK, Mizuno H, Vazquez A, Levine AJ. Proc Natl Acad Sci U S A. 2011, 108:21276-81.

High Gleason score is currently the best prognostic indicator for poor prognosis in prostate cancer. However, a... more High Gleason score is currently the best prognostic indicator for poor prognosis in prostate cancer. However, a significant number of patients with low Gleason scores develop aggressive disease as well. In an effort to understand molecular signatures associated with poor outcome in prostate cancer, we analyzed a microarray dataset characterizing 281 prostate cancers from a Swedish watchful-waiting cohort. Patients were classified on the basis of their mRNA microarray signature profiles indicating embryonic stem cell expression patterns (stemness), inactivation of the tumor suppressors p53 and PTEN, activation of several oncogenic pathways, and the TMPRSS2-ERG fusion. Unsupervised clustering identified a subset of tumors manifesting stem-like signatures together with p53 and PTEN inactivation, which had very poor survival outcome, a second group with intermediate survival outcome, characterized by the TMPRSS2-ERG fusion, and three groups with benign outcome. The stratification was validated on a second independent dataset of 150 tumor and metastatic samples from a clinical cohort at Memorial Sloan-Kettering Cancer Center. This classification is independent of Gleason score and therefore provides useful unique molecular profiles for prostate cancer prognosis, helping to predict poor outcome in patients with low or average Gleason scores.

PrognoScan: a new database for meta-analysis of the prognostic value of genes

by Hideaki Mizuno

Mizuno H, Kitada K, Nakai K, Sarai A. BMC Med Genomics. 2009, 2:18.

Background
In cancer research, the association between a gene and clinical outcome suggests the underlying... more Background
In cancer research, the association between a gene and clinical outcome suggests the underlying etiology of the disease and consequently can motivate further studies. The recent availability of published cancer microarray datasets with clinical annotation provides the opportunity for linking gene expression to prognosis. However, the data are not easy to access and analyze without an effective analysis platform.

Description
To take advantage of public resources in full, a database named "PrognoScan" has been developed. This is 1) a large collection of publicly available cancer microarray datasets with clinical annotation, as well as 2) a tool for assessing the biological relationship between gene expression and prognosis. PrognoScan employs the minimum P-value approach for grouping patients for survival analysis that finds the optimal cutpoint in continuous gene expression measurement without prior biological knowledge or assumption and, as a result, enables systematic meta-analysis of multiple datasets.

Conclusion
PrognoScan provides a powerful platform for evaluating potential tumor markers and therapeutic targets and would accelerate cancer research. The database is publicly accessible at http://gibk21.bse.kyutech.ac.jp/PrognoScan/index.html webcite.

ORI-GENE: gene classification based on the evolutionary tree.

by Hideaki Mizuno

Mizuno H, Tanaka Y, Nakai K, Sarai A. Bioinformatics. 2001, 17:167-73.

MOTIVATION:
Genome projects have produced large amounts of data on the sequences of new genes whose functions are... more MOTIVATION:
Genome projects have produced large amounts of data on the sequences of new genes whose functions are as yet unknown. The functions of new genes are usually inferred by comparing their sequences with those of known genes, but evaluation of the sequence homology of individual genes does not make the most of the available sequence information. Therefore, new methods and tools for extracting more biological information from homology searches would be advantageous.
RESULTS:
We have developed a computational tool, ORI-GENE, to analyze the results of sequence homology searches from the perspective of the evolution of selected sets of new genes. ORI-GENE has a graphical interface and accomplishes two important tasks: first, based on the output of homology searches, it identifies species with similar genes and displays their pattern of distribution on the phylogenetic tree. This function enables one to infer the way in which a given gene may have propagated among species over time. Second, from the distribution patterns, it predicts the point at which a given gene may have been first acquired (i.e. its 'origin'), then classifies the gene on that basis. Because it makes use of available evolutionary information to show the way in which genes cluster among species, ORI-GENE should be an effective tool for the screening and classification of new genes revealed by genome analysis.
AVAILABILITY:
ORI-GENE is retrievable via the Internet at: http://www.rtc.riken.go.jp/jouhou/ORI-GENE.

A signature-based method for indexing cell cycle phase distribution from microarray profiles.

by Hideaki Mizuno

Mizuno H, Nakanishi Y, Ishii N, Sarai A, Kitada K. BMC Genomics. 2009, 10:137.

Background
The cell cycle machinery interprets oncogenic signals and reflects the biology of cancers. To date,... more Background
The cell cycle machinery interprets oncogenic signals and reflects the biology of cancers. To date, various methods for cell cycle phase estimation such as mitotic index, S phase fraction, and immunohistochemistry have provided valuable information on cancers (e.g. proliferation rate). However, those methods rely on one or few measurements and the scope of the information is limited. There is a need for more systematic cell cycle analysis methods.

Results
We developed a signature-based method for indexing cell cycle phase distribution from microarray profiles under consideration of cycling and non-cycling cells. A cell cycle signature masterset, composed of genes which express preferentially in cycling cells and in a cell cycle-regulated manner, was created to index the proportion of cycling cells in the sample. Cell cycle signature subsets, composed of genes whose expressions peak at specific stages of the cell cycle, were also created to index the proportion of cells in the corresponding stages. The method was validated using cell cycle datasets and quiescence-induced cell datasets. Analyses of a mouse tumor model dataset and human breast cancer datasets revealed variations in the proportion of cycling cells. When the influence of non-cycling cells was taken into account, "buried" cell cycle phase distributions were depicted that were oncogenic-event specific in the mouse tumor model dataset and were associated with patients' prognosis in the human breast cancer datasets.

Conclusion
The signature-based cell cycle analysis method presented in this report, would potentially be of value for cancer characterization and diagnostics.

Fine-scale detection of population-specific linkage disequilibrium using haplotype entropy in the human genome

by Hideaki Mizuno

Mizuno H, Atwal G, Wang H, Levine AJ, Vazquez A. BMC Genetics 2010, 11:27.

Background
The creation of a coherent genomic map of recent selection is one of the greatest challenges towards a... more Background
The creation of a coherent genomic map of recent selection is one of the greatest challenges towards a better understanding of human evolution and the identification of functional genetic variants. Several methods have been proposed to detect linkage disequilibrium (LD), which is indicative of natural selection, from genome-wide profiles of common genetic variations but are designed for large regions.

Results
To find population-specific LD within small regions, we have devised an entropy-based method that utilizes differences in haplotype frequency between populations. The method has the advantages of incorporating multilocus association, conciliation with low allele frequencies, and independence from allele polarity, which are ideal for short haplotype analysis. The comparison of HapMap SNPs data from African and Caucasian populations with a median resolution size of ~23 kb gave us novel candidates as well as known selection targets. Enrichment analysis for the yielded genes showed associations with diverse diseases such as cardiovascular, immunological, neurological, and skeletal and muscular diseases. A possible scenario for a selective force is discussed. In addition, we have developed a web interface (ENIGMA, available at http://gibk21.bse.kyutech.ac.jp/ENIGMA/index.html webcite), which allows researchers to query their regions of interest for population-specific LD.

Conclusion
The haplotype entropy method is powerful for detecting population-specific LD embedded in short regions and should contribute to further studies aiming to decipher the evolutionary histories of modern humans.

Application of Genomic and Proteomic Technologies in Biomarker Discovery

by Elana Fertig

EJ Fertig, R Slebos, and CH Chung. Application of Genomic and Proteomic Technologies in Biomarker Discovery. In: Govindan R, ed. 2012 ASCO Educational Book. Alexandria, VA: American Society of Clinical Oncology; 2012;377-382.

Overview: Sequencing of the human genome was completed in 2001. Building on the technology and experience of... more Overview: Sequencing of the human genome was completed in 2001. Building on the technology and experience of whole-exome sequencing, numerous cancer genomes have been sequenced, including head and neck squamous cell carcinoma (HNSCC) in 2011. Although DNA sequencing data reveals a complex genome with numerous mutations, the biologic interaction and clinical significance of the overall genetic aberrations are largely unknown. Comprehensive analyses of the tumors using genomics and proteomics beyond sequencing data can potentially accelerate the rate and number of biomarker discoveries to improve biology-driven classification of tumors for prognosis and patient selection for a specific therapy. In this review, we will summarize the current genomic and proteomic technologies, general biomarker-discovery paradigms using the technology and published data in HNSCC---including potential clinical applications and limitations.

Lipid metabolic pathways as lung cancer therapeutic targets: A computational study.

by Kojiro Yano

Published in International Journal of Molecular Medicine, Volume 29 Number 4, 2012

Inhibitors of lipid metabolic pathways, particularly drugs targeting the mevalonate pathway, have been suggested to be... more Inhibitors of lipid metabolic pathways, particularly drugs targeting the mevalonate pathway, have been suggested to be valuable in enhancing the effectiveness of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and these compounds may also be effective in patients with inherent or acquired resistance to EGFR-TKIs. The present study examined gene expression profiles in lung adenocarcinoma to characterize the interaction between growth factor signals and lipid metabolic pathways at the transcriptional level. Gene expression correlation analysis showed that genes involved in the mevalonate pathway and unsaturated fatty acid synthesis were negatively correlated with the expression of EGFR, MET and other growth factor receptor genes, as well as with the expression of genes involved in cell migration and adhesion. On the other hand, the expression of genes related to cell cycle progression, DNA repair and DNA replication were positively correlated with the metabolic pathway genes mentioned above, and a significant number of such genes had promoter domains for nuclear factor Y (NFY). Genes whose expression showed a positive correlation with NFY expression and mevalonate pathway genes were found to exhibit protein-protein interactions with several 'hub' genes, including BRCA1, that have been associated with both lung cancer and cell division. These results support the idea that inhibition of lipid metabolic pathways may be valuable as an alternative therapeutic option for the treatment of lung adenocarcinoma, and suggest that NFY is a possible molecular target for such efforts.

Biodiversity assessment of Niah National Park. 2008

by M.T. Abdullah, PhD

A transect survey was conducted from 2  6 December 2004 in Niah National Park to estimate species diversity and... more A transect survey was conducted from 2  6 December 2004 in Niah National Park to estimate species diversity and relative abundance of birds and mammals. This study was conducted in four forest line transects: Madu Trail (TR1), Sungai Tangap (TR2), Niah Great Cave (TR3), Bukit Kasut (TR4), and one river transect along the Niah River (RT). A total of 521 birds representing 59 species from 23 families were recorded. The Black-Nest Swiftlet (Aerodramus maximus) and the Mossy-Nest Swiftlet (Aerodramus salanganus) were the most common species in the park. The family Timaliidae (babblers), with nine species, was recorded as the most diverse family, whereas Strigidae (owls) and Hirundinidae (swallows) were the least diverse families with one species in each. A total of 29 mammalian individuals representing seven species from four families were recorded. The family Sciuridae (squirrels) with three species was recorded as the most diverse family, whereas Cynocephalidae (flying lemurs) and Muridae (rodents) were the least diverse families with one species and one individual each. TR1 was recorded with the highest Shannon-Weiner index (diversity index) of H = 4.75 and H = 2.20 for birds and mammals respectively. The lowest bird H = 3.73 was recorded for TR2, whereas the lowest mammal H = 0 was recorded for TR2 and RT. Although this study does not identify factors that contribute to different species diversity at each transect line, field observations suggest that vegetation and human activities were the major elements that contributed to the observations found at each transect in this study. Studies on the vegetation types and potential disturbances that influence the faunal diversity will provide useful insights in conservation and management planning of this park.

Diversity of bats in two protected limestone areas, Sarawak, Borneo. 2010b. Ridwan_et_al_SMJ

by M.T. Abdullah, PhD

This paper updates that of Hall et al 2004. Found new records. This paper updates that of Hall et al 2004. Found new records.

In silico Modification of (1R, 2R, 3R, 5S)-(-)- Isopinocampheylamine as Inhibitors of M2 Proton Channel in Influenza A Virus Subtype H1N1, using the Molecular Docking Approach

by Arli Parikesit

Co-authored with Usman Sumo Friend Tambunan and Rahayu Harganingtyas

In 2009, swine flu attacked various countries in the world. World Health Organization (WHO) set influenza A H1N1 virus... more In 2009, swine flu attacked various countries in the world. World Health Organization (WHO) set influenza A H1N1 virus disease as a global pandemic on June 11, 2009. At least, there are approximately 18,449 people worldwide who died from this virus attack. Then, on August 10, 2010, WHO officially announced that the swine flu pandemic in the world has ended and changed into post-pandemic phase. The post-pandemic phase is the most appropriate phase to find an antiviral that can overcome the infection with this virus. The existing antivirals, amantadine and rimantadine, are reported to have experienced resistance. Therefore, it is necessary to find a new antiviral to replace amantadine and rimantadine as the M2 channel protein inhibitor of influenza A H1N1 virus. Later, it was reported that compound (1R, 2R, 3R, 5S)-(-)- isopinocampheylamine has the ability to inhibit channel M2 protein of influenza A H1N1 virus. This research modified (1R, 2R, 3R, 5S)-(-)- isopinocampheylamine in silico to obtain better inhibitors. Three inhibitors docking with standard and 52 inhibitor modifications were performed against the M2 protein channel and drug scan for modification inhibitors was also conducted. Docking results had the three best binding affinity of modification inhibitors and its potency of inhibition is much better than the standard ligands. Based on drug analysis scan, the modified inhibitor has good pharmacological properties which are indicated by the value of drug-likeness, drug score, oral bioavailability and toxicity.

Bat Survey of Mount Penrisen and Notes on the Rare Kerivoula minuta, Kerivoula intermedia and Hipposideros coxi in Sarawak, Borneo

by M.T. Abdullah, PhD

Biogeography of fruit bats in Southeast Asia. Les S. Hall, Gordon G. Grigg, Craig Moritz, Besar Ketol, Isa Sait, Wahab Marni and M.T. Abdullah.

by M.T. Abdullah, PhD

Should read Abdullah (2003).

We studied on the biogeography and diversity of fruit bats in Southeast Asia, from Borneo to Asian Mainland.The... more We studied on the biogeography and diversity of fruit bats in Southeast Asia, from Borneo to Asian Mainland.The patterns of distribution of distribution, diversity and abundance are related to ecological and biogeographical factors and possible past Pleistocene events.

Les S. Hall, Gordon G. Grigg, Craig Moritz, Besar Ketol, Isa Sait, Wahab Marni and M.T. Abdullah. 2004. Sarawak Museum Journal 81: 191-284.

A morphometric analysis of Rhinolophus species complex. 2008.

by M.T. Abdullah, PhD

DFA and CVA analyses were used to differentiate Malaysian Rhinolophus species complex. DFA and CVA analyses were used to differentiate Malaysian Rhinolophus species complex.

Morphometrical Variations of Malaysian Hipposideros Species. 2012

by M.T. Abdullah, PhD

Read Vijaya et al (2012)

A study on the morphometrical variations among four Malaysian Hipposideros species was conducted using voucher... more A study on the morphometrical variations among four Malaysian Hipposideros species was conducted using voucher specimens deposited in Universiti Malaysia Sarawak (UNIMAS) Zoological Museum and the Department of Widlife and National Park (DWNP) Kuala Lumpur. Twenty two individuals from four species of Hipposideros ater, H. bicolor, H. cineraceus and H. dyacorum were morphologically measured, in which a total of 27 linear parameters of body, skull and dentals of each were appropriately recorded. The statistical data were later subjected to discriminant function analysis (DFA) and canonical variate analysis (CVA) using SPSS version 15.0 and unweighted pair-group method average (UPGMA) cluster analysis using Minitab version 14.4. The highest character loadings observed in Function l, Function 2 and Function 3 were the forearm length (FA), the third digit second phalanx length (D3P2L) and the palatal length (PL) with standardised canonical discriminant function coefficient values of 21.910, 5.770 and 5.095, respectively. These three characters were identified as the best diagnostic features for discriminating these closely related species of Hipposideros. Hence, this morphometric approach could be a promising tool as an alternative to the molecular
DNA analysis for identification of Chiroptera species.

A Predictive Model to Differentiate the Fruit Bats Cynopterus brachyotis and C. cf. brachyotis Forest (Chiroptera: Pteropodidae) from Malaysia Using Multivariate Analysis. 2012

by M.T. Abdullah, PhD

Read also Abdullah (2003)

Field discrimination of Cynopterus brachyotis and C. cf. brachyotis Forest (as designated by Francis 2008) in southern... more Field discrimination of Cynopterus brachyotis and C. cf. brachyotis Forest (as designated by Francis 2008) in southern Thailand, Peninsular Malaysia, and Borneo is problematic. These 2 forms are sympatric in this region but are confined to different habitat types: C. brachyotis inhabits open habitats, orchards, and agricultural areas, while C. cf. brachyotis Forest is confined to primary and old secondary forests. In this study, we attempted to develop prediction models to identify both C. brachyotis and C. cf. brachyotis Forest in this region based on multivariate statistics. Two predictive models were generated using a canonical discriminant function, and it was found that 5 characters can be used to accurately identify museum vouchers of C. brachyotis and C. cf. brachyotis Forest. Four characters are needed for field identification of these 2 forms of Cynopterus in southern Thailand, Peninsular Malaysia, and Borneo. A review of the current taxonomy and classification indicated that there is a need to describe the 6 existing forms of the C. brachyotis complex in the Indo-Malayan region. This will aid conservationists, field ecologists, and taxonomists in taxonomic- and conservation-related decisions about this species complex.

Malaysian fruit bats phylogeny inferred using ribosomal RNA. Ryan, J.R., K.H.G. Andy, V.K. Jayaraj, Y. Esa, A.A. Sallehin and Abdullah, M.T. 2008. Pertanika Journal of Tropical Agricultural Science 31(1):107-117. (SCOPUS-Cited Publication).

by M.T. Abdullah, PhD

Fourteen species of the Malaysian fruit bats (Pteropodidae) were used in this DNA taxonomy using 1,334bp of the 12S... more Fourteen species of the Malaysian fruit bats (Pteropodidae) were used in this DNA taxonomy using 1,334bp of the 12S ribosomal RNA (rRNA), transfer RNA (tRNA) valine and 16S rRNA gene segments. Previous studies using DNA found contradictions between morphology and molecular data in inferring the phylogeny of the fruit bats proposed by Andersen (1912). Our phylogenetic analysis using the neighbor-joining and the maximum parsimony methods did not support the monophyly of the subfamily Macroglossinae and the cynopterine group of the subfamily Pteropodinae as proposed by classical taxonomists. This is congruent with previous molecular studies. Here, we provide the first registered 12S rRNA, tRNA valine and 16S rRNA sequence records for Dyacopterus spadiceus in the GenBank database. This study represents the first attempt to infer the phylogenetic relationship of fruit bats from Malaysia using molecular methods.

Molecular phylogenetics and systematics of five genera of Malaysian murine rodents (Maxomys, Sundamys, Leopoldamys, Niviventer and Rattus) inferred from partial mitochondrial cytochrome c oxidase subunit I (COI) gene.

by M.T. Abdullah, PhD

Nur Aida Md Tamrin and M. T. Abdullah. 2011. Journal of Science and Technology in the Tropics 7: 75-86. (SCOPUS-indexed).

We genetically analysed 50 specimens of Murinae from Peninsular Malaysia and Sarawak, assigned to 12 species.... more We genetically analysed 50 specimens of Murinae from Peninsular Malaysia and Sarawak, assigned to 12 species. Phylogenetic analyses of partial mitochondrial cytochrome c oxidase subunit I (476 base pairs) using four methods, namely, neighbour-joining (NJ), maximum parsimony (MP), maximum likelihood (ML) and Bayesian method resulted in similar statistically supported clades with minimal change in branching order. The analyses discovered that there were intermediate form of Maxomys species within M. whiteheadi and M. ochraceiventer populations. They display same external morphology as M. whiteheadi but genetically closer to M. ochraceiventer. Craniodental measurements showed significant differences between the three populations. Rattus and Sundamys appeared not fully resolved while Leopoldamys and Niviventer were steadily clustered. The intraspecific geographic variation in some species agrees with previous studies on the vicariance scenario and diversification of flora and fauna in Malaysia and Borneo.

Nur Aida Md Tamrin and M. T. Abdullah. 2011. Journal of Science and Technology in the Tropics 7: 75-86. (SCOPUS-indexed).

A morphological analysis of Malaysian Kerivoula (Chiroptera, Vespertilionidae).

by M.T. Abdullah, PhD

Related study by Faisal Anwali Khan et al. 2010

Recent identification of new species within the genus Kerivoula from the Southeast Asian region has indicated that... more Recent identification of new species within the genus Kerivoula from the Southeast Asian region has indicated that this genus was understudied and currently underestimated in terms of its species diversity. Thus, this morphological study was carried out to record and analyse the morphological characters of available specimens of Malaysian Kerivoula from the Museum of Zoology, Universiti Malaysia Sarawak. Thirty-one external, skull and dental characters were taken and analysed using the multivariate analysis, dicriminant function analysis. As the result, six groupings of Kerivoula was identified, namely K. intermedia, K. hardwickii, K. pellucida, K. lenis and K. papillosa which were divided into two distinctive groupings of K. papillosa type large (K.
papillosa type L, hereafter) and K. papillosa type small (K. papillosa type S, hereafter). Variable dentary length was identified as the best predictor to characterize each group of Kerivoula. The
separation of the K. papillosa specimens into two separate morphotypes were characterised by their different sizes whereby the former group was larger in size compared to the latter. It is suggested that each represents an independent species even though both morphotypes occur sympatrically. The homogenising effect of the previous environmental events might have been the primary factor of the sympatric occurrence of both morphotypes. Nevertheless, further study regarding ecology, morphology and genetics should be carried out to provide a better insight regarding the cryptic population of K. papillosa in Borneo and Malaysia.

Hasan, N.H., Abdullah, M.T. 2011. Mammal Study 36: 87-97.

Probes containing runs of guanines provide insights into the biophysics and bioinformatics of Affymetrix GeneChips

by Andrew Harrison

Evolving Regular Expressions for GeneChip Probe Performance Prediction

by Andrew Harrison