Article
Oncology
Xin Zhang, Liangliang Ren, Junhua Wu, Rongni Feng, Yunyang Chen, Ronggang Li, Meimei Wu, Mingzhu Zheng, Xing Gui Wu, Wanjun Luo, Hongle He, Yanming Huang, Miaoling Tang, Jun Li
Summary: ARHGEF37 is upregulated in HCC and associated with tumor invasiveness, pulmonary metastasis and poor prognosis. Overexpression of ARHGEF37 enhances HCC cell extravasation and metastasis by promoting cell adhesion and migration. ARHGEF37 activates Cdc42 to promote invadopodia formation in HCC cells, disrupting the interaction between endothelial cells and pericytes.
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
(2022)
Review
Cell Biology
Sana Abdul Khaliq, Zobia Umair, Mee-Sup Yoon
Summary: ARHGEF3 is a selective guanine nucleotide exchange factor that activates RhoA and RhoB and inhibits mTORC2 and Akt. It is also involved in autophagy-related muscle pathologies and plays roles in controlling bone mineral density, platelet formation and differentiation, and Hirschsprung disease.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Article
Medicine, General & Internal
Timothy M. Miller, Merit E. Cudkowicz, Angela Genge, Pamela J. Shaw, Gen Sobue, Robert C. Bucelli, Adriano Chio, Philip Van Damme, Albert C. Ludolph, Jonathan D. Glass, Jinsy A. Andrews, Suma Babu, Michael Benatar, Christopher J. McDermott, Thos Cochrane, Sowmya Chary, Sheena Chew, Han Zhu, Fan Wu, Ivan Nestorov, Danielle Graham, Peng Sun, Manjit McNeill, Laura Fanning, Toby A. Ferguson, Stephanie Fradette
Summary: This study examined the use of tofersen in patients with SOD1 ALS and found that it can reduce protein concentrations in the cerebrospinal fluid and plasma, but does not improve clinical outcomes and is associated with adverse events. Further investigation is needed to evaluate the effects of early initiation of tofersen.
NEW ENGLAND JOURNAL OF MEDICINE
(2022)
Review
Urology & Nephrology
Jun Matsuda, Kana Asano-Matsuda, Thomas M. Kitzler, Tomoko Takano
Summary: Rho GTPases play a crucial role in regulating the actin cytoskeleton and are implicated in the pathogenesis of proteinuric glomerular diseases. These GTPases are primarily regulated by three families of proteins – GEFs, GAPs, and GDIs – with their upstream regulatory mechanisms largely unknown in podocytes. Further studies are needed to bridge the knowledge gap in the field.
KIDNEY INTERNATIONAL
(2021)
Article
Biochemistry & Molecular Biology
Alamzeb Khan, Weiming Ni, Francesc Lopez-Giraldez, Martin S. Kluger, Jordan S. Pober, Richard W. Pierce
Summary: Inflammation in sepsis disrupts capillary endothelial cell tight junctions and leads to leakage of fluids, proteins, and small molecules into tissues. TNF treatment induces RhoB activation in capillary endothelial cells, but the specific GEF responsible for activating RhoB remains unknown.
Article
Cell Biology
Bing-Ru Yan, Taoyingnan Li, Etienne Coyaud, Estelle M. N. Laurent, Jonathan St-Germain, Yuhuan Zhou, Peter K. Kim, Brian Raught, John H. Brumell
Summary: The protein C5orf51 plays a crucial role in regulating the activity of RAB7A during mitophagy, facilitating the shuttle of RAB7A between late endosomes and mitochondria. Depletion of C5orf51 leads to compromised localization of RAB7A on depolarized mitochondria, degradation by the proteasome, and inhibition of ATG9A recruitment to depolarized mitochondria.
Review
Cardiac & Cardiovascular Systems
Shane P. Comer
Summary: Platelet cytoskeletal reorganisation is important for platelet activation and thrombus formation. Rho GTPases play a critical role in this process, cycling between active and inactive states through the regulation of GAPs and GEFs. However, the functionality of Rho GTPase specific GAPs and GEFs in platelets is not well understood.
FRONTIERS IN CARDIOVASCULAR MEDICINE
(2022)
Article
Cell Biology
Zhuofu Ni, Xiaodong Cheng
Summary: EPAC proteins are only present in multicellular Metazoa, with EPAC1 only associated with chordates and EPAC2 spanning the entire animal kingdom. EPAC1 has undergone more selection and evolved faster than EPAC2.
Editorial Material
Biochemistry & Molecular Biology
Jianjun Duan, David G. Lambright
Summary: The article explores the structural basis for Sar1 activation by the Sec12 guanine nucleotide exchange factor during COPII vesicle biogenesis at the endoplasmic reticulum.
Article
Biochemistry & Molecular Biology
Aaron M. N. Joiner, Ben P. Phillips, Kumar Yugandhar, Ethan J. Sanford, Marcus B. Smolka, Haiyuan Yu, Elizabeth A. Miller, J. Christopher Fromme
Summary: The study revealed the regulation of Rab1 activation by the TRAPPIII complex, with the Trs85 subunit serving as a membrane anchor for the entire complex via its amphipathic helix. These findings provide a structural understanding of Rab activation on organelle and vesicle membranes.
Article
Neurosciences
David Wegrzyn, Josephine Zokol, Andreas Faissner
Summary: Vav proteins are a type of GEFs that catalyze the exchange of GDP with GTP. In the rodent CNS, Vav3 plays a significant role in neuronal development, but its functions in other cell types are less understood.
FRONTIERS IN CELLULAR NEUROSCIENCE
(2022)
Article
Biochemistry & Molecular Biology
Josie E. Bircher, Ellen E. Corcoran, TuKiet T. Lam, Michael J. Trnka, Anthony J. Koleske
Summary: Variants in the TRIO gene are associated with neurodevelopmental disorders, with evidence showing that the SRs of Trio interact intramolecularly with the GEF1 domain to inhibit its enzymatic activity. NDD-associated variants relieve this autoinhibitory constraint, suggesting a potential new target for therapeutic intervention.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Cell Biology
Yitian Guo, Judeah Negre, Gary Eitzen
Summary: When mast cells are stimulated by antigens, they release preformed inflammatory mediators through a process called degranulation. A protein called GEF-H1 is found to be activated during antigen stimulation and plays a role in activating RhoA to promote mast cell spreading and focal adhesion formation. Depletion of GEF-H1 leads to reduced cell spreading, granule movement, and exocytosis, which can be restored by expressing a constitutively active RhoA mutant. Inhibition of Syk kinase, a protein involved in the Fc epsilon RI signaling pathway, also blocks GEF-H1 activation and suppresses cell spreading, granule movement, and exocytosis.
Article
Immunology
Polly A. Machin, Anna-Karin E. Johnsson, Ellie J. Massey, Chiara Pantarelli, Stephen A. Chetwynd, Julia Y. Chu, Hanneke Okkenhaug, Anne Segonds-Pichon, Simon Walker, Angeliki Malliri, Yoshinori Fukui, Heidi C. E. Welch
Summary: Rac-GTPases and their Rac-GEF activators are essential for neutrophil-mediated host defence. Different Rac-GEFs activate distinct pools of Rac and regulate various neutrophil responses. Among them, Dock2 is the primary regulator, controlling neutrophil polarization, migration, and phagocytosis.
FRONTIERS IN IMMUNOLOGY
(2023)
Article
Chemistry, Analytical
Jiarong Wang, Bo Wu, Youjia Zhang, Liang Ge, Junfeng Wang
Summary: In this study, a 1D F-19 NMR-based method was developed for rapid detection of GEF activity of sGTPases, by tracking the conformational changes of the Arf6 switch region. This strategy could potentially be applied to monitor the conformational change of Arf6 or other sGTPase and detect the activities of sGTPase regulatory proteins in physiology and pathology environments.
ANALYTICAL CHEMISTRY
(2022)
Editorial Material
Pathology
Erin O. Jacob, Robert A. Hegele
EXPERT REVIEW OF MOLECULAR DIAGNOSTICS
(2023)
Article
Pharmacology & Pharmacy
Shehan D. Perera, Jian Wang, Adam D. McIntyre, Jacqueline S. Dron, Robert A. Hegele, Cert Endo
Summary: In this study, the longitudinal triglyceride (TG) phenotype of individuals with heterozygous pathogenic LPL variants was evaluated. The results showed that TG levels varied widely among patients and within the same patient. Most patients exhibited mild-to-moderate and severe hypertriglyceridemia (HTG), and the severity likely depended on secondary factors.
JOURNAL OF CLINICAL LIPIDOLOGY
(2023)
Editorial Material
Cardiac & Cardiovascular Systems
Robert A. Hegele
EUROPEAN JOURNAL OF PREVENTIVE CARDIOLOGY
(2023)
Article
Cardiac & Cardiovascular Systems
Pei Jun Zhao, Robert A. Hegele
Summary: The Canadian Society of Clinical Chemists has recommended adopting the more accurate Sampson/US NIH LDL-C equation for cardiovascular disease prevention. Based on the comparison of survey data, it is estimated that approximately 123,000 Canadians who are already taking cholesterol-lowering medications may need to intensify treatment due to the equation change.
Editorial Material
Cardiac & Cardiovascular Systems
Robert A. Hegele
EUROPEAN HEART JOURNAL
(2023)
Review
Cardiac & Cardiovascular Systems
Marina Cuchel, Frederick J. Raal, Robert A. Hegele, Khalid Al-Rasadi, Marcello Arca, Maurizio Averna, Eric Bruckert, Tomas Freiberger, Daniel Gaudet, Mariko Harada-Shiba, Lisa C. Hudgins, Meral Kayikcioglu, Luis Masana, Klaus G. Parhofer, Jeanine E. Roeters van Lennep, Raul D. Santos, Erik S. G. Stroes, Gerald F. Watts, Albert Wiegman, Jane K. Stock, Lale S. Tokgoezoglu, Alberico L. Catapano, Kausik K. Ray
Summary: This 2023 statement provides updated clinical guidance for the management of homozygous familial hypercholesterolaemia (HoFH), including criteria for diagnosis, genetic testing interpretation, and treatment recommendations. The statement emphasizes the importance of considering both phenotype and genotype in the diagnosis of HoFH, with a LDL-C level >10 mmol/L (>400 mg/dL) being indicative of the condition. Combination therapy targeting LDL-C, including the use of novel therapies like proprotein convertase subtilisin/kexin type 9 inhibitors, is recommended to achieve LDL-C goals and reduce the need for lipoprotein apheresis. To improve HoFH care globally, the statement recommends the implementation of national screening programs, education to increase awareness, and management guidelines adapted to local healthcare systems.
EUROPEAN HEART JOURNAL
(2023)
Article
Biochemistry & Molecular Biology
Brandon Chalazan, Emma Freeth, Arezoo Mohajeri, Krishnan Ramanathan, Matthew Bennett, Jagdeep Walia, Laura Halperin, Thomas Roston, Julieta Lazarte, Robert A. Hegele, Anna Lehman, Zachary Laksman
Summary: This study aims to determine the prevalence of likely pathogenic and pathogenic variants from AF genes in early-onset AF patients. The results suggest a potential clinical utility for offering different screening and treatment regimens in AF patients with a genetic defect.
EUROPEAN JOURNAL OF HUMAN GENETICS
(2023)
Review
Pharmacology & Pharmacy
Catherine M. Spagnuolo, Robert A. Hegele
Summary: Mild-to-moderate hypertriglyceridemia (HTG) is associated with atherosclerotic cardiovascular disease (ASCVD) and elevated triglyceride (TG) levels. Apolipoprotein C-III (apo C-III) inhibition is a promising treatment approach for reducing TG levels and ASCVD risk. Biologic agents like volanesorsen, olezarsen, and ARO-APOC3 significantly reduce apo C-III and TG levels, but further study is needed on their impact on cardiovascular outcomes.
EXPERT OPINION ON PHARMACOTHERAPY
(2023)
Article
Cardiac & Cardiovascular Systems
Gerald F. Watts, Samuel S. Gidding, Robert A. Hegele, Frederick J. Raal, Amy C. Sturm, Laney K. Jones, Mitchell N. Sarkies, Khalid Al-Rasadi, Dirk J. Blom, Magdalena Daccord, Sarah D. de Ferranti, Emanuela Folco, Peter Libby, Pedro Mata, Hapizah M. Nawawi, Uma Ramaswami, Kausik K. Ray, Claudia Stefanutti, Shizuya Yamashita, Jing Pang, Gilbert R. Thompson, Raul D. Santos
Summary: Familial hypercholesterolaemia (FH) is a preventable cause of premature coronary artery disease and death. This guidance article from the International Atherosclerosis Society provides a comprehensive overview of FH care that includes recommendations on the detection and management of patients with FH, as well as strategies to maximize implementation.
NATURE REVIEWS CARDIOLOGY
(2023)
Article
Cardiac & Cardiovascular Systems
Ahsen Chaudhry, Mark Trinder, Kristin Vesely, Lubomira Cermakova, Linda Jackson, Jian Wang, Robert A. Hegele, Liam R. Brunham
Summary: A study found that approximately 0.9% of patients clinically diagnosed with heterozygous familial hypercholesterolemia (HeFH) actually had homozygous familial hypercholesterolemia (HoFH) based on genetic diagnosis. These patients had higher levels of low-density lipoprotein cholesterol and a higher prevalence of premature cardiovascular disease.
CIRCULATION-GENOMIC AND PRECISION MEDICINE
(2023)
Review
Cardiac & Cardiovascular Systems
Iulia Iatan, G. B. John Mancini, Eunice Yeoh, Robert A. Hegele
Summary: Statins are important for reducing the risk of atherosclerotic cardiovascular disease, but they are underutilized due to concerns about side effects. Statin-associated muscle symptoms are a common cause of intolerance and discontinuation, leading to increased risk of adverse cardiovascular outcomes.
EXPERT REVIEW OF CARDIOVASCULAR THERAPY
(2023)
Review
Endocrinology & Metabolism
Praneet K. K. Gill, Robert A. A. Hegele
Summary: This article reviews the causes and consequences of hypocholesterolemia resulting from genetic and non-genetic factors, and discusses therapeutic strategies inspired by genetic hypocholesterolemia.
EXPERT REVIEW OF ENDOCRINOLOGY & METABOLISM
(2023)
Editorial Material
Hematology
Ann Marie Schmidt, Mary G. Sorci-Thomas, Yabing Chen, Robert A. Hegele
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
(2023)
Editorial Material
Cardiac & Cardiovascular Systems
Robert A. Hegele
Article
Genetics & Heredity
Shengjie Ying, Tracy Heung, Bhooma Thiruvahindrapuram, Worrawat Engchuan, Yue Yin, Christina Blagojevic, Zhaolei Zhang, Robert A. Hegele, Ryan K. C. Yuen, Anne S. Bassett
Summary: Elevated TG levels are modifiable risk factors for cardiovascular disease, and this study found that the TG-PRS, along with sex and BMI, were significant predictors of TG levels, especially in individuals with obesity. A combination of TG-PRS, sex, and BMI showed the greatest accuracy in predicting mild-moderate hypertriglyceridemia.
BMC MEDICAL GENOMICS
(2023)