Targeting integrin pathways: mechanisms and advances in therapy

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Янв. 2, 2023

Abstract Integrins are considered the main cell-adhesion transmembrane receptors that play multifaceted roles as extracellular matrix (ECM)-cytoskeletal linkers and transducers in biochemical mechanical signals between cells their environment a wide range of states health diseases. Integrin functions dependable on delicate balance active inactive status via multiple mechanisms, including protein-protein interactions, conformational changes, trafficking. Due to exposure cell surface sensitivity molecular blockade, integrins have been investigated pharmacological targets for nearly 40 years, but given complexity sometimes opposite characteristics, targeting integrin therapeutics has challenge. To date, only seven drugs successfully marketed, abciximab, eptifibatide, tirofiban, natalizumab, vedolizumab, lifitegrast, carotegrast. Currently, there approximately 90 kinds integrin-based therapeutic or imaging agents clinical studies, small molecules, antibodies, synthetic mimic peptides, antibody–drug conjugates (ADCs), chimeric antigen receptor (CAR) T-cell therapy, agents, etc. A serious lesson from past drug discovery research efforts is successes rely both deep understanding integrin-regulatory mechanisms unmet needs. Herein, we provide systematic complete review all family members integrin-mediated downstream signal transduction highlight ongoing develop new therapies/diagnoses bench clinic. In addition, further discuss trend development, how improve success rate trials therapies, key points research, basic translational research.

Язык: Английский

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Fibroblast and myofibroblast activation in normal tissue repair and fibrosis

Nature Reviews Molecular Cell Biology, Год журнала: 2024, Номер 25(8), С. 617 - 638

Опубликована: Апрель 8, 2024

Язык: Английский

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Defining blood-induced microglia functions in neurodegeneration through multiomic profiling

Nature Immunology, Год журнала: 2023, Номер 24(7), С. 1173 - 1187

Опубликована: Июнь 8, 2023

Abstract Blood protein extravasation through a disrupted blood–brain barrier and innate immune activation are hallmarks of neurological diseases emerging therapeutic targets. However, how blood proteins polarize cells remains largely unknown. Here, we established an unbiased blood-innate immunity multiomic genetic loss-of-function pipeline to define the transcriptome global phosphoproteome blood-induced polarization its role in microglia neurotoxicity. induced widespread microglial transcriptional changes, including changes involving oxidative stress neurodegenerative genes. Comparative functional multiomics showed that induce distinct receptor-mediated programs macrophages, such as redox, type I interferon lymphocyte recruitment. Deletion coagulation factor fibrinogen reversed signatures. Genetic elimination fibrinogen-binding motif CD11b Alzheimer’s disease mice reduced lipid metabolism signatures were shared with autoimmune-driven neuroinflammation multiple sclerosis mice. Our data provide interactive resource for investigation immunology could support targeting by vascular signals.

Язык: Английский

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Ten Years of Extracellular Matrix Proteomics: Accomplishments, Challenges, and Future Perspectives

Molecular & Cellular Proteomics, Год журнала: 2023, Номер 22(4), С. 100528 - 100528

Опубликована: Март 12, 2023

•ECM alterations cause or accompany diseases and disorders of all organ systems.•Proteomics is a method choice to profile the composition ECM tissues.•ECM proteomics can identify novel prognostic diagnostic biomarkers.•ECM uncover proteins playing functional roles in disease etiology.•Further technical advances are needed capture diversity proteoforms The extracellular matrix (ECM) complex assembly hundreds forming architectural scaffold multicellular organisms. In addition its structural role, conveys signals orchestrating cellular phenotypes. Alterations composition, abundance, structure, mechanics have been linked affecting physiological systems, including fibrosis cancer. Deciphering protein how it changes pathophysiological contexts thus first step toward understanding health development therapeutic strategies correct disease-causing alterations. Potentially, also represents vast, yet untapped reservoir biomarkers. characterized by unique biochemical properties that hindered their study: they large, heavily uniquely posttranslationally modified, highly insoluble. Overcoming these challenges, we others devised mass-spectrometry–based proteomic approaches define "matrisome," tissues. This part this review provides historical overview research presents latest now allow profiling healthy diseased second highlights recent examples illustrating has emerged as powerful discovery pipeline cancer third discusses remaining challenges limiting our ability translate findings clinical application proposes overcome them. Lastly, introduces readers resources available facilitate interpretation datasets. was once thought be impenetrable. Mass spectrometry–based proven tool decode ECM. light progress made over past decade, there reasons believe in-depth exploration matrisome within reach may soon witness translational proteomics. organisms (1Hynes R.O. evolution metazoan matrix.J. Cell Biol. 2012; 196: 671-679Crossref PubMed Scopus (177) Google Scholar, 2Adams J.C. Extracellular evolution: an overview.in: Keeley F.W. Mecham R.P. Evolution Matrix. Springer, Berlin, Heidelberg2013: 1-25https://doi.org/10.1007/978-3-642-36002-2_1Crossref 3Karamanos N.K. Theocharis A.D. Piperigkou Z. Manou D. Passi A. Skandalis S.S. et al.A guide functions matrix.FEBS J. 2021; 288: 6850-6912Crossref (34) Scholar). As such, guides cell polarization serves substrate migration, organizes cells into tissues organs, confers mechanical roles, exerts signaling through mechanotransduction (4Humphrey J.D. Dufresne E.R. Schwartz M.A. Mechanotransduction homeostasis.Nat. Rev. Mol. 2014; 15: 802-812Crossref (1185) 5Dooling L.J. Saini K. Anlaş A.A. Discher D.E. Tissue coevolves with fibrillar matrisomes fibrotic tissues.Matrix 2022; 111: 153-188Crossref (0) It cues interpreted via cell-surface receptors (e.g., integrins (6Kanchanawong P. Calderwood D.A. Organization, dynamics mechanoregulation integrin-mediated cell–ECM adhesions.Nat. 24: 142-161Crossref (7) Scholar), syndecans, adhesion GPCRs (7Liebscher I. Cevheroğlu O. Hsiao C.C. Maia A.F. Schihada H. Scholz N. GPCR research.FEBS 289: 7610-7630Crossref (5) Scholar)) orchestrate most, if not all, functions, from proliferation survival stemness differentiation. plays critical during development, growth, other processes wound healing aging (8Yamada K.M. Collins J.W. Cruz Walma Doyle Morales S.G. Lu al.Extracellular invasion tissue morphogenesis.Int. Exp. Pathol. 2019; 100: 144-152Crossref (47) 9Dzamba B.J. DeSimone D.W. sculpting embryonic tissues.Curr. Top Dev. 2018; 130: 245-274Crossref (49) 10Karamanos Neill T. Iozzo R.V. 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Chou Remodelling disease.Nat. 786-801Crossref (2349) 16Theocharis Karamanos multitasking player disease.FEBS 286: 2830-2869Crossref (190) Scholar) musculoskeletal system Ehlers–Danlos syndrome (17Malfait Castori M. Francomano C.A. Giunta Kosho Byers P.H. Ehlers-Danlos syndromes.Nat. Dis. Primers. 6: 64Crossref (82) arthritis), skin scleroderma (18Schulz J.N. Plomann Sengle G. Gullberg Krieg Eckes B. New developments on - emanating control myofibroblasts.Matrix 68–69: 522-532Crossref (48) epidermolysis bullosa (19Bruckner-Tuderman L. Has Disorders cutaneous basement membrane zone--the paradigm bullosa.Matrix 33: 29-34Crossref Scholar)), cardiovascular Marfan (20Cook J.R. Carta Galatioto Ramirez Cardiovascular manifestations related diseases; multiple causing similar phenotypes.Clin. Genet. 2015; 87: 11-20Crossref (52) respiratory (lung (21Zhou Y. Horowitz Naba Ambalavanan Atabai Balestrini lung disease.Matrix 73: 77-104Crossref (138) excretory Alport syndrome, Goodpasture renal (22Bülow R.D. Boor fibrosis: more than just scaffold.J. Histochem. Cytochem. 67: 643-661Crossref (134) 23Chew Basement defects genetic diseases.Front. Pediatr. 11Crossref (50) list few. addition, excessive accumulation hallmark (24Pakshir Hinz big five macrophages, myofibroblasts, matrix, mechanics, miscommunication.Matrix 81-93Crossref (211) (25Pickup M.W. Mouw J.K. modulates hallmarks cancer.EMBO Rep. 1243-1253Crossref (1078) 26Cox T.R. cancer.Nat. Cancer. 21: 217-238Crossref (222) 27Winkler Abisoye-Ogunniyan Metcalf K.J. Concepts remodelling tumour progression metastasis.Nat. Commun. 11: 5120Crossref (584) extent deposition context cancer, assessed tumor:stroma ratio, shown value patients colorectal (28Souza da Silva R.M. Queiroga E.M. Paz A.R. Neves F.F.P. Cunha K.S. Dias E.P. Standardized assessment tumor-stroma ratio cancer: interobserver validation reproducibility potential factor.Clin. 14https://doi.org/10.1177/2632010X21989686Crossref 29van Pelt G.W. Sandberg T.P. Morreau Gelderblom van Krieken J.H.J.M. Tollenaar R.A.E.M. al.The tumour-stroma colon role impact.Histopathology. 197-206Crossref Nine 70-gene MammaPrint panel used early breast diagnosis (30Cardoso van't Veer Bogaerts Slaets Viale Delaloge S. al.70-Gene signature aid treatment decisions early-stage cancer.N. Engl. Med. 2016; 375: 717-729Crossref genes. present advantage being readily accessible, outside cells. Consequently, targeted delivery imaging agents (31Jailkhani Ingram Rashidian Rickelt Tian Mak al.Noninvasive tumor progression, metastasis, using nanobody targeting matrix.Proc. Nat. Acad. Sci. U. 116: 14181-14190Crossref 32Santimaria Moscatelli G.L. Giovannoni Neri Viti al.Immunoscintigraphic detection ED-B domain fibronectin, marker angiogenesis, cancer.Clin. Cancer Res. 2003; 9: 571-579PubMed 33Steiner Antibody-radionuclide conjugates therapy: considerations new trends.Clin. 17: 6406-6416Crossref (125) drugs, example, bispecific composed moiety recognizing disease-specific immunomodulatory cytokine (34Pasche Immunocytokines: class potent armed antibodies.Drug Discov. Today. 583-590Crossref (129) 35Lieverse R.I.Y. Van Limbergen E.J. Oberije C.J.G. Troost E.G.C. Hadrup Dingemans A.M.C. al.Stereotactic ablative body radiotherapy (SABR) combined immunotherapy (L19-IL2) versus standard care stage IV NSCLC patients, ImmunoSABR: multicentre, randomised controlled open-label phase II trial.BMC 20: 557Crossref 36Momin Mehta Bennett N.R. Ma Palmeri Chinn M.M. al.Anchoring intratumorally administered cytokines collagen safely potentiates systemic immunotherapy.Sci. Transl. 11eaaw2614Crossref (98) proposed modulating architecture biophysical ECM–cell interactions could valid various (37Nyström Bernasconi Bornert Therapies skin.Matrix 71–72: 330-347Crossref (18) 38Schuppan Ashfaq-Khan Yang A.T. Kim Y.O. Liver direct antifibrotic therapies.Matrix 435-451Crossref (244) 39Bejarano Jordāo M.J.C. Joyce J.A. Therapeutic microenvironment.Cancer 933-959Crossref (274) 40Hauge Rofstad E.K. Antifibrotic therapy normalize microenvironment.J. 18: 207Crossref (40) 41Lampi M.C. Reinhart-King Targeting stiffness attenuate disease: molecular mechanisms trials.Sci. 10eaao0475Crossref (279) 42Ley Rivera-Nieves Sandborn W.J. Shattil Integrin-based therapeutics: basis, use drugs.Nat. Drug 173-183Crossref (273) constitutes large biomarkers targets. Yet, while some elastin) families collagens, tenascins) extensively studied, whole, remained, until recently, largely underexplored (43Wilson matrix: but important proteome.Expert Proteomics. 2010; 7: 803-806Crossref (14) uncharted (44Filipe E.C. Chitty J.L. Cox Charting unexplored cancer.Int. 99: 58-76Crossref very allowing assemble capable withstanding significant stress deformations study global core, tend average 1045 amino acids long. undergo extensive intracellular posttranslational modifications (PTMs), glycosylation, lysine proline hydroxylation collagens collagen-domain-containing contribute stabilization triple-helical structure (45Rappu Salo A.M. Myllyharju Heino Role prolyl collagens.Essays Biochem. 63: 325-335Crossref glycation. higher-order structures established hydrogen bonds (46Buehler Nature designs tough collagen: explaining nanostructure fibrils.Proc. Natl. 2006; 103: 12285-12290Crossref (593) 47Shoulders M.D. Raines R.T. Collagen stability.Annu. 2009; 78: 929-958Crossref (2243) disulfide fibronectin dimers (48Schwarzbauer J.E. Fibronectins, fibrillogenesis, vivo functions.Cold 2011 Jul 1; a005041Crossref (280) covalent cross-links elastin (49Ozsvar Cain S.A. Baldock Tarakanova Weiss A.S. Tropoelastin assembly.Front. Bioeng. Biotechnol. 9643110Crossref (35) (50Ricard-Blum family.Cold a004978Crossref (1080) Scholar)). These making insoluble and, hence, challenging like SDS-PAGE, immunoprecipitation pull-down assays mass spectrometry (MS). Because high insolubility, underrepresented Further contributing underrepresentation fact that, apart few exceptions, small fraction mass. challenge comprehensive characterization broad range terms abundance. comprised abundant components, which generate many peptides (for 121 trypsin cleavage sites alpha 1 chain I), smaller secreted factors, such ECM-remodeling enzymes, growth morphogens, much lower limitation ECM, instrumentations methods fractionate peptide samples, will discussed here, key complexity different subproteomes applied (see below). attempts at ECM-rich tissues, cartilage, following enrichment employed SDS-PAGE 2D gel electrophoresis separate subsets solubilized, followed liquid chromatography coupled tandem (LC-MS/MS). studies reported up dozen proteins. At time, no feat instrumental helping shape field (51Wilson Cartilage proteomics: solutions advances.Proteomics Clin. Appl. 2008; 2: 251-263Crossref 52Lammi Häyrinen Mahonen Proteomic analysis cartilage- bone-associated samples.Electrophoresis. 27: 2687-2701Crossref 53Hattar Maller McDaniel Hansen K.C. Hedman Lyons al.Tamoxifen induces pleiotrophic mammary stroma resulting suppresses transformed phenotypes.Breast R5Crossref (53) 54Wilson Diseberg Gordon Zivkovic Tatarczuch Mackie al.Comprehensive cartilage formation maturation sequential extraction label-free quantitative proteomics.Mol. 1296-1313Abstract (63) 55Belluoccio Wilson Thornton D.J. Wallis Gorman J.J. mouse plate cartilage.Proteomics. 6549-6553Crossref (30) 56Hansen Kiemele O'Brien Shankar Fornetti al.An in-solution ultrasonication-assisted digestion improved proteome coverage.Mol. 8: 1648-1657Abstract (85) Of note, sample preparation protocols tailored account posed (insolubility, glycosylation), separation 1D resulted identification nearly 100 distinct (57Didangelos Yin X. Mandal Baumert Jahangiri Mayr Proteomics space components human aorta.Mol. 2048-2062Abstract (214) 58Didangelos Saje Smith Xu Q. abdominal aortic aneurysms: approach.Mol. 10https://doi.org/10.1074/mcp.M111.008128Abstract (146) However, most studies, known proteins, expected detected those were identified. One then ask: ensure capturing tissues? And indeed, faced when attempting characterize, unbiased manner, lack defined parts systematically annotate experimental output. result, days proteomics, listed "ECM" involved adhesions incorporated Conversely, prior knowledge existed would fail annotated belonging represented any attempt aiming states. became obvious analytical decipher discuss enhancement purpose biomarker target focus Special Issue Clinical Proteomics, article highlight selected performed samples rodent models show promise. organisms, zebrafish (59Chen W.C.W. Wang Missinato Park Long Liu H.J. al.Decellularized cardiac mammalian heart regeneration.Sci. Adv. 2e1600844Crossref (83) 60Garcia-Puig Mosquera Jiménez-Delgado García-Pastor Jorba Navajas al.Proteomics regeneration.Mol. 1745-1755Abstract 61Kessels M.Y. Huitema L.F.A. Boeren Kranenbarg Schulte-Merker Leeuwen JL skeletal matrix.PLoS One. 9e90568Crossref (32) drosophila (62Sessions A.O. Kaushik Parker Raedschelders Bodmer Eyk downregulation Drosophila preserves contractile function improves lifespan.Matrix 2017; 62: 15-27Crossref (15) planarians (63Sonpho E. Mann F.G. Levy Ross Guerrero-Hernández Florens al.Decellularization Enables planarian 20100137Abstract produced culture. advance fundamental disease. bottom-up MS-based but, worth noting modalities facets glycosylation patterns glycomics (64Raghunathan Sethi M.K. Klein Zaia glycomics, glycoproteomics molecules.Mol. 2138-2148Abstract (29) 65de Haan Pučić-Baković Novokmet Falck Lageveen-Kammeijer Razdorov al.Developments perspectives high-throughput glycomics: enabling thousands samples.Glycobiology. 32: 651-663Crossref 66Kellman B.P. Lewis N.E. Big-data tools connect glycan biosynthesis communication.Trends 46: 284-300Abstract (23) 67Riley N.M. Bertozzi C.R. Pitteri S.J. A pragmatic spectrometry-based glycoproteomics.Mol. 20100029Abstract fragments degradomics (68Haack Overall C.M. auf dem Keller Degradomics technologies exploration.Matrix 114: 1-17Crossref localization distribution MS (69Angel P.M. Comte-Walters Ball L.E. Talbot Brockbank K.G.M. al.Mapping formalin-fixed, paraffin-embedded MALDI spectrometry.J. Proteome 635-646Crossref (51) 70Clift C.L. Drake R.R. Angel Multiplexed serial enzyme digests formalin-fixed sections.Anal. Bioanal. Chem. 413: 2709-2719Crossref (8) 2012, published journal describing two-pronged (71Naba Clauser K.R. Hoersch Carr Hynes matrisome: silico definition normal matrices.Mol. 11https://doi.org/10.1074/mcp.M111.014647Abstract (668) While had attempted limitations described above decellularizing extracting guanidine hydrochloride), set tackle them all. brief, took differential solubility deplete non-ECM incubations extraction, decellularization, buffers concomitantly enriching Observing incubation 8 M urea mM DTT did fully solubilize ECM-enriched suspecting found material, processed "crude" M-urea-resuspended samples. We hypothesized deglycosylating enhance accessibility treated Peptide-N-glycosidase F (PNGaseF). further preincubated deglycosylated suspension LysC, protease digesting tightly folded tryptic digestion. To fractionated off-gel electrophoresis. Last, quantification stipulated ECM-specific PTMs hydroxylations variable database search. Indeed, 19% acid sequence I positions X Y X-Y-Gly repeats often hydroxylated parallel, developed robust nomenclature classify characteristic domain-based organization (72Hohenester Eng

Язык: Английский

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Mechanisms of assembly and remodelling of the extracellular matrix

Nature Reviews Molecular Cell Biology, Год журнала: 2024, Номер unknown

Опубликована: Сен. 2, 2024

Язык: Английский

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The role and regulation of integrins in cell migration and invasion

Nature Reviews Molecular Cell Biology, Год журнала: 2024, Номер unknown

Опубликована: Сен. 30, 2024

Язык: Английский

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Ligand binding initiates single-molecule integrin conformational activation

Cell, Год журнала: 2024, Номер 187(12), С. 2990 - 3005.e17

Опубликована: Май 20, 2024

Integrins link the extracellular environment to actin cytoskeleton in cell migration and adhesiveness. Rapid coordination between events outside inside is essential. Single-molecule fluorescence dynamics show that ligand binding bent-closed integrin conformation, which predominates on surfaces, followed within milliseconds by two concerted changes, leg extension headpiece opening, give high-affinity conformation. The extended-closed conformation not an intermediate but can be directly accessed from extended-open provides a pathway for dissociation. In contrast ligand, talin, links β-subunit cytoplasmic domain cytoskeleton, modestly stabilizes does induce or opening. Integrin activation thus initiated outside-in signaling inside-out signaling. Our results further imply talin insufficient tensile force transmission through ligand-integrin-talin-actin complex required.

Язык: Английский

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Progress in biomaterials inspired by the extracellular matrix

Giant, Год журнала: 2024, Номер 19, С. 100323 - 100323

Опубликована: Июль 10, 2024

Inspired by the extracellular matrix (ECM), biomaterials have emerged as promising strategies in biomedical research and engineering domain, offering unique characteristics for tissue regeneration, drug delivery, therapeutic interventions, cellular investigations. The ECM, a dynamic network structure secreted various cells, primarily comprises diverse proteins capable of facilitating tissue-ECM signaling regulatory functions through its rich array bioactive substances multi-level structural properties. Drawing inspiration from intricate biochemical composition natural researchers developed to encapsulate these features create biomimetic microenvironments, such electrospinning, hydrogels/hydrogel microspheres, decellularized ECM(dECM), ECM-mimicking peptides. Furthermore, mimicking ECM components, ECM-inspired exhibit varying degrees functionalization, including providing support, cell adhesion, signal transduction, mitigating immune responses, remodeling. In summary, advancements offer significant promise addressing key challenges fields engineering, regenerative medicine, delivery.

Язык: Английский

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MYO18B promotes lysosomal exocytosis by facilitating focal adhesion maturation

The Journal of Cell Biology, Год журнала: 2025, Номер 224(3)

Опубликована: Янв. 3, 2025

Many cancer cells exhibit increased amounts of paucimannose glycans, which are truncated N-glycan structures rarely found in mammals. Paucimannosidic proteins proposedly generated within lysosomes and exposed on the cell surface through a yet uncertain mechanism. In this study, we revealed that paucimannosidic produced by lysosomal glycosidases secreted via exocytosis. Interestingly, exocytosis preferentially occurred vicinity focal adhesions, protein complexes connecting actin cytoskeleton to extracellular matrix. Through genome-wide knockout screening, identified MYO18B, an crosslinker, is required for adhesion maturation, facilitating release milieu. Moreover, mechanosensitive cation channel PIEZO1 locally activated at adhesions imports Ca2+ necessary lysosome-plasma membrane fusion. Collectively, our study unveiled intimate relationship between adhesion, shedding light unexpected interplay activities cellular mechanosensing.

Язык: Английский

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Redox regulation: mechanisms, biology and therapeutic targets in diseases

Signal Transduction and Targeted Therapy, Год журнала: 2025, Номер 10(1)

Опубликована: Март 7, 2025

Redox signaling acts as a critical mediator in the dynamic interactions between organisms and their external environment, profoundly influencing both onset progression of various diseases. Under physiological conditions, oxidative free radicals generated by mitochondrial respiratory chain, endoplasmic reticulum, NADPH oxidases can be effectively neutralized NRF2-mediated antioxidant responses. These responses elevate synthesis superoxide dismutase (SOD), catalase, well key molecules like nicotinamide adenine dinucleotide phosphate (NADPH) glutathione (GSH), thereby maintaining cellular redox homeostasis. Disruption this finely tuned equilibrium is closely linked to pathogenesis wide range Recent advances have broadened our understanding molecular mechanisms underpinning dysregulation, highlighting pivotal roles genomic instability, epigenetic modifications, protein degradation, metabolic reprogramming. findings provide foundation for exploring regulation mechanistic basis improving therapeutic strategies. While antioxidant-based therapies shown early promise conditions where stress plays primary pathological role, efficacy diseases characterized complex, multifactorial etiologies remains controversial. A deeper, context-specific signaling, particularly redox-sensitive proteins, designing targeted aimed at re-establishing balance. Emerging small molecule inhibitors that target specific cysteine residues proteins demonstrated promising preclinical outcomes, setting stage forthcoming clinical trials. In review, we summarize current intricate relationship disease also discuss how these insights leveraged optimize strategies practice.

Язык: Английский

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