Frontiers in molecular medicine最新文献

{"title":"The COVID-19 explorer-An integrated, whole patient knowledge model of COVID-19 disease.","authors":"Stephan Brock, Theodoros G Soldatos, David B Jackson, Francesca Diella, Klaus Hornischer, Anne Schäfer, Simon P Hoerstrup, Maximilian Y Emmert","doi":"10.3389/fmmed.2022.1035215","DOIUrl":"10.3389/fmmed.2022.1035215","url":null,"abstract":"<p><p>Since early 2020 the COVID-19 pandemic has paralyzed the world, resulting in more than half a billion infections and over 6 million deaths within a 28-month period. Knowledge about the disease remains largely disjointed, especially when considering the molecular mechanisms driving the diversity of clinical manifestations and symptoms. Despite the recent availability of vaccines, there remains an urgent need to develop effective treatments for cases of severe disease, especially in the face of novel virus variants. The complexity of the situation is exacerbated by the emergence of COVID-19 as a complex and multifaceted systemic disease affecting independent tissues and organs throughout the body. The development of effective treatment strategies is therefore predicated on an integrated understanding of the underlying disease mechanisms and their potentially causative link to the diversity of observed clinical phenotypes. To address this need, we utilized a computational technology (the Dataome platform) to build an integrated clinico-molecular view on the most important COVID-19 clinical phenotypes. Our results provide the first integrated, whole-patient model of COVID-19 symptomatology that connects the molecular lifecycle of SARS-CoV-2 with microvesicle-mediated intercellular communication and the contact activation and kallikrein-kinin systems. The model not only explains the clinical pleiotropy of COVID-19, but also provides an evidence-driven framework for drug development/repurposing and the identification of critical risk factors. The associated knowledge is provided in the form of the open source COVID-19 Explorer (https://covid19.molecularhealth.com), enabling the global community to explore and analyze the key molecular features of systemic COVID-19 and associated implications for research priorities and therapeutic strategies. Our work suggests that knowledge modeling solutions may offer important utility in expediting the global response to future health emergencies.</p>","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":" ","pages":"1035215"},"PeriodicalIF":0.0,"publicationDate":"2022-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285624/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43578020","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Three year results of Blessed: Expanded access for DeltaRex-G for an intermediate size population with advanced pancreatic cancer and sarcoma (NCT04091295) and individual patient use of DeltaRex-G for solid malignancies (IND# 19130).","authors":"Sant P Chawla, Steven Wong, Doris Quon, Ania Moradkhani, Victoria S Chua, Don A Brigham, Rebecca A Reed, William Swaney, Frederick L Hall, Erlinda M Gordon","doi":"10.3389/fmmed.2022.1092286","DOIUrl":"10.3389/fmmed.2022.1092286","url":null,"abstract":"<p><p><b>Background:</b> Innovative treatments are urgently needed for metastatic cancer. DeltaRex-G, a tumor-targeted retrovector encoding a dominant-negative/cytocidal cyclin G1 (CCNG1 gene) inhibitor construct-has been tested in over 280 cancer patients worldwide in phase 1, phase 2 studies and compassionate use studies, demonstrating long term (>10 years) survivorship in patients with advanced cancers, including pancreatic cancer, osteosarcoma, malignant peripheral nerve sheath tumor, breast cancer, and B-cell lymphoma. <b>Patient and Methods:</b> Endpoints: Survival, response, treatment-related adverse events. Study one is entitled \"Blessed: Expanded Access for DeltaRex-G for Advanced Pancreatic Cancer and Sarcoma (NCT04091295)\". Study two is entitled \"Individual Patient Use of DeltaRex-G for Solid Malignancies (Investigational New Drug#19130). In both studies, patients will receive DeltaRex-G at 1-3 x 10e11 cfu i.v. over 30-45 min, three x a week until significant disease progression or unacceptable toxicity or death occurs. <b>Results:</b> Seventeen patients were enrolled, nine sarcoma, two pancreatic adenocarcinoma, one non-small cell lung cancer, two breast carcinoma, one prostate cancer, one cholangiocarcinoma and one basal cell carcinoma and actinic keratosis. Three patients were enrolled in Study 1 and 14 patients were enrolled in Study 2. Twelve of 17 enrolled patients were treated with DeltaRex-G monotherapy or in combination with United States Food and Drug Administration-approved cancer therapies. Five patients died before receiving DeltaRex-G. Efficacy Analysis: Of the 12 treated patients, 5 (42%) are alive 15-36 months from DeltaRex-G treatment initiation. Two patients with early-stage HR + HER2+ positive or triple receptor negative invasive breast cancer who received DeltaRex-G as adjuvant/first line therapy are alive in complete remission 23 and 16 months after DeltaRex-G treatment initiation respectively; three patients with metastatic chordoma, chondrosarcoma and advanced basal cell carcinoma are alive 36, 31, and 15 months after DeltaRex-G treatment initiation respectively. Safety Analysis: There were no treatment-related adverse events reported. <b>Conclusion:</b> Taken together, the data suggest that 1) DeltaRex-G may evoke tumor growth stabilization after failing standard chemotherapy, 2) DeltaRex-G may act synergistically with standard chemotherapy/targeted therapies, and 3) Adjuvant/first line therapy with DeltaRex-G for early-stage invasive carcinoma of breast may be authorized by the USFDA when patients refuse to receive toxic chemotherapy.</p>","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":" ","pages":"1092286"},"PeriodicalIF":0.0,"publicationDate":"2022-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285611/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44751046","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel modular chimeric antigen receptor spacer for T cells derived from signal regulatory protein alpha Ig-like domains.","authors":"Jan Koski, Farhana Jahan, Annu Luostarinen, Diana Schenkwein, Seppo Ylä-Herttuala, Helka Göös, Hector Monzo, Päivi M Ojala, Pilvi Maliniemi, Matti Korhonen","doi":"10.3389/fmmed.2022.1049580","DOIUrl":"10.3389/fmmed.2022.1049580","url":null,"abstract":"<p><p><b>Background:</b> T cells equipped with chimeric antigen receptors (CAR) have shown remarkable efficacy in targeting B lineage malignancies. Improvement of the CAR structure is needed, however, with a view to developing flexibly modifiable spacers that are inert in interactions with unwanted cells. Specifically, binding to cells carrying receptors for IgG's crystallizable fragment (FcR), that recognize IgG-derived domains in CARs is to be avoided. <b>Methods:</b> Two novel CARs targeting the CD19 antigen where the IgG1-CH2 and -CH3 domains were replaced with Ig-like domains from signal-regulatory protein α (SIRPα) were designed <i>in silico</i>. An IgG1-based CAR and a CAR lacking both SIRPα and IgG1 domains were used as comparators. The phenotype and memory phenotype of the expanded cells were analyzed by flow cytometry, and CAR T cell activation and cytotoxic efficacy were assessed in co-culture experiments in response to CD19⁺ target cells. Unwanted interactions with FcR-expressing myeloid cells were interrogated in co-culture assays with THP-1 monocytic cells. <b>Results:</b> T cells carrying the novel SIRPα-based CARs enacted potent <i>in vitro</i> cytotoxicity against CD19 positive B-lineage leukemia cells, comparable to traditional IgG1-based CAR T cells. Co-culture of IgG1-based CAR T cells with FcR-expressing THP-1 monocytic cells led to prominent cell surface expression of CD69 on T cells together with production of Interleukin (IL)-2 and Interferon-γ, and production of IL-1β, indicating activation of the T cells and monocytes, respectively. Longer co-culture led to killing of the monocytes. No signs of T cell nor monocyte activation were detected in co-cultures of SIRPα-based CAR T cells with THP-1 cells. Arming T cells with the SIRPα-based CARs favored differentiation towards CD4⁺ phenotype during expansion, while the effects on memory phenotype of the T cells were equivalent between the SIRPα- and IgG1-based CARs. In a pilot experiment, T cells modified with one of the SIRPα-based CARs showed dose dependent leukemia cell control. <b>Conclusion:</b> The novel SIRPα based spacers offer a suitable backbone for developing chimeric antigen receptors that evade the off-target binding to FcR while the cells retain a favorable memory phenotype and efficient cytotoxicity, establishing a promising candidate for future <i>in vivo</i> and clinical testing.</p>","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":" ","pages":"1049580"},"PeriodicalIF":0.0,"publicationDate":"2022-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285650/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41938783","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cancer cell targeting by CAR-T cells: A matter of stemness.","authors":"Caterina D'Accardo, Gaetana Porcelli, Laura Rosa Mangiapane, Chiara Modica, Vincenzo Davide Pantina, Narges Roozafzay, Simone Di Franco, Miriam Gaggianesi, Veronica Veschi, Melania Lo Iacono, Matilde Todaro, Alice Turdo, Giorgio Stassi","doi":"10.3389/fmmed.2022.1055028","DOIUrl":"10.3389/fmmed.2022.1055028","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR)-T cell therapy represents one of the most innovative immunotherapy approaches. The encouraging results achieved by CAR-T cell therapy in hematological disorders paved the way for the employment of CAR engineered T cells in different types of solid tumors. This adoptive cell therapy represents a selective and efficacious approach to eradicate tumors through the recognition of tumor-associated antigens (TAAs). Binding of engineered CAR-T cells to TAAs provokes the release of several cytokines, granzyme, and perforin that ultimately lead to cancer cells elimination and patient's immune system boosting. Within the tumor mass a subpopulation of cancer cells, known as cancer stem cells (CSCs), plays a crucial role in drug resistance, tumor progression, and metastasis. CAR-T cell therapy has indeed been exploited to target CSCs specific antigens as an effective strategy for tumor heterogeneity disruption. Nevertheless, a barrier to the efficacy of CAR-T cell-based therapy is represented by the poor persistence of CAR-T cells into the hostile milieu of the CSCs niche, the development of resistance to single targeting antigen, changes in tumor and T cell metabolism, and the onset of severe adverse effects. CSCs resistance is corroborated by the presence of an immunosuppressive tumor microenvironment (TME), which includes stromal cells, cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and immune cells. The relationship between TME components and CSCs dampens the efficacy of CAR-T cell therapy. To overcome this challenge, the double strategy based on the use of CAR-T cell therapy in combination with chemotherapy could be crucial to evade immunosuppressive TME. Here, we summarize challenges and limitations of CAR-T cell therapy targeting CSCs, with particular emphasis on the role of TME and T cell metabolic demands.</p>","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":" ","pages":"1055028"},"PeriodicalIF":0.0,"publicationDate":"2022-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285689/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45299909","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Grand challenges in molecular cardiology.","authors":"Leon J De Windt","doi":"10.3389/fmmed.2022.920039","DOIUrl":"10.3389/fmmed.2022.920039","url":null,"abstract":"","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":" ","pages":"920039"},"PeriodicalIF":0.0,"publicationDate":"2022-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285535/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45666372","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acetyl-CoA: An interplay between metabolism and epigenetics in cancer.","authors":"Yang Hao, Qin Yi, Xu XiaoWu, Chen WeiBo, Zu GuangChen, Chen XueMin","doi":"10.3389/fmmed.2022.1044585","DOIUrl":"10.3389/fmmed.2022.1044585","url":null,"abstract":"<p><p>Due to its high mortality and severe economic burden, cancer has become one of the most difficult medical problems to solve today. As a key node in metabolism and the main producer of energy, acetyl-coenzyme A (acetyl-CoA) plays an important role in the invasion and migration of cancer. In this review, we discuss metabolic pathways involving acetyl-CoA, the targeted therapy of cancer through acetyl-CoA metabolic pathways and the roles of epigenetic modifications in cancer. In particular, we emphasize that the metabolic pathway of acetyl-CoA exerts a great impact in cancer; this process is very different from normal cells due to the \"Warburg effect\". The concentration of acetyl-CoA is increased in the mitochondria of cancer cells to provide ATP for survival, hindering the growth of normal cells. Therefore, it may be possible to explore new feasible and more effective treatments through the acetyl-CoA metabolic pathway. In addition, a growing number of studies have shown that abnormal epigenetic modifications have been shown to play contributing roles in cancer formation and development. In most cancers, acetyl-CoA mediated acetylation promotes the growth of cancer cells. Thus, acetylation biomarkers can also be detected and serve as potential cancer prediction and prognostic markers.</p>","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":" ","pages":"1044585"},"PeriodicalIF":0.0,"publicationDate":"2022-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285595/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46562261","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The vascular protective effect of matrix Gla protein during kidney injury.","authors":"Yujiro Kida, Ikuyo Yamaguchi","doi":"10.3389/fmmed.2022.970744","DOIUrl":"10.3389/fmmed.2022.970744","url":null,"abstract":"<p><p>Matrix Gla protein (MGP) is a small secreted protein and requires vitamin K dependent γ-carboxylation for its function. MGP has been identified as a local inhibitor of vascular calcification because MGP-deficient mice die due to severe arterial calcification and resulting arterial rupture. Clinical trials revealed that reduction in active MGP predicts poor prognosis in patients due to cardiovascular complications. However, recent studies showed that MGP controls angiogenesis during development. MGP-deficient mice demonstrated abnormal hypervascularization and arteriovenous malformations in kidneys and other organs. This abnormal angiogenesis is largely caused by excessive expression of vascular endothelial growth factor-A (VEGF-A) and VEGF receptor-2 (VEGFR2). However, only a few studies have investigated the roles of MGP in tissue injury. We observed mesangial cell proliferation and mild interstitial fibrosis in addition to increased capillaries in kidneys of MGP-null mice even without injury. We also created a mouse model with kidney injury and found that kidney damage greatly increases MGP expression in peritubular capillary endothelial cells and tubular epithelial cells. Finally, our study showed that impairment of MGP expression aggravates peritubular capillary rarefaction and accumulation of collagen-producing myofibroblasts following kidney injury. Peritubular capillary damage induces capillary loss as well as trans-differentiation of vascular pericytes into myofibroblasts. These results indicate that MGP has the vascular protective effect in the injured kidney. Clinical trials have already started to test the efficacy of MGP activation to repair vascular calcification in patients with chronic kidney diseases. In this \"Hypothesis and Theory\" article, we discuss possible mechanisms by which MGP protects against vascular damage during tissue injury based on our experimental results and previous results from other research groups.</p>","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":" ","pages":"970744"},"PeriodicalIF":0.0,"publicationDate":"2022-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285670/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48056630","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Strategies to improve safety profile of AAV vectors.","authors":"Tuisku Suoranta, Nihay Laham-Karam, Seppo Ylä-Herttuala","doi":"10.3389/fmmed.2022.1054069","DOIUrl":"10.3389/fmmed.2022.1054069","url":null,"abstract":"<p><p>Adeno-associated virus (AAV) vectors are currently used in four approved gene therapies for Leber congenital amaurosis (Luxturna), spinal muscular atrophy (Zolgensma), aromatic L-amino acid decarboxylase deficiency (Upstaza) and Haemophilia A (Roctavian), with several more therapies being investigated in clinical trials. AAV gene therapy has long been considered extremely safe both in the context of immunotoxicity and genotoxicity, but recent tragic deaths in the clinical trials for X-linked myotubular myopathy and Duchenne's muscular dystrophy, together with increasing reports of potential hepatic oncogenicity in animal models have prompted re-evaluation of how much trust we can place on the safety of AAV gene therapy, especially at high doses. In this review we cover genome and capsid engineering strategies that can be used to improve safety of the next generation AAV vectors both in the context of immunogenicity and genotoxicity and discuss the gaps that need filling in our current knowledge about AAV vectors.</p>","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":" ","pages":"1054069"},"PeriodicalIF":0.0,"publicationDate":"2022-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285686/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48401743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Calcineurin-NFAT dynamics correspond to cardiac remodeling during aortic banding and debanding, mimicking aortic valve replacement.","authors":"Ida G Lunde, Biljana Skrbic, Ivar Sjaastad, Geir Christensen, Cathrine R Carlson, Theis Tønnessen","doi":"10.3389/fmmed.2022.980717","DOIUrl":"10.3389/fmmed.2022.980717","url":null,"abstract":"<p><p>Aortic valve stenosis (AS) is a major health problem. Extensive myocardial remodeling increases operative risk and might lead to incomplete reverse remodeling with persistent symptoms after aortic valve replacement (AVR); this makes the optimal timing of AVR a clinical challenge. The pathogenesis behind incomplete reverse remodeling is unclear. Central among signaling pathways in the remodeling heart is the pro-hypertrophic Ca²⁺-activated calcineurin and its downstream nuclear factor of activated T-cell (NFATc1-c4) transcription factors. We investigated calcineurin-NFATc dynamics in patient and mouse hearts during remodeling and reverse remodeling. Myocardial biopsies were obtained from AS patients during AVR and left ventricles harvested from mice subjected to aortic banding (AB) and debanding (DB). The transcript and protein of the NFATc-responsive gene regulator of calcineurin 1-4 (RCAN1-4) and luciferase activity in NFAT-luciferase mice were used as read-outs for calcineurin-NFATc activity. Calcineurin-NFATc activation was sustained through AB 24 h to 18 weeks and elevated in AS patients. All four NFATc isoforms were elevated in AS, while NFATc4 was persistently elevated during chronic remodeling after AB in mice. NFAT activation remained reversible when 1 week's AB was followed by 1 week's DB and accompanied functional improvement. However, when DB for 1 week followed AB for 4 weeks, NFAT activation was not reversed. In conclusion, calcineurin-NFAT dynamics correspond with cardiac remodeling and reverse remodeling during experimental AB and DB. Our data suggest that calcineurin-NFATc attenuation is important for reverse remodeling and outcomes after AVR for AS.</p>","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":" ","pages":"980717"},"PeriodicalIF":0.0,"publicationDate":"2022-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285616/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48793898","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetics in parkinson's disease: From better disease understanding to machine learning based precision medicine.","authors":"Mohamed Aborageh, Peter Krawitz, Holger Fröhlich","doi":"10.3389/fmmed.2022.933383","DOIUrl":"10.3389/fmmed.2022.933383","url":null,"abstract":"<p><p>Parkinson's Disease (PD) is a neurodegenerative disorder with highly heterogeneous phenotypes. Accordingly, it has been challenging to robustly identify genetic factors associated with disease risk, prognosis and therapy response via genome-wide association studies (GWAS). In this review we first provide an overview of existing statistical methods to detect associations between genetic variants and the disease phenotypes in existing PD GWAS. Secondly, we discuss the potential of machine learning approaches to better quantify disease phenotypes and to move beyond disease understanding towards a better-personalized treatment of the disease.</p>","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":" ","pages":"933383"},"PeriodicalIF":0.0,"publicationDate":"2022-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285583/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43914387","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}