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TRPM8 (transient receptor potential cation channel, subfamily M, member 8)

Written2013-05María Llanos Valero, Luis A Pardo
Molecular Oncology Laboratory. Facultad de Medicina. CRIB. UCLM. Albacete, Spain (MLV); Department of Molecular Biology of Neuronal Signals, Max-Planck Institute of Experimental Medicine, Gottingen, Germany (LAP)

(Note : for Links provided by Atlas : click)

Identity

Alias_namestransient receptor potential cation channel
Other aliasLTRPC6
TRPP8
HGNC (Hugo) TRPM8
LocusID (NCBI) 79054
Atlas_Id 42709
Location 2q37.1  [Link to chromosome band 2q37]
Location_base_pair Starts at 234826043 and ends at 234928166 bp from pter ( according to hg19-Feb_2009)  [Mapping TRPM8.png]
Fusion genes
(updated 2016)
GIGYF2 (2q37.1) / TRPM8 (2q37.1)SCYL1 (11q13.1) / TRPM8 (2q37.1)TRPM8 (2q37.1) / RABEP1 (17p13.2)

DNA/RNA

 
  Genomic structure of human TRPM8.
Description TRPM8 consists of 27 exons that span102 kilo base pairs located at 2q37. The open reading frame (ORF) has 3312 bp resulting in an 1104 residue product. It exhibits the highly conserved region characteristic of the TRP family. The ion pore domains are located between exons 16 and 20.
Transcription The 1104 aa compose a each of the 130 KDa subunits that convey to form a homotetramer. Alternative splicing produces 11 mRNA species. The promoter contains some transcription factor binding sites for NKX3-1, NKX2-5, USF1, MYC, LMOR and ARNt (Kaiser, 2004). There are two short functional splice variants described in prostate cancer; SM8α and SM8β, that act as regulatory subunits of the full-length protein (Bidaux et al., 2012).

Protein

 
  Schematic representation of TRPM8 protein (adapted from Latorre et al., 2011).
Description Structurally, the TRPM8 channel is formed by four identical subunits. Each subunit shows 6 transmembrane domains (S1-S6) that surround the central pore, with S5 and S6 forming the gate and selective filter. The N- and C-terminal domains are in the cytoplasmic side (Peier et al., 2002; Latorre et al., 2011). The C- terminal domain is essential for the maturation, oligomerization and trafficking of the channel to the plasma membrane (Erler et al., 2006; Cayouette and Boulay, 2007). The "TRP box", in common with all the TRP family members and a binding site for PIP2, are located in this C-terminal tail. Functional TRPM8 channels require the presence of the COOH terminal as well as the region compromised between amino acids 40 to 86 of the NH2 terminal (Phelps and Gaudet, 2007). The protein shows 8 putative glycosylation sites and an immunogenic epitope that will facilitate the future design of peptide vaccination (Kiessling et al., 2003).
Expression TRPM8 is expressed mainly in a subpopulation of primary afferent neurons from both, dorsal root and trigeminal ganglia, and in the nodose and geniculate ganglia in the peripheral nervous system. The protein has been also identified in prostate and genitourinary tract, bladder, sperm, vascular smooth muscle, liver, lung and odontoblasts (Latorre et al., 2011).
Localisation The channel is expressed in the plasma membrane and in the membrane rafts. In prostate cancer cells, it is expressed in the endoplasmic reticulum membrane too (Latorre et al., 2011).
Function TRPM8 is a non-selective cation channel that primarily mediates the detection of cold thermal stimuli by primary afferent sensory neurons of afferent nerve fibres. In these cells, a temperature decrease from 28 to 8°C generates an increase in the intracellular calcium and action potential firing (McKemy et al., 2002; Peier et al., 2002; Bautista et al., 2007). This cold sensitivity is strongly compromised in the knock-out mice, disclosing a central role for TRPM8 in the detection of innocuous cold in vivo (Knowlton et al., 2013).
TRPM8 is a polymodal receptor, activated by cold and also by membrane depolarization, as well as several inflammatory agents, and natural and chemical compounds as menthol and icilin. The activation by icilin requiries the presence of intracellular calcium (Chuang et al., 2004).
The residues involved in menthol activation are Tyr745 in the S2 segment and Tyr1005 and Leu1009, located in the C-terminus (Bandell et al., 2006).
Besides menthol and icilin, there are many agonist described for the channel as WS-12, CPS-39, linalool, geraniol, frescolat etc, as well as well-known antagonists; BCTC, thio-BCTC, capsazepine, AMTB and JNJ41876666 (Behrendt et al., 2004; Valero et al., 2012; Journigan and Zaveri, 2013).
One year before being cloned, TRPM8 was described as a transcript overexpressed in prostate cancer cells (Tsavaler et al., 2001; Zhang and Barritt, 2004). Nowadays, the presence of the channel has been described for a variety of tumours (Lehen'kyi and Prevarskaya, 2011) as melanoma (Guo et al., 2012), colon or breast (Dhennin-Duthille et al., 2011).

Modulation
TRPM8 channels are activated by stimulation of tyrosin-kinase and protein G-coupled receptors. The channel is also capable of activating Gq protein (Klasen et al., 2012).
PI(4,5)P2 acts as a positive modulator of cold and menthol sensitivity by changing the voltage-sensitivity of the channel (Rohacs et al., 2005; Daniels et al., 2009; Yudin and Rohacs, 2012).
Protein Kinase C is implicated in TRPM8 desensitization (Yudin and Rohacs, 2012).
Phospolipase C (PLC)-coupled receptors mediate adaptation of TRPM8 to thermal stimuli (Daniels et al., 2009; Yudin and Rohacs, 2012).
There are indications of modulation by PKC and PKA, which would underlie reduced responses to cold and menthol in neurons in the presence of bradykinin and prostaglandin E2 (Latorre et al., 2011; Yudin and Rohacs, 2012).
TRPM8 also co-expresses with TrkA, the high affinity tyrosine kinase receptor for NGF (Latorre et al., 2011).

Implicated in

Note
  
Entity Prostate cancer
Note The TRPM8 channel is expressed in prostate cancer and normal prostatic cells. In the prostate cancer cells, the channel is functional in the cells of the different stadia of the illness. Inhibition of the expression or function of the channel reduces proliferation rates and proliferative fraction in the tumor cells, but not in non-tumor prostate cells. There is no consistent acceleration of growth after stimulation of the channel with menthol or icilin, indicating that basal TRPM8 expression is enough to sustain growth of prostate cancer cells. The evidence supports a tumor-specific role of TRPM8 rather than a tumor-specific expression of the channel, thus reinforcing the relevance of this channel as a candidate for prostate cancer therapy (Zhang and Barritt, 2004; Van Haute et al., 2010; Valero et al., 2012).
  
  
Entity Melanoma
Note TRPM8 channels are expressed in human melanocytes and melanoma cells where its activation produces sustained Ca2+ influx. Different studies have revealed the involvement of the channel in inhibition of pigmentation and melanoma proliferation. Targeting TRPM8 with natural compounds as adjuvant may help in melanoma therapy (Guo et al., 2012).
  
  
Entity Pain
Note The hypersensitivity to cold manifested as cold hyperalgesia or allodynia, often noted in patients with neuropathic pain, is mediated by TRPM8, making the channel a potential molecular target for pain relief. There are however concerns regarding thermoregulation upon manipulation of TRPM8 activity (Belmonte et al., 2009; Caspani et al., 2009; Brederson et al., 2013).
  

Bibliography

High-throughput random mutagenesis screen reveals TRPM8 residues specifically required for activation by menthol.
Bandell M, Dubin AE, Petrus MJ, Orth A, Mathur J, Hwang SW, Patapoutian A.
Nat Neurosci. 2006 Apr;9(4):493-500. Epub 2006 Mar 5.
PMID 16520735
 
The menthol receptor TRPM8 is the principal detector of environmental cold.
Bautista DM, Siemens J, Glazer JM, Tsuruda PR, Basbaum AI, Stucky CL, Jordt SE, Julius D.
Nature. 2007 Jul 12;448(7150):204-8. Epub 2007 May 30.
PMID 17538622
 
Characterization of the mouse cold-menthol receptor TRPM8 and vanilloid receptor type-1 VR1 using a fluorometric imaging plate reader (FLIPR) assay.
Behrendt HJ, Germann T, Gillen C, Hatt H, Jostock R.
Br J Pharmacol. 2004 Feb;141(4):737-45. Epub 2004 Feb 2.
PMID 14757700
 
Converting cold into pain.
Belmonte C, Brock JA, Viana F.
Exp Brain Res. 2009 Jun;196(1):13-30. doi: 10.1007/s00221-009-1797-2. Epub 2009 Apr 28. (REVIEW)
PMID 19399484
 
Regulation of activity of transient receptor potential melastatin 8 (TRPM8) channel by its short isoforms.
Bidaux G, Beck B, Zholos A, Gordienko D, Lemonnier L, Flourakis M, Roudbaraki M, Borowiec AS, Fernandez J, Delcourt P, Lepage G, Shuba Y, Skryma R, Prevarskaya N.
J Biol Chem. 2012 Jan 27;287(5):2948-62. doi: 10.1074/jbc.M111.270256. Epub 2011 Nov 28.
PMID 22128173
 
Targeting TRP channels for pain relief.
Brederson JD, Kym PR, Szallasi A.
Eur J Pharmacol. 2013 Mar 14. pii: S0014-2999(13)00173-8. doi: 10.1016/j.ejphar.2013.03.003. [Epub ahead of print]
PMID 23500195
 
The contribution of TRPM8 and TRPA1 channels to cold allodynia and neuropathic pain.
Caspani O, Zurborg S, Labuz D, Heppenstall PA.
PLoS One. 2009 Oct 8;4(10):e7383. doi: 10.1371/journal.pone.0007383.
PMID 19812688
 
Intracellular trafficking of TRP channels.
Cayouette S, Boulay G.
Cell Calcium. 2007 Aug;42(2):225-32. Epub 2007 Mar 21. (REVIEW)
PMID 17368756
 
The super-cooling agent icilin reveals a mechanism of coincidence detection by a temperature-sensitive TRP channel.
Chuang HH, Neuhausser WM, Julius D.
Neuron. 2004 Sep 16;43(6):859-69.
PMID 15363396
 
Activity of the neuronal cold sensor TRPM8 is regulated by phospholipase C via the phospholipid phosphoinositol 4,5-bisphosphate.
Daniels RL, Takashima Y, McKemy DD.
J Biol Chem. 2009 Jan 16;284(3):1570-82. doi: 10.1074/jbc.M807270200. Epub 2008 Nov 18.
PMID 19019830
 
High expression of transient receptor potential channels in human breast cancer epithelial cells and tissues: correlation with pathological parameters.
Dhennin-Duthille I, Gautier M, Faouzi M, Guilbert A, Brevet M, Vaudry D, Ahidouch A, Sevestre H, Ouadid-Ahidouch H.
Cell Physiol Biochem. 2011;28(5):813-22. doi: 10.1159/000335795. Epub 2011 Dec 15.
PMID 22178934
 
Trafficking and assembly of the cold-sensitive TRPM8 channel.
Erler I, Al-Ansary DM, Wissenbach U, Wagner TF, Flockerzi V, Niemeyer BA.
J Biol Chem. 2006 Dec 15;281(50):38396-404. Epub 2006 Oct 25.
PMID 17065148
 
Role of TRPM in melanocytes and melanoma.
Guo H, Carlson JA, Slominski A.
Exp Dermatol. 2012 Sep;21(9):650-4. doi: 10.1111/j.1600-0625.2012.01565.x.
PMID 22897572
 
TRPM8 ion channel ligands for new therapeutic applications and as probes to study menthol pharmacology.
Journigan VB, Zaveri NT.
Life Sci. 2013 Mar 19;92(8-9):425-37. doi: 10.1016/j.lfs.2012.10.032. Epub 2012 Nov 16. (REVIEW)
PMID 23159643
 
Identification and Characterization of the Ion Channel TRPM8 in Prostate Cancer.
Kaiser S.
Dissertation; http://edoc.hu-berlin.de/dissertationen/kaiser-simone-2004-06-10/HTML/
 
Identification of an HLA-A*0201-restricted T-cell epitope derived from the prostate cancer-associated protein trp-p8.
Kiessling A, Fussel S, Schmitz M, Stevanovic S, Meye A, Weigle B, Klenk U, Wirth MP, Rieber EP.
Prostate. 2003 Sep 1;56(4):270-9.
PMID 12858355
 
The TRPM8 ion channel comprises direct Gq protein-activating capacity.
Klasen K, Hollatz D, Zielke S, Gisselmann G, Hatt H, Wetzel CH.
Pflugers Arch. 2012 Jun;463(6):779-97. doi: 10.1007/s00424-012-1098-7. Epub 2012 Mar 30.
PMID 22460725
 
A sensory-labeled line for cold: TRPM8-expressing sensory neurons define the cellular basis for cold, cold pain, and cooling-mediated analgesia.
Knowlton WM, Palkar R, Lippoldt EK, McCoy DD, Baluch F, Chen J, McKemy DD.
J Neurosci. 2013 Feb 13;33(7):2837-48. doi: 10.1523/JNEUROSCI.1943-12.2013.
PMID 23407943
 
A cool channel in cold transduction.
Latorre R, Brauchi S, Madrid R, Orio P.
Physiology (Bethesda). 2011 Aug;26(4):273-85. doi: 10.1152/physiol.00004.2011. (REVIEW)
PMID 21841075
 
Oncogenic TRP channels.
Lehen'kyi V, Prevarskaya N.
Adv Exp Med Biol. 2011;704:929-45. doi: 10.1007/978-94-007-0265-3_48. (REVIEW)
PMID 21290334
 
Identification of a cold receptor reveals a general role for TRP channels in thermosensation.
McKemy DD, Neuhausser WM, Julius D.
Nature. 2002 Mar 7;416(6876):52-8. Epub 2002 Feb 10.
PMID 11882888
 
A TRP channel that senses cold stimuli and menthol.
Peier AM, Moqrich A, Hergarden AC, Reeve AJ, Andersson DA, Story GM, Earley TJ, Dragoni I, McIntyre P, Bevan S, Patapoutian A.
Cell. 2002 Mar 8;108(5):705-15.
PMID 11893340
 
The role of the N terminus and transmembrane domain of TRPM8 in channel localization and tetramerization.
Phelps CB, Gaudet R.
J Biol Chem. 2007 Dec 14;282(50):36474-80. Epub 2007 Oct 1.
PMID 17908685
 
PI(4,5)P2 regulates the activation and desensitization of TRPM8 channels through the TRP domain.
Rohacs T, Lopes CM, Michailidis I, Logothetis DE.
Nat Neurosci. 2005 May;8(5):626-34. Epub 2005 Apr 24.
PMID 15852009
 
Trp-p8, a novel prostate-specific gene, is up-regulated in prostate cancer and other malignancies and shares high homology with transient receptor potential calcium channel proteins.
Tsavaler L, Shapero MH, Morkowski S, Laus R.
Cancer Res. 2001 May 1;61(9):3760-9.
PMID 11325849
 
TRPM8 ion channels differentially modulate proliferation and cell cycle distribution of normal and cancer prostate cells.
Valero ML, Mello de Queiroz F, Stuhmer W, Viana F, Pardo LA.
PLoS One. 2012;7(12):e51825. doi: 10.1371/journal.pone.0051825. Epub 2012 Dec 14.
PMID 23251635
 
TRP channels in human prostate.
Van Haute C, De Ridder D, Nilius B.
ScientificWorldJournal. 2010 Aug 17;10:1597-611. doi: 10.1100/tsw.2010.149. (REVIEW)
PMID 20730379
 
Regulation of TRPM8 channel activity.
Yudin Y, Rohacs T.
Mol Cell Endocrinol. 2012 Apr 28;353(1-2):68-74. doi: 10.1016/j.mce.2011.10.023. Epub 2011 Oct 28. (REVIEW)
PMID 22061619
 
Evidence that TRPM8 is an androgen-dependent Ca2+ channel required for the survival of prostate cancer cells.
Zhang L, Barritt GJ.
Cancer Res. 2004 Nov 15;64(22):8365-73.
PMID 15548706
 

Citation

This paper should be referenced as such :
Valero, ML ; Pardo, LA
TRPM8 (transient receptor potential cation channel, subfamily M, member 8)
Atlas Genet Cytogenet Oncol Haematol. 2013;17(12):841-844.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/TRPM8ID42709ch2q37.html


External links

Nomenclature
HGNC (Hugo)TRPM8   17961
Cards
AtlasTRPM8ID42709ch2q37
Entrez_Gene (NCBI)TRPM8  79054  transient receptor potential cation channel subfamily M member 8
AliasesLTRPC6; TRPP8
GeneCards (Weizmann)TRPM8
Ensembl hg19 (Hinxton)ENSG00000144481 [Gene_View]  chr2:234826043-234928166 [Contig_View]  TRPM8 [Vega]
Ensembl hg38 (Hinxton)ENSG00000144481 [Gene_View]  chr2:234826043-234928166 [Contig_View]  TRPM8 [Vega]
ICGC DataPortalENSG00000144481
TCGA cBioPortalTRPM8
AceView (NCBI)TRPM8
Genatlas (Paris)TRPM8
WikiGenes79054
SOURCE (Princeton)TRPM8
Genetics Home Reference (NIH)TRPM8
Genomic and cartography
GoldenPath hg19 (UCSC)TRPM8  -     chr2:234826043-234928166 +  2q37   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)TRPM8  -     2q37   [Description]    (hg38-Dec_2013)
EnsemblTRPM8 - 2q37 [CytoView hg19]  TRPM8 - 2q37 [CytoView hg38]
Mapping of homologs : NCBITRPM8 [Mapview hg19]  TRPM8 [Mapview hg38]
OMIM606678   
Gene and transcription
Genbank (Entrez)AB061779 AK303811 AY090109 AY328400 AY532375
RefSeq transcript (Entrez)NM_024080
RefSeq genomic (Entrez)NC_000002 NC_018913 NT_005403 NW_004929306
Consensus coding sequences : CCDS (NCBI)TRPM8
Cluster EST : UnigeneHs.366053 [ NCBI ]
CGAP (NCI)Hs.366053
Alternative Splicing GalleryENSG00000144481
Gene ExpressionTRPM8 [ NCBI-GEO ]   TRPM8 [ EBI - ARRAY_EXPRESS ]   TRPM8 [ SEEK ]   TRPM8 [ MEM ]
Gene Expression Viewer (FireBrowse)TRPM8 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)79054
GTEX Portal (Tissue expression)TRPM8
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ7Z2W7   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ7Z2W7  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ7Z2W7
Splice isoforms : SwissVarQ7Z2W7
PhosPhoSitePlusQ7Z2W7
Domains : Interpro (EBI)Ion_trans_dom    TRPM8   
Domain families : Pfam (Sanger)Ion_trans (PF00520)   
Domain families : Pfam (NCBI)pfam00520   
Conserved Domain (NCBI)TRPM8
DMDM Disease mutations79054
Blocks (Seattle)TRPM8
SuperfamilyQ7Z2W7
Human Protein AtlasENSG00000144481
Peptide AtlasQ7Z2W7
HPRD09454
IPIIPI00152033   IPI00031662   IPI00515002   IPI01013269   IPI00917600   IPI00917744   IPI00917283   
Protein Interaction databases
DIP (DOE-UCLA)Q7Z2W7
IntAct (EBI)Q7Z2W7
FunCoupENSG00000144481
BioGRIDTRPM8
STRING (EMBL)TRPM8
ZODIACTRPM8
Ontologies - Pathways
QuickGOQ7Z2W7
Ontology : AmiGOcalcium channel activity  protein binding  endoplasmic reticulum membrane  plasma membrane  cellular calcium ion homeostasis  response to cold  external side of plasma membrane  integral component of membrane  detection of temperature stimulus  protein homodimerization activity  membrane raft  thermoception  protein homotetramerization  protein homotrimerization  calcium ion transmembrane transport  
Ontology : EGO-EBIcalcium channel activity  protein binding  endoplasmic reticulum membrane  plasma membrane  cellular calcium ion homeostasis  response to cold  external side of plasma membrane  integral component of membrane  detection of temperature stimulus  protein homodimerization activity  membrane raft  thermoception  protein homotetramerization  protein homotrimerization  calcium ion transmembrane transport  
REACTOMEQ7Z2W7 [protein]
REACTOME Pathways3295583 [pathway]   
NDEx NetworkTRPM8
Atlas of Cancer Signalling NetworkTRPM8
Wikipedia pathwaysTRPM8
Orthology - Evolution
OrthoDB79054
GeneTree (enSembl)ENSG00000144481
Phylogenetic Trees/Animal Genes : TreeFamTRPM8
HOVERGENQ7Z2W7
HOGENOMQ7Z2W7
Homologs : HomoloGeneTRPM8
Homology/Alignments : Family Browser (UCSC)TRPM8
Gene fusions - Rearrangements
Fusion : MitelmanGIGYF2/TRPM8 [2q37.1/2q37.1]  [t(2;2)(q37;q37)]  
Fusion : MitelmanSCYL1/TRPM8 [11q13.1/2q37.1]  [t(2;11)(q37;q13)]  
Fusion : MitelmanTRPM8/RABEP1 [2q37.1/17p13.2]  [t(2;17)(q37;p13)]  
Fusion: TCGASCYL1 11q13.1 TRPM8 2q37.1 PRAD
Fusion: TCGATRPM8 2q37.1 RABEP1 17p13.2 PRAD
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerTRPM8 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)TRPM8
dbVarTRPM8
ClinVarTRPM8
1000_GenomesTRPM8 
Exome Variant ServerTRPM8
ExAC (Exome Aggregation Consortium)TRPM8 (select the gene name)
Genetic variants : HAPMAP79054
Genomic Variants (DGV)TRPM8 [DGVbeta]
DECIPHER (Syndromes)2:234826043-234928166  ENSG00000144481
CONAN: Copy Number AnalysisTRPM8 
Mutations
ICGC Data PortalTRPM8 
TCGA Data PortalTRPM8 
Broad Tumor PortalTRPM8
OASIS PortalTRPM8 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICTRPM8  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDTRPM8
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch TRPM8
DgiDB (Drug Gene Interaction Database)TRPM8
DoCM (Curated mutations)TRPM8 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)TRPM8 (select a term)
intoGenTRPM8
NCG5 (London)TRPM8
Cancer3DTRPM8(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM606678   
Orphanet
MedgenTRPM8
Genetic Testing Registry TRPM8
NextProtQ7Z2W7 [Medical]
TSGene79054
GENETestsTRPM8
Huge Navigator TRPM8 [HugePedia]
snp3D : Map Gene to Disease79054
BioCentury BCIQTRPM8
ClinGenTRPM8
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD79054
Chemical/Pharm GKB GenePA38270
Clinical trialTRPM8
Miscellaneous
canSAR (ICR)TRPM8 (select the gene name)
Probes
Litterature
PubMed101 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineTRPM8
EVEXTRPM8
GoPubMedTRPM8
iHOPTRPM8
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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