Mechanistic patterns and clinical implications of oncogenic tyrosine kinase fusions in human cancers.

Humans Neoplasms / genetics Oncogene Proteins, Fusion / genetics Protein-Tyrosine Kinases / genetics Proto-Oncogene Proteins c-ret / genetics Translocation, Genetic Anaplastic Lymphoma Kinase / genetics Receptor, trkA / genetics Protein Kinase Inhibitors / pharmacology Proto-Oncogene Proteins / genetics Signal Transduction / genetics Cell Line, Tumor

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
14 Jun 2024
Historique:
received: 08 01 2024
accepted: 04 06 2024
medline: 15 6 2024
pubmed: 15 6 2024
entrez: 14 6 2024
Statut: epublish

Résumé

Tyrosine kinase (TK) fusions are frequently found in cancers, either as initiating events or as a mechanism of resistance to targeted therapy. Partner genes and exons in most TK fusions are followed typical recurrent patterns, but the underlying mechanisms and clinical implications of these patterns are poorly understood. By developing Functionally Active Chromosomal Translocation Sequencing (FACTS), we discover that typical TK fusions involving ALK, ROS1, RET and NTRK1 are selected from pools of chromosomal rearrangements by two major determinants: active transcription of the fusion partner genes and protein stability. In contrast, atypical TK fusions that are rarely seen in patients showed reduced protein stability, decreased downstream oncogenic signaling, and were less responsive to inhibition. Consistently, patients with atypical TK fusions were associated with a reduced response to TKI therapies. Our findings highlight the principles of oncogenic TK fusion formation and selection in cancers, with clinical implications for guiding targeted therapy.

Identifiants

DOI: 10.1038/s41467-024-49499-0 PMID: 38877018
pubmed: 38877018
doi: 10.1038/s41467-024-49499-0
pii: 10.1038/s41467-024-49499-0
doi:

Substances chimiques

Oncogene Proteins, Fusion 0
Protein-Tyrosine Kinases EC 2.7.10.1
Proto-Oncogene Proteins c-ret EC 2.7.10.1
Anaplastic Lymphoma Kinase EC 2.7.10.1
ROS1 protein, human EC 2.7.10.1
Receptor, trkA EC 2.7.10.1
Protein Kinase Inhibitors 0
Proto-Oncogene Proteins 0
RET protein, human EC 2.7.10.1
ALK protein, human EC 2.7.10.1
NTRK1 protein, human 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

5110

Subventions

Organisme : U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
ID : 1R01-CA222598-01

Informations de copyright

© 2024. The Author(s).

Références

Maddalo, D. et al. In vivo engineering of oncogenic chromosomal rearrangements with the CRISPR/Cas9 system. Nature 516, 423–427 (2014).
pubmed: 25337876 pmcid: 4270925 doi: 10.1038/nature13902
Stransky, N., Cerami, E., Schalm, S., Kim, J. L. & Lengauer, C. The landscape of kinase fusions in cancer. Nat. Commun. 5, 4846 (2014).
pubmed: 25204415 doi: 10.1038/ncomms5846
Lee, J. J. et al. Tracing oncogene rearrangements in the mutational history of lung adenocarcinoma. Cell 177, 1842–1857 e1821 (2019).
pubmed: 31155235 doi: 10.1016/j.cell.2019.05.013
Gao, Q. et al. Driver fusions and their implications in the development and treatment of human cancers. Cell Rep. 23, 227–238 e223 (2018).
pubmed: 29617662 pmcid: 5916809 doi: 10.1016/j.celrep.2018.03.050
Piotrowska, Z. et al. Landscape of acquired resistance to osimertinib in EGFR-Mutant NSCLC and clinical validation of combined EGFR and RET inhibition with Osimertinib and BLU-667 for acquired RET fusion. Cancer Discov. 8, 1529–1539 (2018).
pubmed: 30257958 pmcid: 6279502 doi: 10.1158/2159-8290.CD-18-1022
Oxnard, G. R. et al. Assessment of resistance mechanisms and clinical implications in patients With EGFR T790M-positive lung cancer and acquired resistance to osimertinib. JAMA Oncol. 4, 1527–1534 (2018).
pubmed: 30073261 doi: 10.1001/jamaoncol.2018.2969
Offin, M. et al. Acquired ALK and RET gene fusions as mechanisms of resistance to osimertinib in EGFR-mutant lung cancers. JCO Precis. Oncol. 2, 1–12 (2018).
Awad, M. M. et al. Acquired resistance to KRAS(G12C) inhibition in cancer. N. Engl. J. Med. 384, 2382–2393 (2021).
pubmed: 34161704 pmcid: 8864540 doi: 10.1056/NEJMoa2105281
Yaeger, R. et al. Molecular characterization of acquired resistance to KRASG12C-EGFR inhibition in colorectal cancer. Cancer Discov 13, 41–55 (2023).
pubmed: 36355783 doi: 10.1158/2159-8290.CD-22-0405
Drilon, A. et al. Efficacy of selpercatinib in RET fusion-positive non-small-cell lung cancer. N. Engl. J. Med. 383, 813–824 (2020).
pubmed: 32846060 pmcid: 7506467 doi: 10.1056/NEJMoa2005653
Drilon, A. et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N. Engl. J. Med. 378, 731–739 (2018).
pubmed: 29466156 pmcid: 5857389 doi: 10.1056/NEJMoa1714448
Rotow, J. et al. Osimertinib and selpercatinib efficacy, safety, and resistance in a multicenter, prospectively treated cohort of EGFR-mutant and RET fusion-positive lung cancers. Clin. Cancer Res. 29, 2979–2987 (2023).
pubmed: 36996322 pmcid: 10524391 doi: 10.1158/1078-0432.CCR-22-2189
Chiarle, R., Voena, C., Ambrogio, C., Piva, R. & Inghirami, G. The anaplastic lymphoma kinase in the pathogenesis of cancer. Nat. Rev. Cancer 8, 11–23 (2008).
pubmed: 18097461 doi: 10.1038/nrc2291
Roukos, V. & Misteli, T. The biogenesis of chromosome translocations. Nat. Cell Biol.16, 293–300 (2014).
pubmed: 24691255 pmcid: 6337718 doi: 10.1038/ncb2941
Soda, M. et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 448, 561–566 (2007).
pubmed: 17625570 doi: 10.1038/nature05945
Takeuchi, K. et al. RET, ROS1 and ALK fusions in lung cancer. Nat. Med. 18, 378–381 (2012).
pubmed: 22327623 doi: 10.1038/nm.2658
Chiarle, R. et al. Genome-wide translocation sequencing reveals mechanisms of chromosome breaks and rearrangements in B cells. Cell 147, 107–119 (2011).
pubmed: 21962511 pmcid: 3186939 doi: 10.1016/j.cell.2011.07.049
Klein, I. A. et al. Translocation-capture sequencing reveals the extent and nature of chromosomal rearrangements in B lymphocytes. Cell 147, 95–106 (2011).
pubmed: 21962510 pmcid: 3190307 doi: 10.1016/j.cell.2011.07.048
Frock, R. L. et al. Genome-wide detection of DNA double-stranded breaks induced by engineered nucleases. Nat. Biotechnol. 33, 179–186 (2015).
pubmed: 25503383 doi: 10.1038/nbt.3101
Kobayashi, Y. et al. Genomic and biological study of fusion genes as resistance mechanisms to EGFR inhibitors. Nat. Commun. 13, 5614 (2022).
pubmed: 36153311 pmcid: 9509394 doi: 10.1038/s41467-022-33210-2
Schrock, A. B. et al. Receptor tyrosine kinase fusions and BRAF kinase fusions are rare but actionable resistance mechanisms to EGFR tyrosine kinase inhibitors. J. Thorac. Oncol. 13, 1312–1323 (2018).
pubmed: 29883838 doi: 10.1016/j.jtho.2018.05.027
Nomori, H. et al. Detection of NK activity and antibody-dependent cellular cytotoxicity of lymphocytes by human tumor clonogenic assay-its correlation with the 51Cr-release assay. Int. J. Cancer 35, 449–455 (1985).
pubmed: 3872846 doi: 10.1002/ijc.2910350406
Rho, J. K. et al. The role of MET activation in determining the sensitivity to epidermal growth factor receptor tyrosine kinase inhibitors. Mol. Cancer Res. 7, 1736–1743 (2009).
pubmed: 19808904 doi: 10.1158/1541-7786.MCR-08-0504
Nukaga, S. et al. Amplification of EGFR wild-type alleles in non-small cell lung cancer cells confers acquired resistance to mutation-selective EGFR tyrosine kinase inhibitors. Cancer Res. 77, 2078–2089 (2017).
pubmed: 28202511 doi: 10.1158/0008-5472.CAN-16-2359
Cross, D. A. et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov. 4, 1046–1061 (2014).
pubmed: 24893891 pmcid: 4315625 doi: 10.1158/2159-8290.CD-14-0337
Choi, P. S. & Meyerson, M. Targeted genomic rearrangements using CRISPR/Cas technology. Nat. Commun. 5, 3728 (2014).
pubmed: 24759083 doi: 10.1038/ncomms4728
Blasco, R. B. et al. Simple and rapid in vivo generation of chromosomal rearrangements using CRISPR/Cas9 technology. Cell Rep. 9, 1219–1227 (2014).
pubmed: 25456124 doi: 10.1016/j.celrep.2014.10.051
Zheng, Z. et al. Anchored multiplex PCR for targeted next-generation sequencing. Nat. Med. 20, 1479–1484 (2014).
pubmed: 25384085 doi: 10.1038/nm.3729
Ou, S. I., Zhu, V. W. & Nagasaka, M. Catalog of 5’ fusion partners in ALK-positive NSCLC Circa 2020. JTO Clin. Res. Rep. 1, 100015 (2020).
pubmed: 34589917 pmcid: 8474466
Crystal, A. S. & Shaw, A. T. New targets in advanced NSCLC: EML4-ALK. Clin. Adv. Hematol. Oncol.9, 207–214 (2011).
pubmed: 21475126
Heuckmann, J. M. et al. Differential protein stability and ALK inhibitor sensitivity of EML4-ALK fusion variants. Clin. Cancer Res. 18, 4682–4690 (2012).
pubmed: 22912387 doi: 10.1158/1078-0432.CCR-11-3260
Bandopadhayay, P. et al. MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism. Nat. Genetics 48, 273–282 (2016).
pubmed: 26829751 doi: 10.1038/ng.3500
Zhu, S. et al. Genetic alterations of TRAF proteins in human cancers. Front. Immunol. 9, 2111 (2018).
pubmed: 30294322 pmcid: 6158389 doi: 10.3389/fimmu.2018.02111
Yu, Y. P. et al. Identification of recurrent fusion genes across multiple cancer types. Sci. Rep. 9, 1074 (2019).
pubmed: 30705370 pmcid: 6355770 doi: 10.1038/s41598-019-38550-6
Zhong, M. et al. Malignant transformation of human bronchial epithelial cells induced by arsenic through STAT3/miR-301a/SMAD4 loop. Sci. Rep. 8, 13291 (2018).
pubmed: 30185897 pmcid: 6125593 doi: 10.1038/s41598-018-31516-0
Thai, A. A., Solomon, B. J., Sequist, L. V., Gainor, J. F. & Heist, R. S. Lung cancer. Lancet 398, 535–554 (2021).
pubmed: 34273294 doi: 10.1016/S0140-6736(21)00312-3
Ou, S. I. & Nagasaka, M. A catalog of 5’ fusion partners in ROS1-positive NSCLC circa 2020. JTO Clin. Res. Rep. 1, 100048 (2020).
pubmed: 34589944 pmcid: 8474457
Vaishnavi, A., Le, A. T. & Doebele, R. C. TRKing down an old oncogene in a new era of targeted therapy. Cancer Discov. 5, 25–34 (2015).
pubmed: 25527197 doi: 10.1158/2159-8290.CD-14-0765
Ou, S. I. & Zhu, V. W. Catalog of 5’ fusion partners in RET+ NSCL circa 2020. JTO Clin. Res Rep 1, 100037 (2020).
pubmed: 34589933 pmcid: 8474217
Schroder, B. The multifaceted roles of the invariant chain CD74-More than just a chaperone. Biochim. Biophys. Acta 1863, 1269–1281 (2016).
pubmed: 27033518 doi: 10.1016/j.bbamcr.2016.03.026
Davies, K. D. et al. Dramatic response to crizotinib in a patient with lung cancer positive for an HLA-DRB1-MET gene fusion. JCO Precis. Oncol. 2017, 1–6 (2017).
Devaiah, B. N. & Singer, D. S. CIITA and its dual roles in MHC gene transcription. Front. immunology 4, 476 (2013).
doi: 10.3389/fimmu.2013.00476
Lieber, M. R. Mechanisms of human lymphoid chromosomal translocations. Nat. Rev. Cancer 16, 387–398 (2016).
pubmed: 27220482 pmcid: 5336345 doi: 10.1038/nrc.2016.40
Meng, F. L. et al. Convergent transcription at intragenic super-enhancers targets AID-initiated genomic instability. Cell 159, 1538–1548 (2014).
pubmed: 25483776 pmcid: 4322776 doi: 10.1016/j.cell.2014.11.014
Kohno, T. et al. Beyond ALK-RET, ROS1 and other oncogene fusions in lung cancer. Transl. Lung Cancer Res. 4, 156–164 (2015).
pubmed: 25870798 pmcid: 4384213
Zhang, Y. et al. Spatial organization of the mouse genome and its role in recurrent chromosomal translocations. Cell 148, 908–921 (2012).
pubmed: 22341456 pmcid: 3320767 doi: 10.1016/j.cell.2012.02.002
Hakim, O. et al. DNA damage defines sites of recurrent chromosomal translocations in B lymphocytes. Nature 484, 69–74 (2012).
pubmed: 22314321 pmcid: 3459314 doi: 10.1038/nature10909
Wen, S. et al. Genomic signature of driver genes identified by target next-generation sequencing in Chinese non-small cell lung cancer. The Oncologist 24, e1070–e1081 (2019).
pubmed: 30902917 pmcid: 6853120 doi: 10.1634/theoncologist.2018-0572
Zhao, R. et al. Clinicopathological features of ALK expression in 9889 cases of non-small-cell lung cancer and genomic rearrangements identified by capture-based next-generation sequencing: a Chinese retrospective analysis. Mol Diagn Ther 23, 395–405 (2019).
pubmed: 30840206 doi: 10.1007/s40291-019-00389-y
Tulpule, A. et al. Kinase-mediated RAS signaling via membraneless cytoplasmic protein granules. Cell 184, 2649–2664 e2618 (2021).
pubmed: 33848463 pmcid: 8127962 doi: 10.1016/j.cell.2021.03.031
Fang, D. D. et al. HIP1-ALK, a novel ALK fusion variant that responds to crizotinib. J. Thorac. Oncol. 9, 285–294 (2014).
pubmed: 24496003 doi: 10.1097/JTO.0000000000000087
Consortium, A. P. G. AACR project GENIE: powering precision medicine through an international consortium. Cancer Discov. 7, 818–831 (2017).
doi: 10.1158/2159-8290.CD-17-0151
Lee, J. J. et al. ERalpha-associated translocations underlie oncogene amplifications in breast cancer. Nature 618, 1024–1032 (2023).
pubmed: 37198482 pmcid: 10307628 doi: 10.1038/s41586-023-06057-w
Compagno, M. et al. Phosphatidylinositol 3-kinase delta blockade increases genomic instability in B cells. Nature 542, 489–493 (2017).
pubmed: 28199309 pmcid: 5382874 doi: 10.1038/nature21406
Robbiani, D. F. & Nussenzweig, M. C. Chromosome translocation, B cell lymphoma, and activation-induced cytidine deaminase. Annual Rev. Pathol. 8, 79–103. (2012).
Graf, A. et al. Knockout of histidine decarboxylase decreases bile duct ligation-induced biliary hyperplasia via downregulation of the histidine decarboxylase/VEGF axis through PKA-ERK1/2 signaling. Am. J. Physiol. Gastrointest. Liver Physiol. 307, G813–G823 (2014).
pubmed: 25169977 doi: 10.1152/ajpgi.00188.2014
Oser, M. G., Niederst, M. J., Sequist, L. V. & Engelman, J. A. Transformation from non-small-cell lung cancer to small-cell lung cancer: molecular drivers and cells of origin. The Lancet Oncol. 16, e165–e172 (2015).
pubmed: 25846096 doi: 10.1016/S1470-2045(14)71180-5
Rowbotham, S. P. & Kim, C. F. Diverse cells at the origin of lung adenocarcinoma. Proc. Natl Acad. Sci. USA 111, 4745–4746 (2014).
pubmed: 24707043 pmcid: 3977312 doi: 10.1073/pnas.1401955111
Hamperl, S. & Cimprich, K. A. Conflict resolution in the genome: how transcription and replication make it work. Cell 167, 1455–1467 (2016).
pubmed: 27912056 pmcid: 5141617 doi: 10.1016/j.cell.2016.09.053
Isozaki, H. et al. Therapy-induced APOBEC3A drives evolution of persistent cancer cells. Nature 620, 393–401 (2023).
pubmed: 37407818 pmcid: 10804446 doi: 10.1038/s41586-023-06303-1
Gostissa, M., Alt, F. W. & Chiarle, R. Mechanisms that promote and suppress chromosomal translocations in lymphocytes. Annu. Rev. Immunol. 29, 319–350 (2011).
pubmed: 21219174 doi: 10.1146/annurev-immunol-031210-101329
Alt, F. W., Zhang, Y., Meng, F. L., Guo, C. & Schwer, B. Mechanisms of programmed DNA lesions and genomic instability in the immune system. Cell 152, 417–429 (2013).
pubmed: 23374339 pmcid: 4382911 doi: 10.1016/j.cell.2013.01.007
Liu, Y. et al. Etiology of oncogenic fusions in 5,190 childhood cancers and its clinical and therapeutic implication. Nat. Commun. 14, 1739 (2023).
pubmed: 37019972 pmcid: 10076316 doi: 10.1038/s41467-023-37438-4
Lieberman-Aiden, E. et al. Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science 326, 289–293 (2009).
pubmed: 19815776 pmcid: 2858594 doi: 10.1126/science.1181369
Liu, J. et al. Genetic fusions favor tumorigenesis through degron loss in oncogenes. Nat. Commun. 12, 6704 (2021).
pubmed: 34795215 pmcid: 8602260 doi: 10.1038/s41467-021-26871-y
Rogers, S., Wells, R. & Rechsteiner, M. Amino acid sequences common to rapidly degraded proteins: the PEST hypothesis. Science 234, 364–368 (1986).
pubmed: 2876518 doi: 10.1126/science.2876518
Anai, S. et al. A case of lung adenocarcinoma resistant to Crizotinib harboring a novel EML4-ALK variant, exon 6 of EML4 fused to exon 18 of ALK. J. Thorac. Oncol. 11, e126–e128 (2016).
pubmed: 27663401 doi: 10.1016/j.jtho.2016.07.008
Takeyasu, Y. et al. Impact of ALK inhibitors in patients with ALK-rearranged nonlung solid tumors. JCO Precis. Oncol. 5, 756–766 (2021).
Cheong, T. C., Compagno, M. & Chiarle, R. Editing of mouse and human immunoglobulin genes by CRISPR-Cas9 system. Nat. Commun. 7, 10934 (2016).
pubmed: 26956543 pmcid: 4786874 doi: 10.1038/ncomms10934
Church, A. J. et al. Recurrent EML4-NTRK3 fusions in infantile fibrosarcoma and congenital mesoblastic nephroma suggest a revised testing strategy. Modern Pathol. 31, 463–473 (2018).
doi: 10.1038/modpathol.2017.127
Zang, C. et al. A clustering approach for identification of enriched domains from histone modification ChIP-Seq data. Bioinformatics 25, 1952–1958 (2009).
pubmed: 19505939 pmcid: 2732366 doi: 10.1093/bioinformatics/btp340
Li, H. & Durbin, R. Fast and accurate short read alignment with Burrows–Wheeler transform. Bioinformatics 25, 1754–1760 (2009).
pubmed: 19451168 pmcid: 2705234 doi: 10.1093/bioinformatics/btp324
Zhang, Y. et al. Model-based analysis of ChIP-Seq (MACS). Genome Biol. 9, R137 (2008).
pubmed: 18798982 pmcid: 2592715 doi: 10.1186/gb-2008-9-9-r137
Garcia, E. P. et al. Validation of OncoPanel: A targeted next-generation sequencing assay for the detection of somatic variants in cancer. Arch. Pathol. Lab Med. 141, 751–758 (2017).
pubmed: 28557599 doi: 10.5858/arpa.2016-0527-OA
Karczewski, K. J. et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 581, 434–443 (2020).
pubmed: 32461654 pmcid: 7334197 doi: 10.1038/s41586-020-2308-7
Landrum, M. J. et al. ClinVar: improving access to variant interpretations and supporting evidence. Nucleic Acids Res. 46, D1062–D1067 (2018).
pubmed: 29165669 doi: 10.1093/nar/gkx1153
Wang, Q. A. qwang-flyinggene/GEAT:GEAT v0.1. Zenodo https://doi.org/10.5281/zenodo.6592772(2022) .

Auteurs

Taek-Chin Cheong (TC)

Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA, 02115, USA. taekchin.cheong@childrens.harvard.edu.
ORCID: 0000-0002-0939-9412

Ahram Jang (A)

Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, 02115, USA.
ORCID: 0000-0002-4286-4718

Qi Wang (Q)

Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
ORCID: 0000-0002-4306-3293

Giulia C Leonardi (GC)

Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
Department of Biomedical and Biotechnological Sciences, University of Catania, 95123, Catania, Italy.

Biagio Ricciuti (B)

Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA.

Joao V Alessi (JV)

Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA.

Alessandro Di Federico (A)

Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA.

Mark M Awad (MM)

Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA.

Maria K Lehtinen (MK)

Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
ORCID: 0000-0002-7243-2967

Marian H Harris (MH)

Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
ORCID: 0000-0002-9956-664X

Roberto Chiarle (R)

Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA, 02115, USA. roberto.chiarle@childrens.harvard.edu.
Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, 10126, Italy. roberto.chiarle@childrens.harvard.edu.
Division of Hematopathology, IEO European Institute of Oncology IRCCS, 20141, Milan, Italy. roberto.chiarle@childrens.harvard.edu.
ORCID: 0000-0003-1564-8531

Articles similaires

[Redispensing of expensive oral anticancer medicines: a practical application].

Lisanne N van Merendonk, Kübra Akgöl, Bastiaan Nuijen
1.00
Humans Antineoplastic Agents Administration, Oral Drug Costs Counterfeit Drugs

Smoking Cessation and Incident Cardiovascular Disease.

Jun Hwan Cho, Seung Yong Shin, Hoseob Kim et al.
1.00
Humans Male Smoking Cessation Cardiovascular Diseases Female

Evaluation of Low-Value Services Across Major Medicare Advantage Insurers and Traditional Medicare.

Ciara Duggan, Adam L Beckman, Ishani Ganguli et al.
1.00
Humans United States Aged Cross-Sectional Studies Medicare Part C

Effectiveness of Virtual Yoga for Chronic Low Back Pain: A Randomized Clinical Trial.

Hallie Tankha, Devyn Gaskins, Amanda Shallcross et al.
1.00
Humans Yoga Low Back Pain Female Male

Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Mechanistic patterns and clinical implications...
questionsmedicales.fr › Tumeurs › Mechanistic patterns and clinical implications...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines tumorales › Protéines oncogènes › Protéines de fusion oncogènes › Mechanistic patterns and clinical implications...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-tyrosine kinases › Mechanistic patterns and clinical implications...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines tumorales › Protéines oncogènes › Protéines proto-oncogènes › Protéines proto-oncogènes c-ret › Mechanistic patterns and clinical implications...
questionsmedicales.fr › Phénomènes génétiques › Mutagenèse › Translocation génétique › Mechanistic patterns and clinical implications...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs à activité tyrosine kinase › Kinase du lymphome anaplasique › Mechanistic patterns and clinical implications...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs peptidiques › Récepteur facteur croissance › Récepteurs facteur croissance nerf › Récepteur trkA › Mechanistic patterns and clinical implications...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Antienzymes › Inhibiteurs de protéines kinases › Mechanistic patterns and clinical implications...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines tumorales › Protéines oncogènes › Protéines proto-oncogènes › Mechanistic patterns and clinical implications...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Transduction du signal › Mechanistic patterns and clinical implications...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › Mechanistic patterns and clinical implications...