28,145 results match your criteria gtpases ras


Genome-wide DNA methylome analysis identifies methylation signatures associated with survival and drug resistance of ovarian cancers.

Clin Epigenetics 2021 Jul 22;13(1):142. Epub 2021 Jul 22.

Department of Obstetrics and Gynaecology, L747 Laboratory Block, LKS Faculty of Medicine, 21 Sassoon Road, Pokfulam, Hong Kong, SAR, People's Republic of China.

Background: In contrast to stable genetic events, epigenetic changes are highly plastic and play crucial roles in tumor evolution and development. Epithelial ovarian cancer (EOC) is a highly heterogeneous disease that is generally associated with poor prognosis and treatment failure. Profiling epigenome-wide DNA methylation status is therefore essential to better characterize the impact of epigenetic alterations on the heterogeneity of EOC. Read More

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Divergent Mechanisms Activating RAS and Small GTPases Through Post-translational Modification.

Front Mol Biosci 2021 8;8:707439. Epub 2021 Jul 8.

Institute for Advanced Biosciences, Keio University, Tsuruoka, Japan.

RAS is a founding member of the RAS superfamily of GTPases. These small 21 kDa proteins function as molecular switches to initialize signaling cascades involved in various cellular processes, including gene expression, cell growth, and differentiation. RAS is activated by GTP loading and deactivated upon GTP hydrolysis to GDP. Read More

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Regulation of Leukaemia Associated Rho GEF (LARG/ARHGEF12).

Small GTPases 2021 Jul 25:1-9. Epub 2021 Jul 25.

Cancer Biology Program, University of Hawaii Cancer Center, University of Hawaii at Mānoa, Honolulu, USA.

The Ras homologous (Rho) protein family of GTPases (RhoA, RhoB and RhoC) are the members of the Ras superfamily and regulate cellular processes such as cell migration, proliferation, polarization, adhesion, gene transcription and cytoskeletal structure. Rho GTPases function as molecular switches that cycle between GTP-bound (active state) and GDP-bound (inactive state) forms. Leukaemia-associated RhoGEF (LARG) is a guanine nucleotide exchange factor (GEF) that activates RhoA subfamily GTPases by promoting the exchange of GDP for GTP. Read More

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A Transcriptome-Wide Isoform Landscape of Melanocytic Nevi and Primary Melanomas Identifies Gene Isoforms Associated with Malignancy.

Int J Mol Sci 2021 Jul 2;22(13). Epub 2021 Jul 2.

Department of Dermatology, Venereology and Allergology, University of Leipzig Medical Center, Philipp-Rosenthal-Str. 23, 04103 Leipzig, Germany.

Genetic splice variants have become of central interest in recent years, as they play an important role in different cancers. Little is known about splice variants in melanoma. Here, we analyzed a genome-wide transcriptomic dataset of benign melanocytic nevi and primary melanomas ( = 80) for the expression of specific splice variants. Read More

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Targeting KRAS4A splicing through the RBM39/DCAF15 pathway inhibits cancer stem cells.

Nat Commun 2021 07 13;12(1):4288. Epub 2021 Jul 13.

UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA.

The commonly mutated human KRAS oncogene encodes two distinct KRAS4A and KRAS4B proteins generated by differential splicing. We demonstrate here that coordinated regulation of both isoforms through control of splicing is essential for development of Kras mutant tumors. The minor KRAS4A isoform is enriched in cancer stem-like cells, where it responds to hypoxia, while the major KRAS4B is induced by ER stress. Read More

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Amino Acids in Autophagy: Regulation and Function.

Adv Exp Med Biol 2021 ;1332:51-66

Department of Nutrition, Texas A&M University, College Station, TX, 77843, USA.

Autophagy is a dynamic process in which the eukaryotic cells break down intracellular components by lysosomal degradation. Under the normal condition, the basal level of autophagy removes damaged organelles, misfolded proteins, or protein aggregates to keep cells in a homeostatic condition. Deprivation of nutrients (e. Read More

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Tetrahydrocurcumin ameliorates Alzheimer's pathological phenotypes by inhibition of microglial cell cycle arrest and apoptosis via Ras/ERK signaling.

Biomed Pharmacother 2021 Jul 8;139:111651. Epub 2021 May 8.

Translational Chinese Medicine Key Laboratory of Sichuan Province, Sichuan Academy of Chinese Medicine Sciences, Sichuan Institute for Translational Chinese Medicine, Chengdu 610041, China. Electronic address:

1,7-bis(4-hydroxy-3-methoxyphenyl)heptane-3,5-dione (tetrahydrocurcumin, THC) is a major bioactive metabolite of curcumin, demonstrating the potential anti-inflammatory, antioxidant and neuroprotective properties, etc. In this study, it was found that Aβ induced decreased cell viability, cell cycle arrest and apoptosis in BV-2 cells, which were ameliorated by THC. In vivo, THC administration rescued learning and memory, and reduced Aβ burden in the hippocampus of APP/PS1 mice. Read More

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The RAS GTPase RIT1 compromises mitotic fidelity through spindle assembly checkpoint suppression.

Curr Biol 2021 Jun 30. Epub 2021 Jun 30.

Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, 1450 3(rd) Street, San Francisco, CA 94158, USA. Electronic address:

The spindle assembly checkpoint (SAC) functions as a sensor of unattached kinetochores that delays mitotic progression into anaphase until proper chromosome segregation is guaranteed. Disruptions to this safety mechanism lead to genomic instability and aneuploidy, which serve as the genetic cause of embryonic demise, congenital birth defects, intellectual disability, and cancer. However, despite the understanding of the fundamental mechanisms that control the SAC, it remains unknown how signaling pathways directly interact with and regulate the mitotic checkpoint activity. Read More

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Targeting Small GTPases and Their Prenylation in Diabetes Mellitus.

J Med Chem 2021 Jul 8;64(14):9677-9710. Epub 2021 Jul 8.

Institute of Organic Chemistry, Faculty of Chemistry, Lodz University of Technology, Żeromskiego Street 116, 90-924 Łódź, Poland.

A fundamental role of pancreatic β-cells to maintain proper blood glucose level is controlled by the Ras superfamily of small GTPases that undergo post-translational modifications, including prenylation. This covalent attachment with either a farnesyl or a geranylgeranyl group controls their localization, activity, and protein-protein interactions. Small GTPases are critical in maintaining glucose homeostasis acting in the pancreas and metabolically active tissues such as skeletal muscles, liver, or adipocytes. Read More

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RAS Nanoclusters Selectively Sort Distinct Lipid Headgroups and Acyl Chains.

Front Mol Biosci 2021 17;8:686338. Epub 2021 Jun 17.

Department of Integrative Biology and Pharmacology, University of Texas Health Science Center, Houston, TX, United States.

RAS proteins are lipid-anchored small GTPases that switch between the GTP-bound active and GDP-bound inactive states. RAS isoforms, including HRAS, NRAS and splice variants KRAS4A and KRAS4B, are some of the most frequently mutated proteins in cancer. In particular, constitutively active mutants of KRAS comprise ∼80% of all RAS oncogenic mutations and are found in 98% of pancreatic, 45% of colorectal and 31% of lung tumors. Read More

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SmgGDS: An Emerging Master Regulator of Prenylation and Trafficking by Small GTPases in the Ras and Rho Families.

Front Mol Biosci 2021 16;8:685135. Epub 2021 Jun 16.

Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, United States.

Newly synthesized small GTPases in the Ras and Rho families are prenylated by cytosolic prenyltransferases and then escorted by chaperones to membranes, the nucleus, and other sites where the GTPases participate in a variety of signaling cascades. Understanding how prenylation and trafficking are regulated will help define new therapeutic strategies for cancer and other disorders involving abnormal signaling by these small GTPases. A growing body of evidence indicates that splice variants of SmgGDS (gene name RAP1GDS1) are major regulators of the prenylation, post-prenylation processing, and trafficking of Ras and Rho family members. Read More

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Blocking K-Ras Interaction With the Plasma Membrane Is a Tractable Therapeutic Approach to Inhibit Oncogenic K-Ras Activity.

Front Mol Biosci 2021 16;8:673096. Epub 2021 Jun 16.

Department of Biochemistry and Molecular Biology, School of Boonshoft School of Medicine, Wright State University, Dayton, OH, United States.

Ras proteins are membrane-bound small GTPases that promote cell proliferation, differentiation, and apoptosis. Consistent with this key regulatory role, activating mutations of Ras are present in ∼19% of new cancer cases in the United States per year. K-Ras is one of the three ubiquitously expressed isoforms in mammalian cells, and oncogenic mutations in this isoform account for ∼75% of Ras-driven cancers. Read More

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Analysis of EGFR, KRAS, and PIK3CA gene mutation rates and clinical distribution in patients with different types of lung cancer.

Authors:
Shuo Li Xinju Li

World J Surg Oncol 2021 Jul 3;19(1):197. Epub 2021 Jul 3.

Department of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China.

Background: To analyze and evaluate EGFR, KRAS, and PIK3CA gene mutation rates and clinical distribution in patients with different types of lung cancer METHOD: A total of 221 lung cancer patients treated in our hospital between January 2016 and June 2019 were enrolled. Tissue and whole blood samples were collected and analyzed to determine the mutation status of EGFR, KRAS, and PIK3CA genes. The gene exon mutation rates were determined. Read More

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Small Rho GTPases and their associated RhoGEFs mutations promote immunological defects in primary immunodeficiencies.

Int J Biochem Cell Biol 2021 Aug 1;137:106034. Epub 2021 Jul 1.

Bioprocess Technology Division, School of Industrial Technology, Universiti Sains Malaysia, Gelugor, Penang, 11800, Malaysia. Electronic address:

Primary immunodeficiencies (PIDs) are associated with deleterious mutations of genes that encode proteins involved in actin cytoskeleton reorganisation. This deficiency affects haematopoietic cells. PID results in the defective function of immune cells, such as impaired chemokine-induced motility, receptor signalling, development and maturation. Read More

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Loss-of-function mutations in TRAF7 and KLF4 cooperatively activate RAS-like GTPase signaling and promote meningioma development.

Cancer Res 2021 Jul 2. Epub 2021 Jul 2.

KULeuven-VIB Center for Cancer Biology, VIB; KU Leuven

Meningiomas are the most common benign brain tumors. Mutations of the E3 ubiquitin ligase TRAF7 occur in 25% of meningiomas and commonly co-occur with mutations in KLF4, yet the functional link between TRAF7 and KLF4 mutations remains unclear. By generating an in vitro meningioma model derived from primary meningeal cells, we elucidated the cooperative interactions that promote meningioma development. Read More

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Revising Endosomal Trafficking under Insulin Receptor Activation.

Int J Mol Sci 2021 Jun 29;22(13). Epub 2021 Jun 29.

The John van Geest Cancer Research Centre, School of Science and Technology, Nottingham Trent University, Nottingham NG11 8NS, UK.

The endocytosis of ligand-bound receptors and their eventual recycling to the plasma membrane (PM) are processes that have an influence on signalling activity and therefore on many cell functions, including migration and proliferation. Like other tyrosine kinase receptors (TKR), the insulin receptor (INSR) has been shown to be endocytosed by clathrin-dependent and -independent mechanisms. Once at the early endosome (EE), the sorting of the receptor, either to the late endosome (LE) for degradation or back to the PM through slow or fast recycling pathways, will determine the intensity and duration of insulin effects. Read More

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Ras Isoforms from Lab Benches to Lives-What Are We Missing and How Far Are We?

Int J Mol Sci 2021 Jun 17;22(12). Epub 2021 Jun 17.

National Centre for Cell Science, Ganeshkhind, Pune 411007, India.

The central protein in the oncogenic circuitry is the Ras GTPase that has been under intense scrutiny for the last four decades. From its discovery as a viral oncogene and its non-oncogenic contribution to crucial cellular functioning, an elaborate genetic, structural, and functional map of Ras is being created for its therapeutic targeting. Despite decades of research, there still exist lacunae in our understanding of Ras. Read More

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Emerging Roles of Small GTPases in Islet β-Cell Function.

Cells 2021 Jun 15;10(6). Epub 2021 Jun 15.

Department of Molecular and Cellular Endocrinology, Arthur Riggs Diabetes & Metabolism Research Institute, City of Hope Beckman Research Institute, Duarte, CA 91010, USA.

Several small guanosine triphosphatases (GTPases) from the Ras protein superfamily regulate glucose-stimulated insulin secretion in the pancreatic islet β-cell. The Rho family GTPases Cdc42 and Rac1 are primarily involved in relaying key signals in several cellular functions, including vesicle trafficking, plasma membrane homeostasis, and cytoskeletal dynamics. They orchestrate specific changes at each spatiotemporal region within the β-cell by coordinating with signal transducers, guanine nucleotide exchange factors (GEFs), GTPase-activating factors (GAPs), and their effectors. Read More

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Beyond RAS and BRAF: HER2, a New Actionable Oncotarget in Advanced Colorectal Cancer.

Int J Mol Sci 2021 Jun 24;22(13). Epub 2021 Jun 24.

Division of Medical Oncology, A.O.U. Consorziale Policlinico di Bari, 70124 Bari, Italy.

The human epidermal growth factor receptor 2 (HER2) is a well-established oncogenic driver and a successful therapeutic target in several malignancies, such as breast and gastric cancers. HER2 alterations, including amplification and somatic mutations, have also been detected in a small but not negligible subset of patients affected by advanced colorectal cancer (aCRC). However, to date, there are no available oncotargets in this malignancy beyond RAS and BRAF that are available. Read More

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Intraductal Papillary Mucinous Carcinoma Versus Conventional Pancreatic Ductal Adenocarcinoma: A Comprehensive Review of Clinical-Pathological Features, Outcomes, and Molecular Insights.

Int J Mol Sci 2021 Jun 23;22(13). Epub 2021 Jun 23.

INSERM UMRS_938, Microsatellite Instability and Cancer, Saint-Antoine Research Center, SIRIC CURAMUS, Sorbonne University, 75012 Paris, France.

Intraductal papillary mucinous neoplasms (IPMN) are common and one of the main precursor lesions of pancreatic ductal adenocarcinoma (PDAC). PDAC derived from an IPMN is called intraductal papillary mucinous carcinoma (IPMC) and defines a subgroup of patients with ill-defined specificities. As compared to conventional PDAC, IPMCs have been associated to clinical particularities and favorable pathological features, as well as debated outcomes. Read More

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Amino Acid-Mediated Intracellular Ca Rise Modulates mTORC1 by Regulating the TSC2-Rheb Axis through Ca/Calmodulin.

Int J Mol Sci 2021 Jun 27;22(13). Epub 2021 Jun 27.

Department of Applied Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan.

Mechanistic target of rapamycin complex 1 (mTORC1) is a master growth regulator by controlling protein synthesis and autophagy in response to environmental cues. Amino acids, especially leucine and arginine, are known to be important activators of mTORC1 and to promote lysosomal translocation of mTORC1, where mTORC1 is thought to make contact with its activator Rheb GTPase. Although amino acids are believed to exclusively regulate lysosomal translocation of mTORC1 by Rag GTPases, how amino acids increase mTORC1 activity besides regulation of mTORC1 subcellular localization remains largely unclear. Read More

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Loss function of Bcr mutation causes gastrointestinal dysmotility and brain developmental defects.

Neurogastroenterol Motil 2021 Jun 30:e14190. Epub 2021 Jun 30.

Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.

Background: The breakpoint cluster region (BCR) is a protein that originally forms a fusion protein with c-Abl tyrosine kinase and induces leukemia. Researchers have shown that BCR is enriched in the central nervous system and may contribute to neurological disorders. We aimed to investigate the physiological function of BCR in neural development in the gastrointestinal (GI) tract and brain. Read More

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Active Rap1-mediated inhibition of choroidal neovascularization requires interactions with IQGAP1 in choroidal endothelial cells.

FASEB J 2021 07;35(7):e21642

The John A Moran Eye Center, University of Utah, Salt Lake City, UT, USA.

Neovascular age-related macular degeneration (nAMD) is a leading cause of blindness. The pathophysiology involves activation of choroidal endothelial cells (CECs) to transmigrate the retinal pigment epithelial (RPE) monolayer and form choroidal neovascularization (CNV) in the neural retina. The multidomain GTPase binding protein, IQGAP1, binds active Rac1 and sustains activation of CECs, thereby enabling migration associated with vision-threatening CNV. Read More

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Transcription factor PAX4 facilitates gastric cancer progression through interacting with miR-27b-3p/Grb2 axis.

Aging (Albany NY) 2021 06 23;13(12):16786-16803. Epub 2021 Jun 23.

Department of General Surgery, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu, PR China.

Gastric cancer (GC) is one of the most common aggressive cancers. The discovery of an effective biomarker is necessary for GC diagnosis. In this study, we confirmed that Paired box gene 4 (PAX4) is up-regulated in GC tissues and cells via quantitative real time polymerase chain reaction (qRT-PCR), western blot and immunohistochemical staining. Read More

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Finally, Effective Inhibitors of Mutant KRAS.

Authors:
Neal Rosen

N Engl J Med 2021 06;384(25):2447-2449

From Memorial Sloan Kettering Cancer Center, New York.

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Acquired Resistance to KRAS Inhibition in Cancer.

N Engl J Med 2021 06;384(25):2382-2393

From Dana-Farber Cancer Institute (M.M.A., S.L., J.D., J.O.J., K.E.L., H.F., K.M.H., B.M.W., P.A.J., A.J.A.), Massachusetts General Hospital (R.S.H., Y.P.H.), and Brigham and Women's Hospital (L.M.S., A.J.A.), Boston, and Broad Institute of MIT and Harvard (S.L., X.Y., N.S.P., D.E.R., K.M.H., A.J.A.) and Foundation Medicine (J.L., A.B.S.), Cambridge - all in Massachusetts; Henry Ford Cancer Institute, Detroit (I.I.R.); Memorial Sloan Kettering Cancer Center, New York (K.C.A., G.J.R., P.L.); Chao Family Comprehensive Cancer Center, University of California, Irvine, School of Medicine, Orange (V.W.Z., S.S.Z., S.-H.I.O.), Boundless Bio, La Jolla (J.W., J.C.), and Mirati Therapeutics, San Diego (L.D.E., L.W., J.D.L., P.O., J.G.C.) - all in California; Sarah Cannon Research Institute, Tennessee Oncology/OneOncology, Nashville (M.L.J.); the University of Colorado, Aurora (T.P.); and Resolution Bioscience, Kirkland, WA (L.P.L., K.G., M.L.).

Background: Clinical trials of the KRAS inhibitors adagrasib and sotorasib have shown promising activity in cancers harboring KRAS glycine-to-cysteine amino acid substitutions at codon 12 (KRAS). The mechanisms of acquired resistance to these therapies are currently unknown.

Methods: Among patients with -mutant cancers treated with adagrasib monotherapy, we performed genomic and histologic analyses that compared pretreatment samples with those obtained after the development of resistance. Read More

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Highly metastatic claudin-low mammary cancers can originate from luminal epithelial cells.

Nat Commun 2021 06 18;12(1):3742. Epub 2021 Jun 18.

Department of Oncology, Wayne State University School of Medicine and Tumor Biology Program, Barbara Ann Karmanos Cancer Institute, Detroit, MI, USA.

Claudin-low breast cancer represents an aggressive molecular subtype that is comprised of mostly triple-negative mammary tumor cells that possess stem cell-like and mesenchymal features. Little is known about the cellular origin and oncogenic drivers that promote claudin-low breast cancer. In this study, we show that persistent oncogenic RAS signaling causes highly metastatic triple-negative mammary tumors in mice. Read More

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The small GTP-binding protein TaRop10 interacts with TaTrxh9 and functions as a negative regulator of wheat resistance against the stripe rust.

Plant Sci 2021 Aug 14;309:110937. Epub 2021 May 14.

State Key Laboratory of Crop Stress Biology for Arid Areas, College of Plant Protection, Northwest A&F University, Yangling, Shaanxi 712100, China. Electronic address:

Small GTP-binding proteins, also known as ROPs (Rho of Plants), are a subfamily of the Ras superfamily of signaling G-proteins and are required for numerous signaling processes, ranging from growth and development to biotic and abiotic signaling. In this study, we cloned and characterized wheat TaRop10, a homolog of Arabidopsis ROP10 and member of the class II ROP, and uncovered a role for TaRop10 in wheat response to Puccinia striiformis f. sp. Read More

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Functional Genomics for Undiagnosed Patients: The Impact of Small GTPases Signaling Dysregulation at Pan-Embryo Developmental Scale.

Front Cell Dev Biol 2021 25;9:642235. Epub 2021 May 25.

Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.

While individually rare, disorders affecting development collectively represent a substantial clinical, psychological, and socioeconomic burden to patients, families, and society. Insights into the molecular mechanisms underlying these disorders are required to speed up diagnosis, improve counseling, and optimize management toward targeted therapies. Genome sequencing is now unveiling previously unexplored genetic variations in undiagnosed patients, which require functional validation and mechanistic understanding, particularly when dealing with novel nosologic entities. Read More

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Interaction between RAS gene and lipid metabolism in cancer.

Zhejiang Da Xue Xue Bao Yi Xue Ban 2021 02;50(1):17-22

Cancer Center,Sun Yat-Sen University,Guangzhou 510060,China.

The gene is frequently mutated and abnormally activated in many cancers,and plays an important role in cancer development. Metabolic reprogramming occurs in malignant tumors,which can be one of the key targets for anti-tumor therapy. gene can regulate lipid metabolism through AKT-mTORC1 single axis or multiple pathways,such as lipid synthesis pathways and degradation pathways. Read More

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February 2021