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1.  Novel Hybrid GPU–CPU Implementation of Parallelized Monte Carlo Parametric Expectation Maximization Estimation Method for Population Pharmacokinetic Data Analysis 
The AAPS Journal  2013;15(4):1212-1221.
The development of a population PK/PD model, an essential component for model-based drug development, is both time- and labor-intensive. A graphical-processing unit (GPU) computing technology has been proposed and used to accelerate many scientific computations. The objective of this study was to develop a hybrid GPU–CPU implementation of parallelized Monte Carlo parametric expectation maximization (MCPEM) estimation algorithm for population PK data analysis. A hybrid GPU–CPU implementation of the MCPEM algorithm (MCPEMGPU) and identical algorithm that is designed for the single CPU (MCPEMCPU) were developed using MATLAB in a single computer equipped with dual Xeon 6-Core E5690 CPU and a NVIDIA Tesla C2070 GPU parallel computing card that contained 448 stream processors. Two different PK models with rich/sparse sampling design schemes were used to simulate population data in assessing the performance of MCPEMCPU and MCPEMGPU. Results were analyzed by comparing the parameter estimation and model computation times. Speedup factor was used to assess the relative benefit of parallelized MCPEMGPU over MCPEMCPU in shortening model computation time. The MCPEMGPU consistently achieved shorter computation time than the MCPEMCPU and can offer more than 48-fold speedup using a single GPU card. The novel hybrid GPU–CPU implementation of parallelized MCPEM algorithm developed in this study holds a great promise in serving as the core for the next-generation of modeling software for population PK/PD analysis.
PMCID: PMC3787213  PMID: 24002801
GPU computing; modeling and simulation; Monte Carlo parametric expectation maximization method; nonlinear mixed-effect model; population data analysis
3.  Asymptomatic left ventricular dysfunction with long-term clozapine treatment for schizophrenia: a multicentre cross-sectional cohort study 
Open Heart  2014;1(1):e000030.
Patients with schizophrenia treated with clozapine are at risk of acute myocarditis and dilated cardiomyopathy. However, there are no data on the prevalence of subclinical cardiomyopathy or its associations.
100 consecutive patients with schizophrenia treated with clozapine for >1 year and without a history of cardiac pathology (group 1), 21 controls with a history of schizophrenia treated with non-clozapine antipsychotics for >1 year (group 2) and 20 controls without schizophrenia (group 3) were studied. Comprehensive evaluation by clinical examination, ECG, transthoracic echocardiography including left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) and biochemical profiles were performed.
Patients with schizophrenia were of similar age, but had higher body mass index (BMI), rates of smoking and hyperlipidaemia than controls. Patients with schizophrenia had received clozapine or non-clozapine antipsychotics for a mean duration of 6.8±5.3 and 9.7±6.1 years, respectively. Patients taking clozapine demonstrated globally impaired LVEF (58.3%: group 1 vs 62.2%: group 2 vs 64.8%: group 3, p<0.001) and GLS (−16.7%: group 1 vs −18.6%: group 2 vs −20.2%: group 3, p<0.001). Moreover, LVEF was <50% in 9/100 (9%) patients receiving clozapine and in non-clozapine schizophrenia patients or healthy controls, but this was not statistically significantly different (analysis of covariance, p=0.19). Univariate analysis in patients taking clozapine found that impaired LV was not predicted by high-sensitivity troponin T, but was associated with features of the metabolic syndrome (including increased triglycerides, low high-density lipoprotein cholesterol (HDL-C), high-sensitivity C reactive protein and BMI), elevated neutrophil count, elevated heart rate, smoking and N-terminal probrain natriuretic peptide. In patients taking clozapine, multivariable analysis identified elevated neutrophil count and low HDL-C as the only independent predictors of impaired GLS.
Asymptomatic mild LV impairment is common in patients with schizophrenia receiving long-term clozapine treatment and is associated with neutrophilia and low HDL-C.
PMCID: PMC4195917  PMID: 25332789
5.  CT features and quantification of the characteristics of adrenocortical carcinomas on unenhanced and contrast-enhanced studies 
Clinical radiology  2011;67(1):38-46.
To describe the morphological and contrast-agent washout characteristics of adrenocortical carcinomas (ACCs) on computed tomography (CT).
Forty-one patients with histopathologically proven ACCs were retrospectively evaluated. The morphological characteristics of the ACCs were documented and compared with surgical and histopathological findings. The percentage of contrast agent enhancement washout (PEW) and relative PEW (RPEW) were calculated for 17 patients who had the combination of unenhanced, portal venous, and 15 min delayed phase images.
Characteristic imaging findings of ACCs included large size (38 of 41 tumours were >6 cm), well-defined margin with a thin enhancing rim (25 patients), and central stellate area of low attenuation on contrast-enhanced CT images (21 patients). Tumour extension into the inferior vena cava (IVC) with associated thrombus was identified on CT in six (14.6%) patients. Of 17 tumours evaluated, 12 (71%) had a PEW value of ≤60%, and 14 (82%) had an RPEW value of ≤40%.
Large size, a well-defined margin with a thin enhancing rim, central low attenuation, and a predilection for extension into the IVC are typical morphological characteristics of ACC on CT. The contrast-washout characteristics of ACCs, in concordance with their malignant nature, share those of non-adenomas rather than adenomas.
PMCID: PMC3889671  PMID: 21783181
6.  Structural basis for ribosomal 16S rRNA cleavage by the cytotoxic domain of colicin E3 
Nature structural & molecular biology  2010;17(10):1241-1246.
The toxin colicin E3 targets the 30S subunit of bacterial ribosomes and cleaves a phosphodiester bond in the decoding center. We present the crystal structure of the 70S ribosome in complex with the cytotoxic domain of colicin E3 (E3-rRNase). The structure reveals how the rRNase domain of colicin binds to the A site of the decoding center in the 70S ribosome and cleaves 16S rRNA between A1493 and G1494. The cleavage mechanism involves the concerted action of conserved residues Glu62 and His58 of the cytotoxic domain of colicin E3 that activate the 16S rRNA for 2′ OH induced hydrolysis. Conformational changes observed for E3-rRNase, 16S rRNA and Helix 69 of 23S rRNA suggest that a dynamic binding platform is required for colicin E3 binding and function.
PMCID: PMC3755339  PMID: 20852642
7.  Validation of motion correction techniques for liver CT perfusion studies 
The British Journal of Radiology  2012;85(1016):e514-e522.
Motion in images potentially compromises the evaluation of temporally acquired CT perfusion (CTp) data; image registration should mitigate this, but first requires validation. Our objective was to compare the relative performance of manual, rigid and non-rigid registration techniques to correct anatomical misalignment in acquired liver CTp data sets.
17 data sets in patients with liver tumours who had undergone a CTp protocol were evaluated. Each data set consisted of a cine acquisition during a breath-hold (Phase 1), followed by six further sets of cine scans (each containing 11 images) acquired during free breathing (Phase 2). Phase 2 images were registered to a reference image from Phase 1 cine using two semi-automated intensity-based registration techniques (rigid and non-rigid) and a manual technique (the only option available in the relevant vendor CTp software). The performance of each technique to align liver anatomy was assessed by four observers, independently and blindly, on two separate occasions, using a semi-quantitative visual validation study (employing a six-point score). The registration techniques were statistically compared using an ordinal probit regression model.
306 registrations (2448 observer scores) were evaluated. The three registration techniques were significantly different from each other (p=0.03). On pairwise comparison, the semi-automated techniques were significantly superior to the manual technique, with non-rigid significantly superior to rigid (p<0.0001), which in turn was significantly superior to manual registration (p=0.04).
Semi-automated registration techniques achieved superior alignment of liver anatomy compared with the manual technique. We hope this will translate into more reliable CTp analyses.
PMCID: PMC3587085  PMID: 22374283
8.  Prospective randomised evaluation of traditional Chinese medicine combined with chemotherapy: a randomised phase II study of wild toad extract plus gemcitabine in patients with advanced pancreatic adenocarcinomas 
British Journal of Cancer  2012;107(3):411-416.
An intravenous formulated extract of the venom of the wild toad Bufo bufo gargarizans Cantor or Bufo melanostictus Schneider, huachansu, is currently used in China for the treatment of lung, liver, pancreatic, and colorectal cancers. We performed a randomised, single-blinded, phase II clinical study of huachansu plus gemcitabine versus placebo plus gemcitabine in patients with locally advanced and/or metastatic pancreatic adenocarcinomas.
Patients with tissue-proven locally advanced and/or metastatic pancreatic adenocarinoma were randomly assigned to receive either gemcitabine 1000 mg m−2 on days 1, 8, and 15 with huachansu 20 ml m−2 daily for 21 days (arm A) or placebo (arm B); treatment cycles were 28 days in length. Primary end point was 4-month progression-free overall survival (PFS); secondary end points were objective radiographical response rate (ORR), time to progression (TTP), and toxicity.
A total of 80 subjects were enrolled; 76 patients were evaluable (received at least 1 week therapy). Median overall survival was 160 days for arm A and 156 days for arm B (P=0.339); ORR was 9 and 3% in arms A and B, respectively (P=0.332), median TTP was 98 and 115 days, respectively (P=0.825); the median 4-month PFS was 99 and 98 days, respectively (P=0.679).
Huachansu when combined with gemcitabine did not improve the outcome of patients with locally advanced and/or metastatic pancreatic cancer.
PMCID: PMC3405220  PMID: 22782343
huachansu; gemcitabine; pancreatic cancer; traditional Chinese medicine
9.  Yttrium-90 internal pair production imaging using first generation PET/CT provides high-resolution images for qualitative diagnostic purposes 
The British Journal of Radiology  2012;85(1015):1018-1019.
Yttrium-90 (90Y) internal pair production can be imaged by positron emission tomography (PET)/CT and is superior to bremsstrahlung single-photon emission CT/CT for evaluating hepatic 90Y microsphere biodistribution. We illustrate a case of 90Y imaging using first generation PET/CT technology, producing high-quality images for qualitative diagnostic purposes.
PMCID: PMC3474067  PMID: 21976634
10.  Trends in subtrochanteric, diaphyseal, and distal femur fractures, 1984–2007 
Osteoporosis International  2011;23(6):1721-1726.
The incidence of non-hip femur fractures increased between 1984 and 2007, with an increase in the rates for women after 1996.
Recent reports have suggested that non-hip femur fractures may be decreasing over time, similar to proximal femur fractures.
Incidence rates for non-hip femur fractures among Olmsted County, Minnesota, residents were assessed before and after 1995 when the oral bisphosphonate, alendronate, was approved in the USA.
From 1984 to 2007, 727 non-hip femur fractures were observed in 690 Olmsted County residents (51% female [median age, 71.6 years] and 49% male [21.4 years]). Altogether, 20% of the fractures were subtrochanteric, 51% were diaphyseal, and 29% involved the distal femur. Causes included severe trauma in 51%, minimal to moderate trauma in 34%, and pathologic causes in 15%. The overall age- and sex-adjusted annual incidence of first non-hip femur fracture was 26.7 per 100,000 (25.0 per 100,000 for women and 26.6 per 100,000 for men). Incidence rates increased with age and were greater in women than men. Between 1984–1995 and 1996–2007, age-adjusted rates increased significantly for women (20.4 vs. 28.7 per 100,000; p=0.002) but not for men (22.4 vs. 29.5 per 100,000; p=0.202).
The incidence of first non-hip femur fractures rose between 1984 and 2007, with an increase in the rates for women after 1995.
PMCID: PMC3266989  PMID: 21909727
Aging; Incidence; Non-hip femoral fracture; Population-based study; Subtrochanteric fracture
11.  Genome-wide association study in a Chinese population identifies a susceptibility locus for type 2 diabetes at 7q32 near PAX4 
Diabetologia  2013;56(6):1291-1305.
Most genetic variants identified for type 2 diabetes have been discovered in European populations. We performed genome-wide association studies (GWAS) in a Chinese population with the aim of identifying novel variants for type 2 diabetes in Asians.
We performed a meta-analysis of three GWAS comprising 684 patients with type 2 diabetes and 955 controls of Southern Han Chinese descent. We followed up the top signals in two independent Southern Han Chinese cohorts (totalling 10,383 cases and 6,974 controls), and performed in silico replication in multiple populations.
We identified CDKN2A/B and four novel type 2 diabetes association signals with p < 1 × 10−5 from the meta-analysis. Thirteen variants within these four loci were followed up in two independent Chinese cohorts, and rs10229583 at 7q32 was found to be associated with type 2 diabetes in a combined analysis of 11,067 cases and 7,929 controls (pmeta = 2.6 × 10−8; OR [95% CI] 1.18 [1.11, 1.25]). In silico replication revealed consistent associations across multiethnic groups, including five East Asian populations (pmeta = 2.3 × 10−10) and a population of European descent (p = 8.6 × 10−3). The rs10229583 risk variant was associated with elevated fasting plasma glucose, impaired beta cell function in controls, and an earlier age at diagnosis for the cases. The novel variant lies within an islet-selective cluster of open regulatory elements. There was significant heterogeneity of effect between Han Chinese and individuals of European descent, Malaysians and Indians.
Our study identifies rs10229583 near PAX4 as a novel locus for type 2 diabetes in Chinese and other populations and provides new insights into the pathogenesis of type 2 diabetes.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-013-2874-4) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
PMCID: PMC3648687  PMID: 23532257
Chinese; Diabetes; East Asians; Genetics; Genome-wide association study
12.  ABCB1 polymorphism predicts escitalopram dose needed for remission in major depression 
Translational Psychiatry  2012;2(11):e198-.
The ATP-binding cassette family of transporter proteins, subfamily B (MDR/TAP), member 1 (ABCB1) (P-glycoprotein) transporter is a key component of the blood–brain barrier. Many antidepressants are subject to ABCB1 efflux. Functional polymorphisms of ABCB1 may influence central nervous system bioavailability of antidepressants subject to efflux. Single-nucleotide polymorphisms (SNPs) at rs1045642 (C3435T) of ABCB1 have been associated with efflux pump efficiency. This may explain part of the interindividual variation in antidepressant dose needed to remit. Individuals (N=113) with DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) major depressive disorder (MDD) were treated with escitalopram (ESC) or venlafaxine (VEN) over 8 weeks. The17-item Hamilton Depression Rating Scale was assessed serially, blind to genotype. SNP rs1045642 of ABCB1 along with two SNPs previously reported to be in linkage disequilibrium with it (rs2032582 and rs1128503) were genotyped. Demographic features, clinical features, P450 metabolizer status and 5-HTTLPR (serotonin-transporter-linked promoter region) genotype were controlled for. Carriers of rs1045642 TT needed on average 11 mg of ESC to remit, whereas TC and CC carriers required 24 and 19 mg, respectively (P=0.0001). This equates to a 2.0- (95% confidence interval=1.5–3.4; P<0.001) fold greater ESC dose needed to remit for C carriers compared with TT carriers at rs1045642. Of VEN-treated subjects carrying TT genotype at rs1045642, 73.3% remitted compared with 12.5% for CC genotype (odds ratio=6.69; 95% confidence interval=1.72–25.9, P=0.006). These data suggest that antidepressant dose needed to remit can be predicted by an ABCB1 SNP. This has the potential clinical translation implications for dose selection and remission from MDD.
PMCID: PMC3565756  PMID: 23188198
ABCB1; pharmacogenetics; antidepressant; major depression; blood–brain barrier; P-glycoprotein
13.  Visceral adipose tissue, but not waist circumference is a better measure of metabolic risk in Singaporean Chinese and Indian men 
Nutrition & Diabetes  2012;2(8):e38-.
Visceral adipose tissue (VAT) is an independent risk factor in cardiometabolic diseases and is commonly measured by computed tomography (CT). It is measured clinically by waist circumference (WC). The L4/5 intervertebral space VAT (L4/5 VAT) is traditionally used to represent total VAT volume. We set out to determine (1) the level of intervertebral space on CT that best approximates the total VAT volume; (2) compare the association between WC and VAT in Singaporean Chinese and Indian; and (3) examine the correlation between VAT and cardiometabolic risk factors.
A total of 60 Chinese and 60 Asian Indian men older than 60 years were recruited. Their medical history was taken and anthropometry was measured. Fasting glucose, insulin, lipids, adipokines and inflammatory markers were measured. Insulin resistance was evaluated by homeostasis model assessment-insulin resistance. VAT was determined by CT. Total VAT volume was calculated in 22 patients from VAT areas at seven intervertebral levels. The optimal VAT area most representative of total VAT volume was determined and used for all patients to approximate total VAT volume.
The VAT area at L2/3 intervertebral space (L2/3 VAT) correlated almost perfectly with VAT volume (R2=0.974 and 0.946 for Chinese and Indians, respectively). Subjects from the two races had similar height, weight, body mass index (BMI), WC and L2/3 VAT but more Indian men had hypertension, hyperlipidemia and type 2 diabetes mellitus. WC was correlated with the L2/3 VAT area in both Chinese (r=0.484, P<0.001) and Indian subjects (r=0.366, P=0.004) without racial difference (P=0.2 for interaction term). L2/3 VAT also correlated better with cardiometabolic risk factors, adipokines and C-reactive protein than WC, BMI or L4/5 VAT.
The L2-L3 intervertebral space was the best anatomic level for a single-slice CT cross-sectional area measurement of VAT to approximate total body visceral adipose volume in this population of Chinese and Asian Indian men older than 60 years. L2/3 VAT was better correlated with multiple cardiovascular risk factors, adipokines and inflammatory marker than either L4/5 VAT, WC or BMI.
PMCID: PMC3432182  PMID: 23448802
visceral adipose tissue; waist circumference; metabolic syndrome; Chinese; Asian Indian; Singapore
14.  Reduced SMAD7 leads to overactivation of TGF-beta signaling in MDS that can be reversed by a specific inhibitor of TGF-beta receptor I kinase 
Cancer research  2010;71(3):955-963.
Even though myelodysplastic syndromes are characterized by ineffective hematopoiesis, the molecular alterations that lead to marrow failure have not been well elucidated. We have previously shown that the myelosuppressive TGF-β pathway is constitutively activated in MDS progenitors. Since there is conflicting data about upregulation of extracellular TGF-b levels in MDS, we wanted to determine the molecular basis of TGF-β pathway overactivation and consequent hematopoietic suppression in this disease. We observed that SMAD7, a negative regulator of TGF-β receptor I (TBRI) kinase is markedly decreased in a large meta-analysis of gene expression studies from MDS marrow derived CD34+ cells. SMAD7 protein was also found to be significantly decreased in MDS marrow progenitors when examined immunohistochemically in a bone marrow tissue microarray. Reduced expression of SMAD7 in hematopoietic cells led to increased TGF-β mediated gene transcription and enhanced sensitivity to TGF-β mediated suppressive effects. The increased TGF-β signaling due to SMAD7 reduction could be effectively inhibited by a novel clinically relevant TBRI (ALK5 kinase) inhibitor, LY-2157299. LY-2157299 could inhibit TGF-β mediated SMAD2 activation and hematopoietic suppression in primary hematopoietic stem cells. Furthermore, in vivo administration of LY-2157299 ameliorated anemia in a TGF-β overexpressing transgenic mouse model of bone marrow failure. Most importantly, treatment with LY-2157199 stimulated hematopoiesis from primary MDS bone marrow specimens. These studies demonstrate that reduction in SMAD7 is a novel molecular alteration in MDS that leads to ineffective hematopoiesis by activating of TGF-β signaling in hematopoietic cells. These studies also illustrate the therapeutic potential of TBRI inhibitors in MDS.
PMCID: PMC3032816  PMID: 21189329
Myelodysplasia; TGF; SMAD7; LY-2157299
15.  Intra-tumour genetic heterogeneity and poor chemoradiotherapy response in cervical cancer 
British Journal of Cancer  2010;104(2):361-368.
Intra-tumour genetic heterogeneity has been reported in both leukaemias and solid tumours and is implicated in the development of drug resistance in CML and AML. The role of genetic heterogeneity in drug response in solid tumours is unknown.
To investigate intra-tumour genetic heterogeneity and chemoradiation response in advanced cervical cancer, we analysed 10 cases treated on the CTCR-CE01 clinical study. Core biopsies for molecular profiling were taken from four quadrants of the cervix pre-treatment, and weeks 2 and 5 of treatment. Biopsies were scored for cellularity and profiled using Agilent 180k human whole genome CGH arrays. We compared genomic profiles from 69 cores from 10 patients to test for genetic heterogeneity and treatment effects at weeks 0, 2 and 5 of treatment.
Three patients had two or more distinct genetic subpopulations pre-treatment. Subpopulations within each tumour showed differential responses to chemoradiotherapy. In two cases, there was selection for a single intrinsically resistant subpopulation that persisted at detectable levels after 5 weeks of chemoradiotherapy. Phylogenetic analysis reconstructed the order in which genomic rearrangements occurred in the carcinogenesis of these tumours and confirmed gain of 3q and loss of 11q as early events in cervical cancer progression.
Selection effects from chemoradiotherapy cause dynamic changes in genetic subpopulations in advanced cervical cancers, which may explain disease persistence and subsequent relapse. Significant genetic heterogeneity in advanced cervical cancers may therefore be predictive of poor outcome.
PMCID: PMC3031882  PMID: 21063398
heterogeneity; cervical cancer; chemoradiotherapy; array CGH; selection
16.  Structure and Activity of a Novel Archaeal β-CASP Protein with N-Terminal KH Domains 
Structure(London, England:1993)  2011;19(5):622-632.
MTH1203, a β-CASP metallo-β-lactamase family nuclease from the archaeon Methanothermobacter thermautotrophicus, was identified as a putative nuclease that might contribute to RNA processing. The crystal structure of MTH1203 reveals that, in addition to the metallo-β-lactamase nuclease and the β-CASP domains, it contains two contiguous KH domains that are unique to MTH1203 and its orthologs. RNA-binding experiments indicate that MTH1203 preferentially binds U-rich sequences with a dissociation constant in the micromolar range. In vitro nuclease activity assays demonstrated that MTH1203 is a zinc-dependent nuclease. MTH1203 is also shown to be a dimer and, significantly, this dimerization enhances the nuclease activity. Transcription termination in archaea produces mRNA transcripts with U-rich 3′ ends that could be degraded by MTH1203 considering its RNA-binding specificity. We hypothesize that this nuclease degrades mRNAs of proteins targeted for degradation and so regulates archaeal RNA turnover, possibly in concert with the exosome.
Graphical Abstract
► MTH1203 combines RNA-processing and binding domains, unique to archaea ► MTH1203 is a Zn-dependent β-CASP RNase that functions as a dimer ► The MBL domain of MTH1203 binds U-rich sequences with a Kd in the micromolar range ► We propose MTH1203 acts with the proteasome degrading mRNAs of aberrant proteins
PMCID: PMC3095777  PMID: 21565697
17.  Arthritis in the Canadian Aboriginal Population: North-South Differences in Prevalence and Correlates* *This article is part of a joint publication initiative between Preventing Chronic Disease and Chronic Diseases in Canada. Preventing Chronic Disease is the secondary publisher, while Chronic Diseases in Canada is the primary publisher.  
Preventing Chronic Disease  2010;8(1):A04.
Information on arthritis and other musculoskeletal disorders among Aboriginal people is sparse. Survey data show that arthritis and rheumatism are among the most commonly reported chronic conditions and their prevalence is higher than among non-Aboriginal people.
To describe the burden of arthritis among Aboriginal people in northern Canada and demonstrate the public health significance and social impact of the disease.
Using cross-sectional data from more than 29 000 Aboriginal people aged 15 years and over who participated in the Aboriginal Peoples Survey 2006, we assessed regional differences in the prevalence of arthritis and its association with other risk factors, co-morbidity and health care use.
The prevalence of arthritis in the three northern territories ("North") is 12.7% compared to 20.1% in the provinces ("South") and is higher among females than males in both the North and South. The prevalence among Inuit is lower than among other Aboriginal groups. Individuals with arthritis are more likely to smoke, be obese, have concurrent chronic diseases, and are less likely to be employed. Aboriginal people with arthritis utilized the health care system more often than those without the disease.
Aboriginal-specific findings on arthritis and other chronic diseases as well as recognition of regional differences between North and South will enhance program planning and help identify new priorities in health promotion.
arthritis, Aboriginal people, Northern Canada, Inuit, First Nations, Métis, North American Indians, Aboriginal Peoples Survey
PMCID: PMC3044015  PMID: 21159216
18.  Phase I Trial of a Combination of the Multikinase Inhibitor Sorafenib and the Farnesyltransferase Inhibitor Tipifarnib in Advanced Malignancies 
We evaluated the safety, maximum tolerated dose, pharmacokinetics, and biologic effects of the combination of the Raf-1, RET, KIT, platelet-derived growth factor receptor (PDGFR) and VEGFR2 kinase inhibitor sorafenib and the farnesyltransferase inhibitor tipifarnib.
A standard 3+3 phase I dose-escalation design was used with a 28-day cycle (sorafenib daily and tipifarnib for 21 days, by mouth).
Fifty patients were treated; 43 reached restaging evaluation after cycle 2. The most common side effects were grade 1–2 rash, hyperglycemia and diarrhea. Dose-limiting toxicity was rash, and the recommended phase II dose is sorafenib 400 mg po qam/200 mg po qpm and tipifarnib po 100 mg BID. Despite the low doses of tipifarnib, one-quarter of patients had ≥50% reduction in farnesyltransferase (FTase) levels. Interestingly, 6 of 8 patients with medullary thyroid cancer (MTC) had durable stable disease (N=3) or partial remissions (N=3), lasting 12 to 26+ months. Five of the six responders had available tissue, and RET gene mutations were identified in them. Prolonged (≥ 6 months) stable disease was also seen in nine patients as follows: papillary thyroid cancer (N=4; 18+ to 27+ months); adrenocortical cancer (N=2; 7 and 11 months); and one each of melanoma (PDGFR mutation-positive) (14 months), renal (6 months) and pancreatic cancer (6 months).
Our study shows that the combination of tipifarnib and sorafenib is well tolerated. Activity was seen, especially in patients with medullary thyroid cancer, a tumor characterized by RET mutations.
PMCID: PMC2784003  PMID: 19903778
tipifarnib; sorafenib; thyroid cancer; RET kinase; Phase I
19.  A Randomised, Cross-Over, Placebo-Controlled Study of Aloe vera in Patients with Irritable Bowel Syndrome: Effects on Patient Quality of Life 
ISRN Gastroenterology  2010;2011:206103.
Background. Irritable bowel syndrome (IBS) is a chronic, difficult to treat condition. The efficacy of Aloe vera in treating IBS symptoms is not yet proven. The purpose of this study was to determine if Aloe vera is effective in improving quality of life. Methods. A multicentre, randomised, double-blind, cross-over placebo controlled study design. Patients were randomised to Aloe vera, wash-out, placebo or placebo, washout, Aloe vera. Each preparation (60 mL) was taken orally twice a day. Patient quality of life was measured using the Gastrointestinal Symptoms Rating Score, Irritable Bowel Syndrome Quality of Life, EuroQol and the Short-Form-12 at baseline and treatment periods 1 and 2. Results. A total of 110 patients were randomised, but only 47 completed all questionnaires and both study arms. Statistical analysis showed no difference between the placebo and Aloe vera treatment in quality of life. Discussion. This study was unable to show that Aloe vera was superior to placebo in improving quality of life. Drop outs and other confounding factors may have impacted on the power of the study to detect a clinically important difference. Conclusion. This study failed to find Aloe vera superior to placebo in improving quality of life proven Irritable Bowel Syndrome patients.
PMCID: PMC3168391  PMID: 21991499
20.  Synovial tissue hypoxia and inflammation in vivo 
Annals of the Rheumatic Diseases  2010;69(7):1389-1395.
Hypoxia is a microenvironmental feature in the inflamed joint, which promotes survival advantage for cells. The aim of this study was to examine the relationship of partial oxygen pressure in the synovial tissue (tPO2) in patients with inflammatory arthritis with macroscopic/microscopic inflammation and local levels of proinflammatory mediators.
Patients with inflammatory arthritis underwent full clinical assessment and video arthroscopy to quantify macroscopic synovitis and measure synovial tPO2 under direct visualisation. Cell specific markers (CD3 (T cells), CD68 (macrophages), Ki67 (cell proliferation) and terminal deoxynucleotidyl transferase dUTP nick end labelling (cell apoptosis)) were quantified by immunohistology. In vitro migration was assessed in primary and normal synoviocytes (synovial fibroblast cells (SFCs)) using a wound repair scratch assay. Levels of tumour necrosis factor α (TNFα), interleukin 1β (IL1β), interferon γ (IFNγ), IL6, macrophage inflammatory protein 3α (MIP3α) and IL8 were quantified, in matched serum and synovial fluid, by multiplex cytokine assay and ELISA.
The tPO2 was 22.5 (range 3.2–54.1) mm Hg and correlated inversely with macroscopic synovitis (r=−0.421, p=0.02), sublining CD3 cells (−0.611, p<0.01) and sublining CD68 cells (r=−0.615, p<0.001). No relationship with cell proliferation or apoptosis was found. Primary and normal SFCs exposed to 1% and 3% oxygen (reflecting the median tPO2 in vivo) induced cell migration. This was coupled with significantly higher levels of synovial fluid tumour necrosis factor α (TNFα), IL1β, IFNγ and MIP3α in patients with tPO2 <20 mm Hg (all p values <0.05).
This is the first study to show a direct in vivo correlation between synovial tPO2, inflammation and cell migration, thus it is proposed that hypoxia is a possible primary driver of inflammatory processes in the arthritic joint.
PMCID: PMC2946116  PMID: 20439288
21.  Phase II trial of imatinib mesylate in patients with metastatic melanoma 
British Journal of Cancer  2008;99(5):734-740.
Metastatic melanoma cells express a number of protein tyrosine kinases (PTKs) that are considered to be targets for imatinib. We conducted a phase II trial of imatinib in patients with metastatic melanoma expressing at least one of these PTKs. Twenty-one patients whose tumours expressed at least one PTK (c-kit, platelet-derived growth factor receptors, c-abl, or abl-related gene) were treated with 400 mg of imatinib twice daily. One patient with metastatic acral lentiginous melanoma, containing the highest c-kit expression among all patients, had dramatic improvement on positron emission tomographic scan at 6 weeks and had a partial response lasting 12.8 months. The responder had a substantial increase in tumour and endothelial cell apoptosis at 2 weeks of treatment. Imatinib was fairly well tolerated: no patient required treatment discontinuation because of toxicity. Fatigue and oedema were the only grade 3 or 4 toxicities that occurred in more than 10% of the patients. Imatinib at the studied dose had minimal clinical efficacy as a single-agent therapy for metastatic melanoma. However, based on the characteristics of the responding tumour in our study, clinical activity of imatinib, specifically in patients with melanoma with certain c-kit aberrations, should be examined.
PMCID: PMC2528157  PMID: 18728664
phase II; imatinib; metastatic melanoma; protein tyrosine kinases; antiangiogenesis
22.  Infected left ventricular pseudoaneurysm 
Heart  2006;92(9):1237.
PMCID: PMC1861146  PMID: 16908695
Images in cardiology
23.  Conformational flexibility and molecular interactions of an archaeal homologue of the Shwachman-Bodian-Diamond syndrome protein 
Defects in the human Shwachman-Bodian-Diamond syndrome (SBDS) protein-coding gene lead to the autosomal recessive disorder characterised by bone marrow dysfunction, exocrine pancreatic insufficiency and skeletal abnormalities. This protein is highly conserved in eukaryotes and archaea but is not found in bacteria. Although genomic and biophysical studies have suggested involvement of this protein in RNA metabolism and in ribosome biogenesis, its interacting partners remain largely unknown.
We determined the crystal structure of the SBDS orthologue from Methanothermobacter thermautotrophicus (mthSBDS). This structure shows that SBDS proteins are highly flexible, with the N-terminal FYSH domain and the C-terminal ferredoxin-like domain capable of undergoing substantial rotational adjustments with respect to the central domain. Affinity chromatography identified several proteins from the large ribosomal subunit as possible interacting partners of mthSBDS. Moreover, SELEX (Systematic Evolution of Ligands by EXponential enrichment) experiments, combined with electrophoretic mobility shift assays (EMSA) suggest that mthSBDS does not interact with RNA molecules in a sequence specific manner.
It is suggested that functional interactions of SBDS proteins with their partners could be facilitated by rotational adjustments of the N-terminal and the C-terminal domains with respect to the central domain. Examination of the SBDS protein structure and domain movements together with its possible interaction with large ribosomal subunit proteins suggest that these proteins could participate in ribosome function.
PMCID: PMC2695463  PMID: 19454024
24.  Video assisted thoracic surgery in the management of spontaneous pneumothorax: the current status 
Postgraduate Medical Journal  2006;82(965):179-185.
Over the past decade, video assisted thoracic surgery (VATS) has changed the way spontaneous pneumothorax (SP) is managed. Benefits of VATS include less postoperative pain, shorter hospital stay, and attenuated postoperative inflammatory response are evident compared with open thoracic procedures. Furthermore, the increasing acceptance by patients and referring physicians is testament to its success. Recent studies and the authors decade of experience in management of SP by VATS show that it is quick, safe, and effective, with recurrence rates generally comparable to open procedures, with some exceptions. However, selecting the correct procedure and patient, as well as knowing the limitations of the surgeons and techniques are paramount for success. Even to this day, there are considerable variations in the treatment of SP and large scale controlled studies are needed to better define timing of surgery and the role of the different procedures in the treatment and prevention of SP.
PMCID: PMC2563704  PMID: 16517799
thoracoscopy; video assisted thoracic surgery; spontaneous pneumothorax
25.  Uncorrected refractive error in Singapore teenagers 
To study the prevalence rate of uncorrected refractive error and associated risk factors among Singapore schoolchildren aged 12–16 years (grade 7).
A cross sectional study of 628 participants (participation rate 99.8%) was conducted in two schools. An interviewer led questionnaire asking about sociodemographic variables and risk factors was administered. Refractive errors were measured using a table mounted autorefractor. Participants with habitual visual acuity (VA) of 0.2 logMAR or worse underwent subjective refraction. Uncorrected refractive error was defined as improvement of at least 0.2 logMAR in best corrected visual acuity after subjective refraction.
The prevalence rate of uncorrected refractive error was 22.3% (95% confidence interval (CI) 19.0% to 25.5%). The multivariate adjusted odds ratio of uncorrected refractive error in students with the lowest academic ability was 2.24 (95% CI 1.34 to 3.73). Increasing time interval since the last visit to an eye care provider increased the risk of uncorrected refractive error (trend p = 0.001).
Uncorrected refractive error was a significant problem among Singapore students aged 12–16 years (grade 7). Uncorrected refractive error was more common among students with low academic ability or those who had not visited an eye care provider for a long time.
PMCID: PMC1860154  PMID: 16424534
refractive errors; children; cross sectional studies; Singapore

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