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In: Leukemia, Springer Science and Business Media LLC, Vol. 34, No. 11 ( 2020-11), p. 3007-3018

Type of Medium: Online Resource

ISSN: 0887-6924 , 1476-5551

URL: Article

DOI: 10.1038/s41375-020-0883-0

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2020

detail.hit.zdb_id: 2008023-2

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 3064-3064

Abstract: Background: Genetic characterization is becoming relevant to predict risk of progression in smoldering MM and is fundamental to estimate survival in active MM. Thus, patients undergo multiple bone marrow (BM) aspirates for genetic screening that beyond painful, may not be fully representative due to patchy BM involvement, spatial genomic heterogeneity, or extramedullary disease. Accordingly, cell-free DNA has been investigated and showed high concordance with BM aspirates, but information is typically restricted to a few recurrent mutations since comprehensive genetic characterization (eg. whole-exome sequencing, WES) is applicable to 〈 25% of MM patients (those with ≥10% tumor DNA). By contrast, CTCs are detectable in virtually all smoldering and active MM patients and their numbers are prognostically relevant, but their applicability for non-invasive genetic characterization of MM has been poorly investigated. Aim: To compare the genetic landscape of CTCs vs matched BM clonal plasma cells (PCs) and extramedullary (EM) plasmacytomas, and validate standardized assays for CTCs' detection, isolation and genetic characterization. Methods: We used EuroFlow next-generation flow (NGF) cytometry to detect and isolate peripheral blood (PB) CTCs and matched BM clonal PCs from 38 MM patients (25 at diagnosis and 13 at relapse). In 8 cases, clonal PCs from EM plasmacytomas were also FACSorted. PB T cells were always used as matched germline control. In the training set, we performed custom WES (preceded by triplicates of whole-genome amplification) in matched CTCs, BM and EM clonal PCs from the 8 patients with all three spatially distributed clones. Only those mutations present in 2/3 libraries analyzed per sample were considered positive. In the validation set, we compared mutations, copy number alterations (CNA) and translocations present in CTCs and BM clonal PCs using the Chromium Exome Solution for low DNA-input (n=8), and solely CNA using the Affymetrix CytoScan HD platform (n=22). Read mapping, variant and structural calling were performed with the Multisample Exome (Dreamgenics) and LongRanger (10XGenomics) pipelines. The Chromosome Analysis Suite software (Affymetrix) was used to analyze CNA. Only those mutations with ≥10% variant allele frequency (VAF) and CNA larger than 1Mb were considered. Results: In the training set, 193/226 (85%) and 231/269 (86%) of total mutations present in BM and EM clonal PCs, respectively, were detectable on CTCs. All MM recurrent mutations (eg. BRAF) found in BM or EM clonal PCs were present in CTCs. Of note, there were 39 mutations in EM plasmacytomas that were detectable in CTCs but absent in BM clonal PCs. Furthermore, up to 50 mutations were present in CTCs while undetectable in BM clonal PCs (n=44) or EM plasmacytomas (n=6). After showing that CTCs harbor most mutations present in both medullary and extramedullary disease and even unveil mutations undetectable in single BM aspirates or individual EM plasmacytomas, we sought to evaluate the performance of standardized assays suitable to screen mutations and/or CNA from low cell numbers (ie. CTCs). Using 10XGenomics, 250/266 (94%) of total mutations and 17/17 (100%) of MM recurrent mutations present in BM clonal PCs were detectable on CTCs (eg. KRAS, BRAF, TP53 or FAM46C). The VAF of private mutations ranged between 0.1 and 0.3, suggesting these were subclonal in their respective spatial regions. Using 10XGenomics, 101/119 (85%) CNA and 2/2 (100%) IgH Tx present in BM clonal PCs were detectable in CTCs. Using the Cytoscan HD, there was 100% concordance between CNA in CTCs and BM clonal PCs, both at the chromosomal arm and interstitial levels. All mutations in TP53 were detectable in CTCs. Furthermore, +1q, del(1p), del(17p) or t(4;14) were always detected in CTCs whenever present in BM clonal PCs, and confirmed by FISH. Conversely, such comprehensive genetic characterization unveiled innumerous CNA and translocations not tested by routine FISH panels [eg. MYC amplification or t(6;14)]. Conclusions: Using two different standardized methods, we showed in the largest series in which CTCs were genetically characterized, that these are a reliable surrogate of MM patients' genetic landscape inside and outside the BM. Because NGF is broadly used, quantification, isolation and genetic characterization of CTCs may emerge as an optimal and standardized approach for non-invasive risk-stratification of MM patients. Disclosures Rios: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. San-Miguel:Amgen, Bristol-Myers Squibb, Celgene, Janssen, MSD, Novartis, Roche, Sanofi, and Takeda: Consultancy, Honoraria. Paiva:Amgen, Bristol-Myers Squibb, Celgene, Janssen, Merck, Novartis, Roche and Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene, Janssen, Sanofi and Takeda: Consultancy.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-126527

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Clinical Lymphoma Myeloma and Leukemia, Elsevier BV, Vol. 19, No. 10 ( 2019-10), p. e351-

Type of Medium: Online Resource

ISSN: 2152-2650

URL: Article

DOI: 10.1016/j.clml.2019.09.580

Language: English

Publisher: Elsevier BV

Publication Date: 2019

detail.hit.zdb_id: 2540998-0

detail.hit.zdb_id: 2193618-3

In: Blood, American Society of Hematology, Vol. 134, No. 11 ( 2019-09-12), p. 900-905

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.2019000893

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 13-14

Abstract: Introduction Multiple Myeloma (MM) is a heterogeneous disease with a complex clonal and subclonal architecture with few recurrent mutations. The arrival of next-generation sequencing (NGS) has allowed us to have a deeper understanding of the disease. Due to that complexity and the low recurrence of "driver" mutations, the study of general mutational profile, copy number variation (CNV) and translocations is crucial to make an accurate diagnosis and prognosis. For that reason, a clinically validated NGS capture panel has been designed to analyze in a single assay all interesting genetic aberrations simultaneously including SNVs, indels, CNVs and chromosomal translocations. Methods In addition to genomic DNA (gDNA) from 33 healthy donors to create a robust baseline forCNV detection,we studied 161 DNA samples from 149 newly diagnosed MM patients enrolled in the GEM2012MENOS65clinical trial and treated homogeneously: gDNA from 149 BM CD138+ plasma cells and 12 paired cfDNA from peripheral blood samples obtained at diagnosis. First, starting with 100 ng of gDNA and 200ng for cfDNA samples, a custom targeted NGS panel using SureSelect capture technology (Agilent) followed by NextSeq500 (Illumina) sequencing identified SNVs, indels, CNVs and the most relevant IGH translocations within 26genes involved with MM. The average sequencing depth was 609x across samples; and 98% of the targeted regions were sequenced with & gt;200x. Second, NGS custom panel results were compared with FISH (n=88) and whole exome sequencing (SureSelect XT V6) (n=48) results. Both NGS panel and exome raw data were analyzed by DREAMgenics applying a custom bioinformatic pipeline. Finally, 5 discordant cases were followed-up by SNP-arrays. Results We have identified 408 exonic and non-synonymous variants. At least 1 oncogenic mutation was detected in 86% (128/149) of patients. NRAS was mutated in25% of patients, followed by KRAS(23%), BRAF(12%) DIS3(11%) and TP53(9%). Other interesting pathogenic mutations were identified in FGFR3 andHIST1H1E genes in 9% and 5% of patients, respectively. In 92% (11/12) of cfDNA samples at least 1 oncogenic mutation was detected. For this 12 cases, paired samples (BM CD138+vscfDNA) were available. A total of 39 somatic mutations were identified in those cases. In cfDNA, 10 mutations were detected, and 5 were present in both samples. Furthermore, a mean decrease of 0.19VAF was observed in cfDNA (0.12; 0.01-0.48) vs plasma cells (0.31; 0.01-0.51). Regarding to CNV, 1q gain was detected in 32% of patients (28/88), and 1p and 17p deletions in 17% (15/88) and 13% (11/88), respectively. Additionally, ATR and CRBN gene amplifications were detected in 22% and 16%, respectively. When these data were compared to FISH, a 75% of sensitivity and 91% of specificity was achieved by our method, with a PPV of 68% and a NPG of 93%. Translocations were identified in 28% (25/88) of patients, including 7% (6/88)) t(11;14), 14% (12/88), t(4;14), and 1 patient t(14;16). We also detected t(6;14)(p21;q32) IGH/CCND3 in 3 patients that had also been described in MM.Translocations were detected with a 94% of sensitivity, 99% of specificity, with a predictive positive value of 94% and a predictive negative value of 99%. Importantly, NGS-based method revealed a t(10;14) in 3 patients that had not been identified by FISH, a new translocation implying the miRNA hsa-mir-4537. Finally, the impact on PFS from FISH and NGS results was analyzed separately. PFS was similar for translocations and 17p deletions. However, 1p-detected by NGS showed a higher negative prognostic impact (p=0,006 vs p=0,127 by FISH)(Fig.1). Furthermore, our panel showed that 7% of patients (6/88) had a bi-allelic TP53 inactivation. Survival analysis showed that these patients relapsed significantly earlier than the others (p=0.028). Amplifications (≥4 copies) in 1q+could not identified with this panel. Conclusions Our custom NGS-based test allows in a single assay a more comprehensive study of the genomic landscape of MM patients by (a) detecting with a high sensitivity the most important and recurrent mutations and cytogenetic alterations, (b) identifying translocations and CNVs not previously detected by FISH and (c) identifying a double-hit MM patient. Additionally, cfDNA could be analyzed with this NGS strategy identifying molecular alterations in most of the patients. Disclosures Oriol: Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy. Sureda Balari:Takeda: Consultancy, Honoraria, Speakers Bureau; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Roche: Honoraria; Sanofi: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Gilead/Kite: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Incyte: Consultancy; Celgene: Consultancy, Honoraria; BMS: Speakers Bureau; Merck Sharpe and Dohme: Consultancy, Honoraria, Speakers Bureau. de la Rubia:Janssen: Consultancy, Other: Expert Testimony; Celgene: Consultancy, Other: Expert Testimony; Amgen: Consultancy, Other: Expert Testimony; Ablynx/Sanofi: Consultancy, Other: Expert Testimony. Mateos:Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; PharmaMar-Zeltia: Consultancy; Abbvie/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Honoraria; Regeneron: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Blade Creixenti:Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. San-Miguel:Amgen, BMS, Celgene, Janssen, MSD, Novartis, Takeda, Sanofi, Roche, Abbvie, GlaxoSmithKline and Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees. Garcia-Sanz:Novartis: Honoraria; Janssen: Honoraria, Research Funding; Incyte: Research Funding; Gilead: Honoraria, Research Funding; BMS: Honoraria; Amgen: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria; Takeda: Consultancy, Research Funding. Martinez-Lopez:Novartis: Research Funding; BMS: Research Funding, Speakers Bureau; Incyte: Research Funding, Speakers Bureau; Janssen: Speakers Bureau; Roche: Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau; Vivia Biotech: Honoraria; Altum: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Hosea: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2020-140711

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 135, No. 26 ( 2020-06-25), p. 2375-2387

Abstract: Risk of developing myelodysplastic syndrome (MDS) is significantly increased in both multiple myeloma (MM) and monoclonal gammopathy of undetermined significance, suggesting that it is therapy independent. However, the incidence and sequelae of dysplastic hematopoiesis at diagnosis are unknown. Here, we used multidimensional flow cytometry (MFC) to prospectively screen for the presence of MDS-associated phenotypic alterations (MDS-PA) in the bone marrow of 285 patients with MM enrolled in the PETHEMA/GEM2012MENOS65 trial (#NCT01916252). We investigated the clinical significance of monocytic MDS-PA in a larger series of 1252 patients enrolled in 4 PETHEMA/GEM protocols. At diagnosis, 33 (11.6%) of 285 cases displayed MDS-PA. Bulk and single-cell–targeted sequencing of MDS recurrently mutated genes in CD34+ progenitors (and dysplastic lineages) from 67 patients revealed clonal hematopoiesis in 13 (50%) of 26 cases with MDS-PA vs 9 (22%) of 41 without MDS-PA; TET2 and NRAS were the most frequently mutated genes. Dynamics of MDS-PA at diagnosis and after autologous transplant were evaluated in 86 of 285 patients and showed that in most cases (69 of 86 [80%]), MDS-PA either persisted or remained absent in patients with or without MDS-PA at diagnosis, respectively. Noteworthy, MDS-associated mutations infrequently emerged after high-dose therapy. Based on MFC profiling, patients with MDS-PA have altered hematopoiesis and T regulatory cell distribution in the tumor microenvironment. Importantly, the presence of monocytic MDS-PA at diagnosis anticipated greater risk of hematologic toxicity and was independently associated with inferior progression-free survival (hazard ratio, 1.5; P = .02) and overall survival (hazard ratio, 1.7; P = .01). This study reveals the biological and clinical significance of dysplastic hematopoiesis in newly diagnosed MM, which can be screened with moderate sensitivity using cost-effective MFC.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.2019003382

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 1527-1527

Abstract: Background: Although MYD88 L265P is highly frequent in WM, by itself is insufficient to explain disease progression since most cases with IgM MGUS also have mutated MYD88. In fact, the percentage of MYD88 L265P in CD19+ cells isolated from WM patients is typically & lt;100%, which questions if this mutation initiates the formation of B-cell clones. Furthermore, a few WM patients have detectable MYD88 L265P in total bone marrow (BM) cells and not in CD19+ selected B cells, raising the possibility that other hematopoietic cells carry the MYD88 mutation. However, no one has investigated if the pathogenesis of WM is related to somatic mutations occurring at the hematopoietic stem cell level, similarly to what has been shown in CLL or hairy cell leukemia. Aim: Define the cellular origin of WM by comparing the genetic landscape of WM cells to that of CD34 progenitors, B cell precursors and residual normal B cells. Methods: We used multidimensional FACSorting to isolate a total of 43 cell subsets from BM aspirates of 8 WM patients: CD34+ progenitors, B cell precursors, residual normal B cells (if detectable), WM B cells, plasma cells (PCs) and T cells (germline control). Whole-exome sequencing (WES, mean depth 74x) was performed with the 10XGenomics Exome Solution for low DNA-input due to very low numbers of some cell types. We also performed single-cell RNA and B-cell receptor sequencing (scRNA/BCRseq) in total BM B cells and PCs (n=32,720) from 3 IgM MGUS and 2 WM patients. Accordingly, the clonotypic BCR detected in WM cells was unbiasedly investigated in all B cell maturation stages defined according to their molecular phenotype. In parallel, MYD88p.L252P (orthologous position of the human L265P mutation) transgenic mice were crossed with conditional Sca1Cre, Mb1Cre, and Cγ1Cre mice to selectively induce in vivo expression of MYD88 mutation in CD34 progenitors, B cell precursors and germinal center B cells, respectively. Upon immunization, mice from each cohort were necropsied at 5, 10 and 15 months of age and screened for the presence of hematological disease. Results: All 8 WM patients showed MYD88 L265P and 3 had mutated CXCR4. Notably, we found MYD88 L265P in B cell precursors from 1/8 cases and in residual normal B cells from 3/8 patients, which were confirmed by ASO-PCR. In addition, CXCR4 was simultaneously mutated in B cell precursors and WM B cells from one patient. Overall, CD34+ progenitors, B-cell precursors and residual normal B cells shared a median of 1 (range, 0-4; mean VAF, 0.16), 2 (range, 1-5; mean VAF, 0.14), and 4 (range, 1-13; mean VAF, 0.26) non-synonymous mutations with WM B cells. Some mutations were found all the way from CD34+ progenitors to WM B cells and PCs. Interestingly, concordance between the mutational landscape of WM B cells and PCs was & lt;100% (median of 85%, range: 25%-100%), suggesting that not all WB B cells differentiate into PCs. A median of 7 (range, 2-19; mean VAF, 0.39) mutations were unique to WM B cells. Accordingly, many clonal mutations in WM B cells were undetectable in normal cells. Thus, the few somatic mutations observed in patients' lymphopoiesis could not result from contamination during FACSorting since in such cases, all clonal mutations would be detectable in normal cells. Of note, while somatic mutations were systematically detected in normal cells from all patients, no copy number alterations (CNA) present in WM cells were detectable in normal cells. scRNA/BCRseq unveiled that clonotypic cells were confined mostly within mature B cell and PC clusters in IgM MGUS, whereas a fraction of clonotypic cells from WM patients showed a transcriptional profile overlapping with that of B cell precursors. In mice, induced expression of mutated MYD88 led to a moderate increase in the number of B220+CD138+ plasmablasts and B220-CD138+ PCs in lymphoid tissues and BM, but no signs of clonality or hematological disease. Interestingly, such increment was more evident in mice with activation of mutated MYD88 in CD34+ progenitors and B-cell precursors vs mice with MYD88 L252P induced in germinal center B cells. Conclusions: We show for the first time that WM patients have somatic mutations, including MYD88 L265P and in CXCR4, at the B cell progenitor level. Taken together, this study suggests that in some patients, WM could develop from B cell clones carrying MYD88 L265P rather than it being the initiating event, and that other mutations or CNA are required for the expansion of B cells and PCs with the WM phenotype. Disclosures Roccaro: Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Transcan2-ERANET: Research Funding; AstraZeneca: Research Funding; European Hematology Association: Research Funding; Transcan2-ERANET: Research Funding; Associazione Italiana per al Ricerca sul Cancro (AIRC): Research Funding; Associazione Italiana per al Ricerca sul Cancro (AIRC): Research Funding; European Hematology Association: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees. San-Miguel:Amgen, Bristol-Myers Squibb, Celgene, Janssen, MSD, Novartis, Roche, Sanofi, and Takeda: Consultancy, Honoraria. Paiva:Amgen, Bristol-Myers Squibb, Celgene, Janssen, Merck, Novartis, Roche, and Sanofi; unrestricted grants from Celgene, EngMab, Sanofi, and Takeda; and consultancy for Celgene, Janssen, and Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-126889

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Annual Review of Nutrition, Annual Reviews, Vol. 43, No. 1 ( 2023-08-21), p. 225-250

Abstract: Modernization of society from a rural, hunter-gatherer setting into an urban and industrial habitat, with the associated dietary changes, has led to an increased prevalence of cardiometabolic and additional noncommunicable diseases, such as cancer, inflammatory bowel disease, and neurodegenerative and autoimmune disorders. However, while dietary sciences have been rapidly evolving to meet these challenges, validation and translation of experimental results into clinical practice remain limited for multiple reasons, including inherent ethnic, gender, and cultural interindividual variability, among other methodological, dietary reporting–related, and analytical issues. Recently, large clinical cohorts with artificial intelligence analytics have introduced new precision and personalized nutrition concepts that enable one to successfully bridge these gaps in a real-life setting. In this review, we highlight selected examples of case studies at the intersection between diet–disease research and artificial intelligence. We discuss their potential and challenges and offer an outlook toward the transformation of dietary sciences into individualized clinical translation.

Type of Medium: Online Resource

ISSN: 0199-9885 , 1545-4312

URL: Issue

URL: Article

DOI: 10.1146/nutr.2023.43.issue-1

DOI: 10.1146/annurev-nutr-061121-090535

Language: English

Publisher: Annual Reviews

Publication Date: 2023

detail.hit.zdb_id: 1481486-9

In: The American Journal of Geriatric Pharmacotherapy, Elsevier BV, Vol. 2, No. 4 ( 2004-12), p. 219-229

Type of Medium: Online Resource

ISSN: 1543-5946

URL: Article

DOI: 10.1016/j.amjopharm.2004.12.004

Language: English

Publisher: Elsevier BV

Publication Date: 2004

In: Scientific Reports, Springer Science and Business Media LLC, Vol. 6, No. 1 ( 2016-04-20)

Abstract: Scientific Reports 6: Article number: 20697; published online: 08 February 2016; updated: 20 April 2016. The original version of this Article contained errors in the spelling of the authors Elena Sánchez-Cuartielles and Rafael Valdés-Mas which were incorrectly given as Sánchez-Cuartielles Elena and Valdés-Mas Rafael respectively.

Type of Medium: Online Resource

ISSN: 2045-2322

URL: Article

DOI: 10.1038/srep23880

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2016

detail.hit.zdb_id: 2615211-3