Publications by authors named "Changjiang Xu"

56 Publications

Left atrial appendage orifice area and morphology is closely associated with flow velocity in patients with nonvalvular atrial fibrillation.

BMC Cardiovasc Disord 2021 09 16;21(1):442. Epub 2021 Sep 16.

Department of Cardiology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, Jiangsu, China.

Background: Thromboembolic events are the most serious complication of atrial fibrillation (AF), and the left atrial appendage (LAA) is the most important site of thrombosis in patients with AF. During the period of COVID-19, a non-invasive left atrial appendage detection method is particularly important in order to reduce the exposure of the virus. This study used CT three-dimensional reconstruction methods to explore the relationship between LAA morphology, LAA orifice area and its mechanical function in patients with non-valvular atrial fibrillation (NVAF).

Methods: A total of 81 consecutive patients with NVAF (36 cases of paroxysmal atrial fibrillation and 45 cases of persistent atrial fibrillation) who were planned to undergo catheter radiofrequency ablation were enrolled. All patients were examined by transthoracic echocardiography (TTE), TEE, and computed tomography angiography (CTA) before surgery. The LAA orifice area was obtained according to the images of CTA. According to the left atrial appendage morphology, it was divided into chicken wing type and non-chicken wing type. At the same time, TEE was performed to determine left atrial appendage flow velocity (LAAFV), and the relationship between the left atrial appendage orifice area and LAAFV was analyzed.

Results: The LAAFV in Non-chicken wing group was lower than that in Chicken wing group (36.2 ± 15.0 cm/s vs. 49.1 ± 22.0 cm/s, p-value < 0.05). In the subgroup analysis, the LAAFV in Non-chicken wing group was lower than that in Chicken wing group in the paroxysmal AF (44.0 ± 14.3 cm/s vs. 60.2 ± 22.8 cm/s, p-value < 0.05). In the persistent AF, similar results were observed (29.7 ± 12.4 cm/s vs. 40.8 ± 17.7 cm/s, p-value < 0.05). The LAAFV in persistent AF group was lower than that in paroxysmal AF group (34.6 ± 15.8 cm/s vs. 49.9 ± 20.0 cm/s, p-value < 0.001). The LAAFV was negatively correlated with left atrial dimension (R = - 0.451, p-value < 0.001), LAA orifice area (R= - 0.438, p-value < 0.001) and left ventricular mass index (LVMI) (R= - 0.624, p-value < 0.001), while it was positively correlated with LVEF (R = 0.271, p-value = 0.014). Multiple linear regression analysis showed that LAA morphology (β = - 0.335, p-value < 0.001), LAA orifice area (β = -  0.185, p-value = 0.033), AF type (β = - 0.167, p-value = 0.043) and LVMI (β = - 0.465, p-value < 0.001) were independent factors of LAAFV.

Conclusions: The LAA orifice area is closely related to the mechanical function of the LAA in patients with NVAF. The larger LAA orifice area and LVMI, Non-chicken wing LAA and persistent AF are independent predictors of decreased mechanical function of LAA, and these parameters might be helpful for better management of LA thrombosis.
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http://dx.doi.org/10.1186/s12872-021-02242-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8443967PMC
September 2021

Nicotinamide phosphoribosyltransferase inhibitors selectively induce apoptosis of AML stem cells by disrupting lipid homeostasis.

Cell Stem Cell 2021 Jul 12. Epub 2021 Jul 12.

Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Department of Medicine, University of Toronto, ON, Canada; Division of Medical Oncology and Hematology, Department of Medicine, University Health Network, Toronto, ON, Canada. Electronic address:

Current treatments for acute myeloid leukemia (AML) are often ineffective in eliminating leukemic stem cells (LSCs), which perpetuate the disease. Here, we performed a metabolic drug screen to identify LSC-specific vulnerabilities and found that nicotinamide phosphoribosyltransferase (NAMPT) inhibitors selectively killed LSCs, while sparing normal hematopoietic stem and progenitor cells. Treatment with KPT-9274, a NAMPT inhibitor, suppressed the conversion of saturated fatty acids to monounsaturated fatty acids, a reaction catalyzed by the stearoyl-CoA desaturase (SCD) enzyme, resulting in apoptosis of AML cells. Transcriptomic analysis of LSCs treated with KPT-9274 revealed an upregulation of sterol regulatory-element binding protein (SREBP)-regulated genes, including SCD, which conferred partial protection against NAMPT inhibitors. Inhibition of SREBP signaling with dipyridamole enhanced the cytotoxicity of KPT-9274 on LSCs in vivo. Our work demonstrates that altered lipid homeostasis plays a key role in NAMPT inhibitor-induced apoptosis and identifies NAMPT inhibition as a therapeutic strategy for targeting LSCs in AML.
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http://dx.doi.org/10.1016/j.stem.2021.06.004DOI Listing
July 2021

Phase 1a study of the CDK4/6 inhibitor, FCN-437c, in Chinese patients with HR + /HER2- advanced breast cancer.

Invest New Drugs 2021 Jun 9. Epub 2021 Jun 9.

Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dong an Road, Shanghai, 200032, China.

Purpose This phase 1a, first-in-human study assessed the safety, maximum tolerated dose (MTD), pharmacokinetics (PK), and antitumor activity of FCN-437c, a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor. Methods The study enrolled female patients with HR + /HER2- advanced breast cancer (BC) who failed standard of care therapy. A 3 + 3 dose-escalation design was utilized with a starting dose of 50 mg daily for 3 weeks on and 1 week off treatment in 28-day cycles. Patients received escalating doses of FCN-437c monotherapy (50, 100, 200, 300, and 450 mg). Results Seventeen patients received FCN-437c 50 mg (n = 3), 100 mg (n = 3), 200 mg (n = 3), 300 mg (n = 6), and 450 mg (n = 2). Two patients who received the 450-mg dose experienced dose-limiting toxicities (DLTs; grade 4 thrombocytopenia and neutropenia); no DLT was observed at any other dose level. Frequently reported treatment-emergent adverse events (TEAEs) of any grade were hematological: leukopenia (94.1%), neutropenia (88.2%), anemia (64.7%), and thrombocytopenia (47.1%). Grade 3-4 TEAEs included neutropenia (64.7%) and leukopenia (47.1%). Exposure of FCN-437c increased almost proportionally to doses ranging from 50 to 200 mg. At doses from 200 to 450 mg, there appeared to be a trend of saturation. The MTD was determined to be 300 mg. Of 15 patients with measurable disease, nine (60.0%) patients experienced stable disease; no complete or partial responses were observed. Conclusions These results established an acceptable safety profile for FCN-437c in patients with advanced BC, and there were no unexpected signals relative to other CDK4/6 inhibitors. (NCT04488107; July 13, 2020).
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http://dx.doi.org/10.1007/s10637-021-01133-2DOI Listing
June 2021

Pharmacokinetics of Opicapone and Its Metabolites in Healthy White and Chinese Subjects.

Clin Pharmacol Drug Dev 2021 Apr 17. Epub 2021 Apr 17.

Clinical Trial Center, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Assessment of Clinical Drugs Risk and Individual Application Key Laboratory, Chinese Academy of Medical Sciences, Beijing, China.

Opicapone (OPC) is a third-generation catechol-O-methyltransferase inhibitor developed to treat Parkinson disease and motor fluctuations. This open-label, single-center, phase 1 study aimed to evaluate the pharmacokinetics (PK) of OPC and its metabolites when administered as single and multiple doses in healthy White and Chinese subjects. The study enrolled a total of 30 White and Chinese healthy subjects, equally balanced among groups. The first dose of OPC was administered orally as a single dose of 50 mg on day 1, followed by a 10-day once-daily treatment from day 5 to day 14. Plasma concentrations of OPC and its metabolites were measured at 0 to 72 and 0 to 144 hours after dosing for single dose and multiple dose, respectively. Moreover, urine concentrations of OPC and its metabolite were measured 0 to 24 hours after dosing. PK parameters were derived from noncompartmental analysis. Geometric mean ratios and 90% confidence intervals for the main PK parameters were conducted to evaluate the ethnic difference between White and Chinese subjects. The plasma and urine exposure of OPC and its metabolites in Chinese subjects were similar to those in White subjects. These results indicated that ethnicity had no significant impact on PK of OPC between White and Chinese subjects.
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http://dx.doi.org/10.1002/cpdd.922DOI Listing
April 2021

Synthesis and Anti-Tobacco Mosaic Virus/Fungicidal/Insecticidal/Antitumor Bioactivities of Natural Product Hemigossypol and Its Derivatives.

J Agric Food Chem 2021 Feb 22;69(4):1224-1233. Epub 2021 Jan 22.

State Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic Chemistry, College of Chemistry, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin 300071, People's Republic of China.

To further study the structure-activity relationship of gossypol, hemigossypol () and its derivatives (-) were successfully designed via structure simplification and chemically synthesized. The anti-tobacco mosaic virus (TMV), fungicidal, and insecticidal activities of them were tested systematically. Most of these derivatives exhibited excellent anti-TMV activity. Furthermore, these compounds also exhibited broad-spectrum fungicidal activities against 14 kinds of phytopathogenic fungi. In particular, hemigossypol acid lactone () was stable in the air. In terms of biological activity, it not only showed anti-TMV activity (inhibitory rates of 70.3, 65.4 and 72.4% at 500 μg/mL for inactivation, curative, and protection activity , respectively) comparable to ningnanmycin but also exhibited higher insecticidal activity against mosquito larvae (60%/0.25 mg/kg) than the commercial species rotenone. None of hemigossypol and the tested derivatives showed antitumor activities.
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http://dx.doi.org/10.1021/acs.jafc.0c06058DOI Listing
February 2021

Sphingosine-1-phosphate receptor 3 potentiates inflammatory programs in normal and leukemia stem cells to promote differentiation.

Blood Cancer Discov 2021 Jan 1;2(1):32-53. Epub 2020 Dec 1.

Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.

Acute myeloid leukemia (AML) is a caricature of normal hematopoiesis, driven from leukemia stem cells (LSC) that share some hematopoietic stem cell (HSC) programs including responsiveness to inflammatory signaling. Although inflammation dysregulates mature myeloid cells and influences stemness programs and lineage determination in HSC by activating stress myelopoiesis, such roles in LSC are poorly understood. Here, we show that S1PR3, a receptor for the bioactive lipid sphingosine-1-phosphate, is a central regulator which drives myeloid differentiation and activates inflammatory programs in both HSC and LSC. S1PR3-mediated inflammatory signatures varied in a continuum from primitive to mature myeloid states across AML patient cohorts, each with distinct phenotypic and clinical properties. S1PR3 was high in LSC and blasts of mature myeloid samples with linkages to chemosensitivity, while S1PR3 activation in primitive samples promoted LSC differentiation leading to eradication. Our studies open new avenues for therapeutic target identification specific for each AML subset.
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http://dx.doi.org/10.1158/2643-3230.BCD-20-0155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116590PMC
January 2021

Transcriptome Analyses Reveal Differential Transcriptional Profiles in Early- and Late-Dividing Porcine Somatic Cell Nuclear Transfer Embryos.

Genes (Basel) 2020 12 12;11(12). Epub 2020 Dec 12.

Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China.

Somatic cell nuclear transfer (SCNT) is not only a valuable tool for understanding nuclear reprogramming, but it also facilitates the generation of genetically modified animals. However, the development of SCNT embryos has remained an uncontrollable process. It was reported that the SCNT embryos that complete the first cell division sooner are more likely to develop to the blastocyst stage, suggesting their better developmental competence. Therefore, to better understand the underlying molecular mechanisms, RNA-seq of pig SCNT embryos that were early-dividing (24 h postactivation) and late-dividing (36 h postactivation) was performed. Our analysis revealed that early- and late-dividing embryos have distinct RNA profiles, and, in all, 3077 genes were differentially expressed. Gene ontology (GO)and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed that early-dividing embryos exhibited higher expression in genes that participated in the meiotic cell cycle, while enrichment of RNA processing- and translation-related genes was found in late-dividing embryos. There are also fewer somatic memory genes such as , and , which are abnormally activated or suppressed in early-dividing cloned embryos. These results show that early-dividing SCNT embryos have different transcriptional profiles than late-dividing embryos. Early division of SCNT embryos may be associated with their better reprogramming capacity, and somatic memory genes may act as a reprogramming barrier in pig SCNT reprogramming.
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http://dx.doi.org/10.3390/genes11121499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763450PMC
December 2020

and double-knockout pigs are resistant to PRRSV and TGEV and exhibit decreased susceptibility to PDCoV while maintaining normal production performance.

Elife 2020 09 2;9. Epub 2020 Sep 2.

State Key Laboratory of Animal Nutrition and Key Laboratory of Animal Genetics, Breeding and Reproduction of Ministry of Agriculture and Rural Affairs of China, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, China.

Porcine reproductive and respiratory syndrome virus (PRRSV) and transmissible gastroenteritis virus (TGEV) are two highly infectious and lethal viruses causing major economic losses to pig production. Here, we report generation of double-gene-knockout (DKO) pigs harboring edited knockout alleles for known receptor proteins CD163 and pAPN and show that DKO pigs are completely resistant to genotype 2 PRRSV and TGEV. We found no differences in meat-production or reproductive-performance traits between wild-type and DKO pigs, but detected increased iron in DKO muscle. Additional infection challenge experiments showed that DKO pigs exhibited decreased susceptibility to porcine deltacoronavirus (PDCoV), thus offering unprecedented in vivo evidence of pAPN as one of PDCoV receptors. Beyond showing that multiple gene edits can be combined in a livestock animal to achieve simultaneous resistance to two major viruses, our study introduces a valuable model for investigating infection mechanisms of porcine pathogenic viruses that exploit pAPN or CD163 for entry.
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http://dx.doi.org/10.7554/eLife.57132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7467724PMC
September 2020

Disrupting Mitochondrial Copper Distribution Inhibits Leukemic Stem Cell Self-Renewal.

Cell Stem Cell 2020 06 15;26(6):926-937.e10. Epub 2020 May 15.

Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. Electronic address:

Leukemic stem cells (LSCs) rely on oxidative metabolism and are differentially sensitive to targeting mitochondrial pathways, which spares normal hematopoietic cells. A subset of mitochondrial proteins is folded in the intermembrane space via the mitochondrial intermembrane assembly (MIA) pathway. We found increased mRNA expression of MIA pathway substrates in acute myeloid leukemia (AML) stem cells. Therefore, we evaluated the effects of inhibiting this pathway in AML. Genetic and chemical inhibition of ALR reduces AML growth and viability, disrupts LSC self-renewal, and induces their differentiation. ALR inhibition preferentially decreases its substrate COX17, a mitochondrial copper chaperone, and knockdown of COX17 phenocopies ALR loss. Inhibiting ALR and COX17 increases mitochondrial copper levels which in turn inhibit S-adenosylhomocysteine hydrolase (SAHH) and lower levels of S-adenosylmethionine (SAM), DNA methylation, and chromatin accessibility to lower LSC viability. These results provide insight into mechanisms through which mitochondrial copper controls epigenetic status and viability of LSCs.
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http://dx.doi.org/10.1016/j.stem.2020.04.010DOI Listing
June 2020

The mitochondrial peptidase, neurolysin, regulates respiratory chain supercomplex formation and is necessary for AML viability.

Sci Transl Med 2020 04;12(538)

Princess Margaret Cancer Centre, Toronto, Ontario M5G 1L7, Canada.

Neurolysin (NLN) is a zinc metallopeptidase whose mitochondrial function is unclear. We found that NLN was overexpressed in almost half of patients with acute myeloid leukemia (AML), and inhibition of NLN was selectively cytotoxic to AML cells and stem cells while sparing normal hematopoietic cells. Mechanistically, NLN interacted with the mitochondrial respiratory chain. Genetic and chemical inhibition of NLN impaired oxidative metabolism and disrupted the formation of respiratory chain supercomplexes (RCS). Furthermore, NLN interacted with the known RCS regulator, LETM1, and inhibition of NLN disrupted LETM1 complex formation. RCS were increased in patients with AML and positively correlated with NLN expression. These findings demonstrate that inhibiting RCS formation selectively targets AML cells and stem cells and highlights the therapeutic potential of pharmacologically targeting NLN in AML.
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http://dx.doi.org/10.1126/scitranslmed.aaz8264DOI Listing
April 2020

Tentative identification of 20()-protopanaxadiol metabolites in human plasma and urine using ultra-performance liquid chromatography coupled with triple quadrupole time-of-flight mass spectrometry.

J Ginseng Res 2019 Oct 5;43(4):539-549. Epub 2018 Apr 5.

Department of Pharmaceutical Analysis, School of Pharmacy, Fudan University, Shanghai, China.

Background: 20()-Protopanaxadiol (PPD), the aglycone part of 20()-protopanaxadiol ginsenosides, possesses antidepressant activity among many other pharmacological activities. It is currently undergoing clinical trial in China as an antidepressant.

Methods: In this study, an ultra-performance liquid chromatography coupled with triple quadrupole time-of-flight mass tandem mass spectrometry method was established to identify the metabolites of PPD in human plasma and urine following oral administration in phase IIa clinical trial.

Results: A total of 40 metabolites in human plasma and urine were identified using this method. Four metabolites identified were isolated from rat feces, and two of them were analyzed by NMR to elucidate the exact structures. The structures of isolated compounds were confirmed as (20,24)-epoxydammarane-12,23,25-triol-3-one and (20,24)-epoxydammarane-3,12,23,25-tetrol. Both compounds were found as metabolites in human for the first time. Upon comparing our findings with the findings of the study of PPD metabolism in human liver microsomes and human hepatocytes, metabolites with 475.3783 and phase II metabolites were not found in our study whereas metabolites with 505.3530, 523.3641, and 525.3788 were exclusively detected in our experiments.

Conclusion: The metabolites identified using ultra-performance liquid chromatography coupled with triple quadrupole time-of-flight mass spectrometry in our study were mostly hydroxylated metabolites. This indicated that PPD was metabolized in human body mainly through phase I hepatic metabolism. The main metabolites are in 20,24-oxide form with multiple hydroxylation sites. Finally, the metabolic pathways of PPD (human) were proposed based on structural analysis.
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http://dx.doi.org/10.1016/j.jgr.2018.03.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823760PMC
October 2019

EPIC: software toolkit for elution profile-based inference of protein complexes.

Nat Methods 2019 08 15;16(8):737-742. Epub 2019 Jul 15.

Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada.

Protein complexes are key macromolecular machines of the cell, but their description remains incomplete. We and others previously reported an experimental strategy for global characterization of native protein assemblies based on chromatographic fractionation of biological extracts coupled to precision mass spectrometry analysis (chromatographic fractionation-mass spectrometry, CF-MS), but the resulting data are challenging to process and interpret. Here, we describe EPIC (elution profile-based inference of complexes), a software toolkit for automated scoring of large-scale CF-MS data to define high-confidence multi-component macromolecules from diverse biological specimens. As a case study, we used EPIC to map the global interactome of Caenorhabditis elegans, defining 612 putative worm protein complexes linked to diverse biological processes. These included novel subunits and assemblies unique to nematodes that we validated using orthogonal methods. The open source EPIC software is freely available as a Jupyter notebook packaged in a Docker container (https://hub.docker.com/r/baderlab/bio-epic/).
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http://dx.doi.org/10.1038/s41592-019-0461-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7995176PMC
August 2019

ARGLU1 is a transcriptional coactivator and splicing regulator important for stress hormone signaling and development.

Nucleic Acids Res 2019 04;47(6):2856-2870

Department of Pharmaceutical Sciences, University of Toronto, Toronto, ON M5S 3M2, Canada.

Stress hormones bind and activate the glucocorticoid receptor (GR) in many tissues including the brain. We identified arginine and glutamate rich 1 (ARGLU1) in a screen for new modulators of glucocorticoid signaling in the CNS. Biochemical studies show that the glutamate rich C-terminus of ARGLU1 coactivates multiple nuclear receptors including the glucocorticoid receptor (GR) and the arginine rich N-terminus interacts with splicing factors and binds to RNA. RNA-seq of neural cells depleted of ARGLU1 revealed significant changes in the expression and alternative splicing of distinct genes involved in neurogenesis. Loss of ARGLU1 is embryonic lethal in mice, and knockdown in zebrafish causes neurodevelopmental and heart defects. Treatment with dexamethasone, a GR activator, also induces changes in the pattern of alternatively spliced genes, many of which were lost when ARGLU1 was absent. Importantly, the genes found to be alternatively spliced in response to glucocorticoid treatment were distinct from those under transcriptional control by GR, suggesting an additional mechanism of glucocorticoid action is present in neural cells. Our results thus show that ARGLU1 is a novel factor for embryonic development that modulates basal transcription and alternative splicing in neural cells with consequences for glucocorticoid signaling.
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http://dx.doi.org/10.1093/nar/gkz010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6451108PMC
April 2019

Pathway enrichment analysis and visualization of omics data using g:Profiler, GSEA, Cytoscape and EnrichmentMap.

Nat Protoc 2019 02;14(2):482-517

The Donnelly Centre, University of Toronto, Toronto, ON, Canada.

Pathway enrichment analysis helps researchers gain mechanistic insight into gene lists generated from genome-scale (omics) experiments. This method identifies biological pathways that are enriched in a gene list more than would be expected by chance. We explain the procedures of pathway enrichment analysis and present a practical step-by-step guide to help interpret gene lists resulting from RNA-seq and genome-sequencing experiments. The protocol comprises three major steps: definition of a gene list from omics data, determination of statistically enriched pathways, and visualization and interpretation of the results. We describe how to use this protocol with published examples of differentially expressed genes and mutated cancer genes; however, the principles can be applied to diverse types of omics data. The protocol describes innovative visualization techniques, provides comprehensive background and troubleshooting guidelines, and uses freely available and frequently updated software, including g:Profiler, Gene Set Enrichment Analysis (GSEA), Cytoscape and EnrichmentMap. The complete protocol can be performed in ~4.5 h and is designed for use by biologists with no prior bioinformatics training.
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http://dx.doi.org/10.1038/s41596-018-0103-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6607905PMC
February 2019

Identification of 153 new loci associated with heel bone mineral density and functional involvement of GPC6 in osteoporosis.

Nat Genet 2017 Oct 4;49(10):1468-1475. Epub 2017 Sep 4.

Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

Osteoporosis is a common disease diagnosed primarily by measurement of bone mineral density (BMD). We undertook a genome-wide association study (GWAS) in 142,487 individuals from the UK Biobank to identify loci associated with BMD as estimated by quantitative ultrasound of the heel. We identified 307 conditionally independent single-nucleotide polymorphisms (SNPs) that attained genome-wide significance at 203 loci, explaining approximately 12% of the phenotypic variance. These included 153 previously unreported loci, and several rare variants with large effect sizes. To investigate the underlying mechanisms, we undertook (1) bioinformatic, functional genomic annotation and human osteoblast expression studies; (2) gene-function prediction; (3) skeletal phenotyping of 120 knockout mice with deletions of genes adjacent to lead independent SNPs; and (4) analysis of gene expression in mouse osteoblasts, osteocytes and osteoclasts. The results implicate GPC6 as a novel determinant of BMD, and also identify abnormal skeletal phenotypes in knockout mice associated with a further 100 prioritized genes.
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http://dx.doi.org/10.1038/ng.3949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5621629PMC
October 2017

Tracing the origins of relapse in acute myeloid leukaemia to stem cells.

Nature 2017 07 28;547(7661):104-108. Epub 2017 Jun 28.

Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2M9, Canada.

In acute myeloid leukaemia, long-term survival is poor as most patients relapse despite achieving remission. Historically, the failure of therapy has been thought to be due to mutations that produce drug resistance, possibly arising as a consequence of the mutagenic properties of chemotherapy drugs. However, other lines of evidence have pointed to the pre-existence of drug-resistant cells. For example, deep sequencing of paired diagnosis and relapse acute myeloid leukaemia samples has provided direct evidence that relapse in some cases is generated from minor genetic subclones present at diagnosis that survive chemotherapy, suggesting that resistant cells are generated by evolutionary processes before treatment and are selected by therapy. Nevertheless, the mechanisms of therapy failure and capacity for leukaemic regeneration remain obscure, as sequence analysis alone does not provide insight into the cell types that are fated to drive relapse. Although leukaemia stem cells have been linked to relapse owing to their dormancy and self-renewal properties, and leukaemia stem cell gene expression signatures are highly predictive of therapy failure, experimental studies have been primarily correlative and a role for leukaemia stem cells in acute myeloid leukaemia relapse has not been directly proved. Here, through combined genetic and functional analysis of purified subpopulations and xenografts from paired diagnosis/relapse samples, we identify therapy-resistant cells already present at diagnosis and two major patterns of relapse. In some cases, relapse originated from rare leukaemia stem cells with a haematopoietic stem/progenitor cell phenotype, while in other instances relapse developed from larger subclones of immunophenotypically committed leukaemia cells that retained strong stemness transcriptional signatures. The identification of distinct patterns of relapse should lead to improved methods for disease management and monitoring in acute myeloid leukaemia. Moreover, the shared functional and transcriptional stemness properties that underlie both cellular origins of relapse emphasize the importance of developing new therapeutic approaches that target stemness to prevent relapse.
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http://dx.doi.org/10.1038/nature22993DOI Listing
July 2017

Restricted access magnetic core-mesoporous shell microspheres with C8-modified interior pore walls for the identification of 20(S)-protopanaxadiol metabolites in rat plasma using UPLC-Q-TOF-MS/MS.

J Chromatogr B Analyt Technol Biomed Life Sci 2017 Jun 3;1054:73-79. Epub 2017 Apr 3.

Department of Pharmaceutical Analysis, School of Pharmacy, Fudan University, No. 826 Zhangheng Road, Shanghai 201203, China. Electronic address:

In the present study, a novel sample preparation method based on magnetic core-mesoporous shell microspheres with C8-modified interior pore walls ([email protected]) was established for the identification of 20(S)-protopanaxadiol (PPD) metabolites in rat plasma by UPLC-Q-TOF-MS/MS analysis. [email protected] allowed selective extraction of PPD metabolites from rat plasma by excluding macromolecules in the plasma owing to size exclusion effect. Five extraction conditions including the amount of [email protected] microspheres used, extraction time, elution solvents, elution volume, and elution time were investigated and optimized. The present method was compared with two conventional sample preparation methods: protein precipitation and C8 solid phase extraction (C8-SPE). Our method provided higher UPLC intensity of result than protein precipitation method. While the resulting intensity of our method and that of C8-SPE were not significantly different, it consumed less processing time (15min 55s for [email protected], and 27min 30s for C8-SPE). Finally, the proposed method was successfully applied in the identification of PPD metabolites in vivo, in which a total of 17 metabolites and the parent drug were identified in rat plasma.
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http://dx.doi.org/10.1016/j.jchromb.2017.04.004DOI Listing
June 2017

Synthesis and Biological Evaluation of Danshensu and Tetramethylpyrazine Conjugates as Cardioprotective Agents.

Chem Pharm Bull (Tokyo) 2017 ;65(4):381-388

Institute of New Drug Research and Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine, Jinan University College of Pharmacy.

Myocardial ischemia is a primary cause of sudden death worldwide. Numerous active ingredients of traditional Chinese medicines including danshensu (DSS) and tetramethylpyrazine (TMP) have been widely used for the treatment of myocardial ischemia. To enhance their therapeutic efficacy and improve their drugability, in this work, we designed new DSS and TMP conjugates. Their water solubility and protective effects were studied in vitro and in experimental animal models. The new compounds demonstrated higher activities than the positive control agents acetylated danshensu and tetramethylpyrazine conjugate (ADTM) and salvianolic acid B (SAB) in preventing cells from oxidative insult. Among the new compounds, 14, bearing two glycine moieties, was more water soluble. In addition, compound 14 was much more potent in preventing cells from oxidative injury, at least 10- and 20-fold as potent as ADTM and SAB, respectively. The protective effects of compound 14 may be attributed to its anti-radical activity and anti-apoptotic activity. These results suggest that compound 14 is a promising candidate for the treatment of myocardial ischemia.
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http://dx.doi.org/10.1248/cpb.c16-00839DOI Listing
April 2017

Leveraging increased cytoplasmic nucleoside kinase activity to target mtDNA and oxidative phosphorylation in AML.

Blood 2017 05 10;129(19):2657-2666. Epub 2017 Mar 10.

Princess Margaret Cancer Centre, Toronto, ON, Canada.

Mitochondrial DNA (mtDNA) biosynthesis requires replication factors and adequate nucleotide pools from the mitochondria and cytoplasm. We performed gene expression profiling analysis of 542 human acute myeloid leukemia (AML) samples and identified 55% with upregulated mtDNA biosynthesis pathway expression compared with normal hematopoietic cells. Genes that support mitochondrial nucleotide pools, including mitochondrial nucleotide transporters and a subset of cytoplasmic nucleoside kinases, were also increased in AML compared with normal hematopoietic samples. Knockdown of cytoplasmic nucleoside kinases reduced mtDNA levels in AML cells, demonstrating their contribution in maintaining mtDNA. To assess cytoplasmic nucleoside kinase pathway activity, we used a nucleoside analog 2'3'-dideoxycytidine (ddC), which is phosphorylated to the activated antimetabolite, 2'3'-dideoxycytidine triphosphate by cytoplasmic nucleoside kinases. ddC is a selective inhibitor of the mitochondrial DNA polymerase γ. ddC was preferentially activated in AML cells compared with normal hematopoietic progenitor cells. ddC treatment inhibited mtDNA replication, oxidative phosphorylation, and induced cytotoxicity in a panel of AML cell lines. Furthermore, ddC preferentially inhibited mtDNA replication in a subset of primary human leukemia cells and selectively targeted leukemia cells while sparing normal progenitor cells. In animal models of human AML, treatment with ddC decreased mtDNA, electron transport chain proteins, and induced tumor regression without toxicity. ddC also targeted leukemic stem cells in secondary AML xenotransplantation assays. Thus, AML cells have increased cytidine nucleoside kinase activity that regulates mtDNA biogenesis and can be leveraged to selectively target oxidative phosphorylation in AML.
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http://dx.doi.org/10.1182/blood-2016-10-741207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5766841PMC
May 2017

A highly sensitive HPLC-MS/MS method for quantification of 20(S)-protopanaxadiol in human plasma and its application in phase IIa clinical trial of a novel antidepressant agent.

J Chromatogr B Analyt Technol Biomed Life Sci 2016 Sep 27;1031:214-220. Epub 2016 Jul 27.

Department of Pharmaceutical Analysis, School of Pharmacy, Fudan University, No.826 Zhangheng Road, Shanghai, 201203, PR China. Electronic address:

A highly sensitive HPLC-MS/MS assay method was established to quantify 20(S)-protopanaxadiol (PPD) in human plasma with dexamethasone as an internal standard. The electrospray ion mass spectrometry (ESI-MS) was operated under the multiple reactions monitoring mode (MRM) using positive ion mode. PPD was extracted from 500μL plasma samples by liquid-liquid extraction then separated by a C18 analytical column with gradient elution. The concentration of PPD could be determined by this HPLC-MS/MS method over the range of 0.05-20ng/mL with the lower limit of quantification (LLOQ) of 0.05ng/mL. The method was successfully applied to phase IIa clinical trial of Yuxintine (PPD capsule) in which plasma samples of 87 subjects were analyzed following 6 weeks of oral administration of placebo or PPD capsules in 5 different doses. In this study, the measured concentration was linearly related to the oral dosage with R=0.9901. The minimum and maximum values of measured concentration were 0.06 and 11.60ng/mL, respectively. In addition, plasma concentrations of PPD in depression patients were reported for the first time in our study.
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http://dx.doi.org/10.1016/j.jchromb.2016.07.044DOI Listing
September 2016

Inhibition of Dopamine Receptor D4 Impedes Autophagic Flux, Proliferation, and Survival of Glioblastoma Stem Cells.

Cancer Cell 2016 06;29(6):859-873

Arthur and Sonia Labatt Brain Tumor Research Center and Developmental and Stem Cell Biology, The Hospital for Sick Children (SickKids), Toronto, ON M5G 0A4, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Division of Neurosurgery, SickKids, Toronto, ON M5G 1X8, Canada. Electronic address:

Glioblastomas (GBM) grow in a rich neurochemical milieu, but the impact of neurochemicals on GBM growth is largely unexplored. We interrogated 680 neurochemical compounds in patient-derived GBM neural stem cells (GNS) to determine the effects on proliferation and survival. Compounds that modulate dopaminergic, serotonergic, and cholinergic signaling pathways selectively affected GNS growth. In particular, dopamine receptor D4 (DRD4) antagonists selectively inhibited GNS growth and promoted differentiation of normal neural stem cells. DRD4 antagonists inhibited the downstream effectors PDGFRβ, ERK1/2, and mTOR and disrupted the autophagy-lysosomal pathway, leading to accumulation of autophagic vacuoles followed by G0/G1 arrest and apoptosis. These results demonstrate a role for neurochemical pathways in governing GBM stem cell proliferation and suggest therapeutic approaches for GBM.
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http://dx.doi.org/10.1016/j.ccell.2016.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5968455PMC
June 2016

A novel agent exerts antitumor activity in breast cancer cells by targeting mitochondrial complex II.

Oncotarget 2016 May;7(22):32054-64

State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China.

The mitochondrial respiratory chain, including mitochondrial complex II, has emerged as a potential target for cancer therapy. In the present study, a novel conjugate of danshensu (DSS) and tetramethylpyrazine (TMP), DT-010, was synthesized. Our results showed that DT-010 is more potent than its parental compounds separately or in combination, in inhibiting the proliferation of MCF-7 and MDA-MB-231 cells by inducing cytotoxicity and promoting cell cycle arrest. It also inhibited the growth of 4T1 breast cancer cells in vivo. DT-010 suppressed the fundamental parameters of mitochondrial function in MCF-7 cells, including basal respiration, ATP turnover, maximal respiration. Treatment with DT-010 in MCF-7 and MDA-MB-231 cells resulted in the loss of mitochondrial membrane potential and decreased ATP production. DT-010 also promoted ROS generation, while treatment with ROS scavenger, NAC (N-acetyl-L-cysteine), reversed DT-010-induced cytotoxicity. Further study showed that DT-010 suppressed succinate-induced mitochondrial respiration and impaired mitochondrial complex II enzyme activity indicating that DT-010 may inhibit mitochondrial complex II. Overall, our results suggested that the antitumor activity of DT-010 is associated with inhibition of mitochondrial complex II, which triggers ROS generation and mitochondrial dysfunction in breast cancer cells.
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http://dx.doi.org/10.18632/oncotarget.8410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5077996PMC
May 2016

HOX gene complement and expression in the planarian Schmidtea mediterranea.

Evodevo 2016 30;7. Epub 2016 Mar 30.

Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON M5G10A4 Canada ; Department of Molecular Genetics, University of Toronto, Toronto, ON M5G10A4 Canada ; Ontario Institute for Cancer Research, Toronto, ON M5G10A4 Canada.

Background: Freshwater planarians are well known for their regenerative abilities. Less well known is how planarians maintain spatial patterning in long-lived adult animals or how they re-pattern tissues during regeneration. HOX genes are good candidates to regulate planarian spatial patterning, yet the full complement or genomic clustering of planarian HOX genes has not yet been described, primarily because only a few have been detectable by in situ hybridization, and none have given morphological phenotypes when knocked down by RNAi.

Results: Because the planarian Schmidtea mediterranea (S. mediterranea) is unsegmented, appendage less, and morphologically simple, it has been proposed that it may have a simplified HOX gene complement. Here, we argue against this hypothesis and show that S. mediterranea has a total of 13 HOX genes, which represent homologs to all major axial categories, and can be detected by whole-mount in situ hybridization using a highly sensitive method. In addition, we show that planarian HOX genes do not cluster in the genome, yet 5/13 have retained aspects of axially restricted expression. Finally, we confirm HOX gene axial expression by RNA deep-sequencing 6 anterior-posterior "zones" of the animal, which we provide as a dataset to the community to discover other axially restricted transcripts.

Conclusions: Freshwater planarians have an unappreciated HOX gene complexity, with all major axial categories represented. However, we conclude based on adult expression patterns that planarians have a derived body plan and their asexual lifestyle may have allowed for large changes in HOX expression from the last common ancestor between arthropods, flatworms, and vertebrates. Using our in situ method and axial zone RNAseq data, it should be possible to further understand the pathways that pattern the anterior-posterior axis of adult planarians.
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http://dx.doi.org/10.1186/s13227-016-0044-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4815179PMC
April 2016

The UK10K project identifies rare variants in health and disease.

Nature 2015 Oct 14;526(7571):82-90. Epub 2015 Sep 14.

The contribution of rare and low-frequency variants to human traits is largely unexplored. Here we describe insights from sequencing whole genomes (low read depth, 7×) or exomes (high read depth, 80×) of nearly 10,000 individuals from population-based and disease collections. In extensively phenotyped cohorts we characterize over 24 million novel sequence variants, generate a highly accurate imputation reference panel and identify novel alleles associated with levels of triglycerides (APOB), adiponectin (ADIPOQ) and low-density lipoprotein cholesterol (LDLR and RGAG1) from single-marker and rare variant aggregation tests. We describe population structure and functional annotation of rare and low-frequency variants, use the data to estimate the benefits of sequencing for association studies, and summarize lessons from disease-specific collections. Finally, we make available an extensive resource, including individual-level genetic and phenotypic data and web-based tools to facilitate the exploration of association results.
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http://dx.doi.org/10.1038/nature14962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4773891PMC
October 2015

The complete chloroplast genome sequence of Fagopyrum cymosum.

Mitochondrial DNA A DNA Mapp Seq Anal 2016 07 29;27(4):2410-1. Epub 2015 Jun 29.

a Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences , Beijing , China .

Fagopyrum cymosum is a traditional medicinal plant. In this study, the complete chloroplast genome of Fagopyrum cymosum is presented. The total genome size is 160,546 bp in length, containing a pair of inverted repeats (IRs) of 32,598 bp, separated by large single copy (LSC) and small single copy (SSC) of 84,237 bp and 11,014 bp, respectively. Overall GC contents of the genome were 36.9%. The chloroplast genome harbors 126 annotated genes, including 91 protein coding genes, 29 tRNA genes, and six rRNA genes. Eighteen genes contain one or two introns. Phylogenetic analyses indicated a clear evolutionary relationship among species of Caryophyllales.
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http://dx.doi.org/10.3109/19401736.2015.1030619DOI Listing
July 2016

A mex3 homolog is required for differentiation during planarian stem cell lineage development.

Elife 2015 Jun 26;4. Epub 2015 Jun 26.

Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Canada.

Neoblasts are adult stem cells (ASCs) in planarians that sustain cell replacement during homeostasis and regeneration of any missing tissue. While numerous studies have examined genes underlying neoblast pluripotency, molecular pathways driving postmitotic fates remain poorly defined. In this study, we used transcriptional profiling of irradiation-sensitive and irradiation-insensitive cell populations and RNA interference (RNAi) functional screening to uncover markers and regulators of postmitotic progeny. We identified 32 new markers distinguishing two main epithelial progenitor populations and a planarian homolog to the MEX3 RNA-binding protein (Smed-mex3-1) as a key regulator of lineage progression. mex3-1 was required for generating differentiated cells of multiple lineages, while restricting the size of the stem cell compartment. We also demonstrated the utility of using mex3-1(RNAi) animals to identify additional progenitor markers. These results identified mex3-1 as a cell fate regulator, broadly required for differentiation, and suggest that mex3-1 helps to mediate the balance between ASC self-renewal and commitment.
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http://dx.doi.org/10.7554/eLife.07025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4507787PMC
June 2015

Estimating genome-wide significance for whole-genome sequencing studies.

Genet Epidemiol 2014 May 14;38(4):281-90. Epub 2014 Feb 14.

Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Canada; Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Canada.

Although a standard genome-wide significance level has been accepted for the testing of association between common genetic variants and disease, the era of whole-genome sequencing (WGS) requires a new threshold. The allele frequency spectrum of sequence-identified variants is very different from common variants, and the identified rare genetic variation is usually jointly analyzed in a series of genomic windows or regions. In nearby or overlapping windows, these test statistics will be correlated, and the degree of correlation is likely to depend on the choice of window size, overlap, and the test statistic. Furthermore, multiple analyses may be performed using different windows or test statistics. Here we propose an empirical approach for estimating genome-wide significance thresholds for data arising from WGS studies, and we demonstrate that the empirical threshold can be efficiently estimated by extrapolating from calculations performed on a small genomic region. Because analysis of WGS may need to be repeated with different choices of test statistics or windows, this prediction approach makes it computationally feasible to estimate genome-wide significance thresholds for different analysis choices. Based on UK10K whole-genome sequence data, we derive genome-wide significance thresholds ranging between 2.5 × 10(-8) and 8 × 10(-8) for our analytic choices in window-based testing, and thresholds of 0.6 × 10(-8) -1.5 × 10(-8) for a combined analytic strategy of testing common variants using single-SNP tests together with rare variants analyzed with our sliding-window test strategy.
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http://dx.doi.org/10.1002/gepi.21797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4489336PMC
May 2014

Exploring the potential benefits of stratified false discovery rates for region-based testing of association with rare genetic variation.

Front Genet 2014 29;5:11. Epub 2014 Jan 29.

Lady Davis Institute for Medical Research, Jewish General Hospital Montreal, QC, Canada ; Department of Epidemiology, Biostatistics and Occupational Health, McGill University Montreal, QC, Canada ; Departments of Oncology and Human Genetics, McGill University Montreal, QC, Canada.

When analyzing the data that arises from exome or whole-genome sequencing studies, window-based tests, (i.e., tests that jointly analyze all genetic data in a small genomic region), are very popular. However, power is known to be quite low for finding associations with phenotypes using these tests, and therefore a variety of analytic strategies may be employed to potentially improve power. Using sequencing data of all of chromosome 3 from an interim release of data on 2432 individuals from the UK10K project, we simulated phenotypes associated with rare genetic variation, and used the results to explore the window-based test power. We asked two specific questions: firstly, whether there could be substantial benefits associated with incorporating information from external annotation on the genetic variants, and secondly whether the false discovery rate (FDRs) would be a useful metric for assessing significance. Although, as expected, there are benefits to using additional information (such as annotation) when it is associated with causality, we confirmed the general pattern of low sensitivity and power for window-based tests. For our chosen example, even when power is high to detect some of the associations, many of the regions containing causal variants are not detectable, despite using lax significance thresholds and optimal analytic methods. Furthermore, our estimated FDR values tended to be much smaller than the true FDRs. Long-range correlations between variants-due to linkage disequilibrium-likely explain some of this bias. A more sophisticated approach to using the annotation information may improve power, however, many causal variants of realistic effect sizes may simply be undetectable, at least with this sample size. Perhaps annotation information could assist in distinguishing windows containing causal variants from windows that are merely correlated with causal variants.
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http://dx.doi.org/10.3389/fgene.2014.00011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3905218PMC
February 2014

Multiple regression methods show great potential for rare variant association tests.

PLoS One 2012 8;7(8):e41694. Epub 2012 Aug 8.

Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada.

The investigation of associations between rare genetic variants and diseases or phenotypes has two goals. Firstly, the identification of which genes or genomic regions are associated, and secondly, discrimination of associated variants from background noise within each region. Over the last few years, many new methods have been developed which associate genomic regions with phenotypes. However, classical methods for high-dimensional data have received little attention. Here we investigate whether several classical statistical methods for high-dimensional data: ridge regression (RR), principal components regression (PCR), partial least squares regression (PLS), a sparse version of PLS (SPLS), and the LASSO are able to detect associations with rare genetic variants. These approaches have been extensively used in statistics to identify the true associations in data sets containing many predictor variables. Using genetic variants identified in three genes that were Sanger sequenced in 1998 individuals, we simulated continuous phenotypes under several different models, and we show that these feature selection and feature extraction methods can substantially outperform several popular methods for rare variant analysis. Furthermore, these approaches can identify which variants are contributing most to the model fit, and therefore both goals of rare variant analysis can be achieved simultaneously with the use of regression regularization methods. These methods are briefly illustrated with an analysis of adiponectin levels and variants in the ADIPOQ gene.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0041694PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3420665PMC
May 2013

[Preliminary results of metabolite in serum and urine of lung cancer patients detected by metabolomics].

Zhongguo Fei Ai Za Zhi 2012 Apr;15(4):195-201

Department of Pulmonology, Chest Hospital Affiliated to Jiaotong University, Shanghai 200030, China.

Background And Objective: Lung cancer is one of the most common cancers worldwide. Thus far, good tumor markers for diagnosing this disease have not been found. Therefore, the discovery of novel biomarkers through the application of new methods has become a hotspot in lung cancer research. The aim of this study is to analyze low-molecular-weight metabolites in the serum and urine samples of lung cancer patients and patients with other lung diseases through metabolomics and to explore potential tumor markers further.

Methods: Both serum and urine samples from 19 lung cancer patients and 15 patients with other lung diseases were subjected to metabolomic analysis using gas chromatography mass spectrometry. Orthogonal to partial least squares discriminant analysis was performed for modeling. Two sample t-test was used to identify differences in metabolite concentrations.

Results: A total of 57 metabolites were found in the serum, and 38 metabolites were found in the urine. Multivariate statistical analysis yielded a significant distinction in the metabolic profiles between lung cancer patients and patients with other lung diseases. The t-test results indicated a total of 13 metabolites in the serum and 7 metabolites in the urine with statistically significant differences.

Conclusions: Metabolomics is useful in discriminating between lung cancer and other lung diseases. As a novel approach, it has potential in the diagnosis of lung cancer at molecular level.
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http://dx.doi.org/10.3779/j.issn.1009-3419.2012.04.01DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5999985PMC
April 2012
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