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| Open AccessModulating glycosphingolipid metabolism and autophagy improves outcomes in pre-clinical models of myeloma bone disease
Here, the authors show that the glycosylceramide synthesis inhibitor and FDA approved drug Eliglustat inhibits autophagic degradation of TRAF3 which is a key step for osteoclast differentiation and thereby improves myeloma bone lesions.
- Houfu Leng
- , Hanlin Zhang
- & Nicole J. Horwood
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Article
| Open AccessMeteorin-like is an injectable peptide that can enhance regeneration in aged muscle through immune-driven fibro/adipogenic progenitor signaling
Lee et al. demonstrate the protein Meteorin-like can rejuvenate the body’s immune system to enhance muscle regeneration in old age – in part by inducing the death of pro-fibrotic mesenchymal progenitor cells within the muscle.
- David E. Lee
- , Lauren K. McKay
- & James P. White
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| Open AccessHigh antibody levels and reduced cellular response in children up to one year after SARS-CoV-2 infection
Severity of SARS-CoV-2 infection is different in adults and children which involves the immune response. Here using a parent and children cohort with 4 month and 12 month sampling times, the authors show enhanced levels and increased breadth of anti-spike antibody level over time but reduced specific T cell and B cell numbers in children.
- Eva-Maria Jacobsen
- , Dorit Fabricius
- & Ales Janda
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| Open AccessLow-dose AAV-CRISPR-mediated liver-specific knock-in restored hemostasis in neonatal hemophilia B mice with subtle antibody response
Here, the authors develop an AAV-CRISPR mediated somatic knock-in. They apply this system to restore hemostasis in neonatal hemophilia B mice and show liver-specificity of the knock-in and low serum antibody production.
- Xiangjun He
- , Zhenjie Zhang
- & Bo Feng
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| Open AccessHow Carvedilol activates β2-adrenoceptors
How carvedilol, a β1-blocker, activates β2-adrenoceptors, is unclear. Here, the authors resolve this enigma and show that carvedilol drives all of its detectable cellular β2-adrenoceptor signals by slow and low efficacy G protein activation.
- Tobias Benkel
- , Mirjam Zimmermann
- & Evi Kostenis
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| Open AccessPharmacological inhibition of HDAC6 improves muscle phenotypes in dystrophin-deficient mice by downregulating TGF-β via Smad3 acetylation
Here, authors show that Smad3 acetylation via HDAC6 inhibition reverses Duchenne muscular dystrophy-like symptoms in the mdx mouse model, suggesting a potential therapeutic target for the disorder.
- Alexis Osseni
- , Aymeric Ravel-Chapuis
- & Laurent Schaeffer
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Matters Arising
| Open AccessReply to: The stress-inducible ER chaperone GRP78/BiP is upregulated during SARS-CoV-2 infection and acts as a pro-viral protein
- Mohammed Samer Shaban
- , Christin Müller
- & Michael Kracht
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Article
| Open AccessPleiotropic genetic architecture and novel loci for C-reactive protein levels
Chronic inflammation and lipometabolism share many causal genes and possibly pathways. Here, the authors use a multi-trait GWAS approach to study shared genetic determinants of low-grade inflammation, measured by C-reactive protein (CRP), and closely linked lipid and metabolic pathways.
- Fotios Koskeridis
- , Evangelos Evangelou
- & Ioanna Tzoulaki
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Article
| Open AccessAdenine base editing efficiently restores the function of Fanconi anemia hematopoietic stem and progenitor cells
Fanconi Anemia (FA) is caused by deficiencies in DNA repair, making it hard to correct. Here the authors report a therapeutic base editing strategy to address two of the most prevalent FANCA mutations in patient hematopoietic stem and progenitor cells.
- Sebastian M. Siegner
- , Laura Ugalde
- & Jacob E. Corn
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Article
| Open AccessParkin regulates adiposity by coordinating mitophagy with mitochondrial biogenesis in white adipocytes
Parkin plays a role in mitophagy and has been shown to control adipose tissue browning and thermogenesis. Here the authors report that Parkin coordinates mitophagy with Pgc1α-mediated mitochondrial biogenesis in white adipocytes to regulate adiposity.
- Timothy M. Moore
- , Lijing Cheng
- & Zhenqi Zhou
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Article
| Open Accessvon Willebrand factor links primary hemostasis to innate immunity
von Willebrand factor (VWF) plays a critical role in primary hemostasis following vascular injury by tethering platelets to exposed collagen. Here, VWF binding to macrophages is shown to trigger NF-κB activation and induce pro-inflammatory responses.
- Clive Drakeford
- , Sonia Aguila
- & James S. O’Donnell
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Article
| Open AccessCircular RNA circBNC2 inhibits epithelial cell G2-M arrest to prevent fibrotic maladaptive repair
G2/M arrest of epithelial cells leads to fibrosis with unclear mechanisms. This study identifies a protein-encoding circRNA, circBNC2, which inhibits epithelial cells G2/M arrest to prevent fibrotic maladaptive repair in damaged kidney and liver, revealing a potential intervention target for fibrosis.
- Peng Wang
- , Zhitao Huang
- & Fan Fan Hou
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Article
| Open AccessDNA methyltransferase 3A controls intestinal epithelial barrier function and regeneration in the colon
DNA methyltransferase 3 A (DNMT3A) is involved in DNA methylation, and genetic variants in the DNMT3 locus have been associated with inflammatory bowel disease. Here the authors report that DNMT3A controls intestinal epithelial barrier function and restoration of the gut barrier function after intestinal epithelial perturbation.
- Antonella Fazio
- , Dora Bordoni
- & Philip Rosenstiel
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Article
| Open AccessMolecular characterization of renal cell carcinoma tumors from a phase III anti-angiogenic adjuvant therapy trial
Based on the S-TRAC results, sunitinib is approved as adjuvant treatment for adult patients at high risk of recurrent RCC following nephrectomy. Here, the authors report the results of an integrated multi-omics tumor analysis of 171 patients from the trial and identify specific molecular subtypes as well as potential new targets.
- Robert J. Motzer
- , Jean-François Martini
- & Alain Ravaud
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| Open AccessHigh-resolution genome topology of human retina uncovers super enhancer-promoter interactions at tissue-specific and multifactorial disease loci
The genome-wide high-resolution chromatin contact of the human retina identifies genetic control of cell-type specific gene expression pattern, missing heritability in retinopathies, and candidate genes/variants for diseases including AMD and glaucoma.
- Claire Marchal
- , Nivedita Singh
- & Anand Swaroop
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Article
| Open AccessDeletion of skeletal muscle Akt1/2 causes osteosarcopenia and reduces lifespan in mice
Sasako et al. show that disruption of the insulin/IGF-1 signaling by suppressing Akt activity in mouse skeletal muscle can accelerate osteosarcopenia and shortens lifespan, which is reversed by inactivation of FoxOs rather than activation of mTOR, suggesting FoxOs as therapeutic targets.
- Takayoshi Sasako
- , Toshihiro Umehara
- & Kohjiro Ueki
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| Open AccessAirway basal cells show a dedifferentiated KRT17highPhenotype and promote fibrosis in idiopathic pulmonary fibrosis
The functional role of airway basal cells has not been comprehensively studied in idiopathic pulmonary fibrosis (IPF). Here, the authors show that airway basal cells of IPF patients display a distinct phenotype, are profibrotic if transplanted to mice and that fibrosis can be ameliorated by Src iinhibitors.
- Benedikt Jaeger
- , Jonas Christian Schupp
- & Antje Prasse
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| Open AccessTopical application of an irreversible small molecule inhibitor of lysyl oxidases ameliorates skin scarring and fibrosis
Scars are a significant problem caused by excess collagen in the skin. Here the authors develop a topical drug that reduces collagen stability and leads to improved scar appearance and stiffness in preclinical models.
- Nutan Chaudhari
- , Alison D. Findlay
- & Mark W. Fear
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Article
| Open AccessConserved features of TERT promoter duplications reveal an activation mechanism that mimics hotspot mutations in cancer
TERT promoter mutations are the most common noncoding alterations in cancers, although some remain to be characterised. Here, the authors identify TERT promoter duplications across seven cancer types that are functionally equivalent to well-known hotspot TERT mutations and are clonal in a multifocal glioblastoma patient.
- Carter J. Barger
- , Abigail K. Suwala
- & Joseph F. Costello
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| Open AccessSirtuin 6 inhibition protects against glucocorticoid-induced skeletal muscle atrophy by regulating IGF/PI3K/AKT signaling
Chronic stress induces skeletal muscle atrophy via upregulation of glucocorticoid levels. Here, the authors show that SIRT6 transcriptionally regulates glucocorticoid-induced muscle atrophy by modulating IGF/PI3K/AKT signalling.
- Sneha Mishra
- , Claudia Cosentino
- & Nagalingam R. Sundaresan
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| Open AccessIn vivo adenine base editing reverts C282Y and improves iron metabolism in hemochromatosis mice
Hemochromatosis is a metabolic disorder caused by mutations in the HFE gene. Here, the authors show that a single administration of AAV8 vectors expressing an Adenine Base Editor facilitates efficient in vivo gene correction in hepatocytes and leads to improvement of iron-specific parameters in the liver and the blood in mouse models of the disease.
- Alice Rovai
- , BoMee Chung
- & Michael Ott
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Article
| Open AccessStructural basis of ion uptake in copper-transporting P1B-type ATPases
P1B-type ATPases export excess transition metals from cells. Here, the authors report a molecular structure of CopA, a coppertransporting P1B-ATPase from A. fulgidus, in an inward-facing E1 conformation.
- Nina Salustros
- , Christina Grønberg
- & Pontus Gourdon
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| Open AccessEndophenotype effect sizes support variant pathogenicity in monogenic disease susceptibility genes
Accurate classification of genetic variants is critical for research and patient care. Here, the authors report that population-based associations between rare variants and quantitative endophenotypes for monogenic diseases can provide support for variant pathogenicity.
- Jennifer L. Halford
- , Valerie N. Morrill
- & Steven A. Lubitz
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Article
| Open AccessHnRNPK maintains single strand RNA through controlling double-strand RNA in mammalian cells
Using fibroblast growth factor 2 (FGF-2) induced sense and antisense transcripts IER3 and IER3-AS1 as a model system, authors highlight the role of HnRNPK in regulating double strand RNA formation in the loci with overlapping transcripts.
- Sagar Mahale
- , Meenakshi Setia
- & Meena Kanduri
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Article
| Open AccessELF5 is a potential respiratory epithelial cell-specific risk gene for severe COVID-19
Genetic factors have been found to be associated with severe COVID-19. Here, the authors integrated genomic, proteomic, and single-cell data to identify ELF5 as a candidate risk gene with a possible role in respiratory epithelial cells, which are targeted by SARS-CoV-2.
- Maik Pietzner
- , Robert Lorenz Chua
- & Claudia Langenberg
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Article
| Open AccessReformation of the chondroitin sulfate glycocalyx enables progression of AR-independent prostate cancer
Chondroitin sulfate (CS) is one of the most abundant glycosaminoglycans in prostate cancers. Here the authors show that inhibition of the androgen receptor pathway leads to the upregulation of CS, which promotes prostate cancer growth and metastasis.
- Nader Al-Nakouzi
- , Chris Kedong Wang
- & Mads Daugaard
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Article
| Open AccessComprehensive genomic and epigenomic analysis in cancer of unknown primary guides molecularly-informed therapies despite heterogeneity
The identification of molecular biomarkers in cancer of unknown primary site (CUP) cases may enable the improvement of prognosis in these patients. Here, the authors integrate whole genome/exome, transcriptome and methylome data in 70 CUP patients, recommend therapies based on their analysis and report clinical outcome data.
- Lino Möhrmann
- , Maximilian Werner
- & Hanno Glimm
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Article
| Open AccessMolecular and in vivo studies of a glutamate-class prolyl-endopeptidase for coeliac disease therapy
Celiac disease is characterized by intolerance to gluten, a cereal protein. Here, the authors show that neprosin, a glutamate peptidase from the pitcher plant, efficiently cleaves gluten components under physiological conditions in vitro and in the gut of mice.
- Laura del Amo-Maestro
- , Soraia R. Mendes
- & F. Xavier Gomis-Rüth
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Article
| Open AccessCDC-like kinase 4 deficiency contributes to pathological cardiac hypertrophy by modulating NEXN phosphorylation
Phosphorylation catalyzed by kinases is a key event in signaling pathways involved in cardiomyocyte hypertrophy. Here the authors show that the kinase CLK4 ameliorates cardiac hypertrophy by phosphorylating NEXN.
- Jian Huang
- , Luxin Wang
- & Yi-Han Chen
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Article
| Open AccessMouse fetal growth restriction through parental and fetal immune gene variation and intercellular communications cascade
Natural Killer cells regulate foetal growth. Here the authors use a humanized transgenic mouse to demonstrate that specific HLA-C KIR2DL interactions promote changes in maternal and foetal cell transcriptomes, resulting in modifications to placental vasculature, intercellular communications and foetal growth restriction.
- Gurman Kaur
- , Caroline B. M. Porter
- & Lars Fugger
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Article
| Open AccessAn automated 13.5 hour system for scalable diagnosis and acute management guidance for genetic diseases
Rapid diagnosis and implementation of treatments is crucial in many genetic conditions. Here the authors describe Genome-to-Treatment, a virtual disease management system that can achieve a rapid diagnosis by expedited whole genome sequencing in 13.5 hours and provide guidance to clinicians for possible therapies.
- Mallory J. Owen
- , Sebastien Lefebvre
- & Stephen F. Kingsmore
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| Open AccessIntegrin α3β1 promotes vessel formation of glioblastoma-associated endothelial cells through calcium-mediated macropinocytosis and lysosomal exocytosis
Tumour-associated angiogenesis facilitates the growth of tumours. Here the authors show that integrin α3β1 promotes blood vessel formation in glioblastoma through calcium-mediated macropinocytosis and lysosomal exocytosis.
- Eunnyung Bae
- , Ping Huang
- & Candece L. Gladson
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| Open AccessQualitative differences in disease-associated MEK mutants reveal molecular signatures and aberrant signaling-crosstalk in cancer
MEK1 mutations are found in cancer and RASopathies, but their effects remain unclear. Here, the authors reveal a mutant MEK1 structure and qualitative differences in biological properties between the cancer- and RASopathy-associated mutants, providing insights into the pathophysiology, diagnosis, and treatment of these diseases.
- Yuji Kubota
- , Yuko Fujioka
- & Mutsuhiro Takekawa
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Matters Arising
| Open AccessQuestioning whether IgM Fc receptor (FcµR) is expressed by innate immune cells
- Christopher M. Skopnik
- , René Riedel
- & Hiromi Kubagawa
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Matters Arising
| Open AccessLimitations of molecular testing in combination with computerized tomographic for lung cancer screening
- Frederic W. Grannis Jr
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Article
| Open AccessThe contribution of common regulatory and protein-coding TYR variants to the genetic architecture of albinism
Albinism is a rare disorder often caused by high-effect rare variants in the TYR gene. Here, the authors study a large albinism cohort and find that a common variant in the TYR promoter contributes to albinism by modifying the penetrance of other common variants, demonstrating a complex genetic architecture.
- Vincent Michaud
- , Eulalie Lasseaux
- & Panagiotis I. Sergouniotis
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| Open AccessInhibitory role of Annexin A1 in pathological bone resorption and therapeutic implications in periprosthetic osteolysis
Periprosthetic osteolysis is a cause of arthroplasty failure without available therapies. Here the authors show that Annexin A1 (AnxA1) is involved in in periprosthetic osteolysis and exerts potential therapeutic effects through suppressing NFκB signaling and promoting the PPAR-γ pathway resulting in inhibition of inflammation and osteoclasts differentiation induced by wear debris.
- Hend Alhasan
- , Mohamad Alaa Terkawi
- & Norimasa Iwasaki
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| Open AccessNeutralization capacity of antibodies elicited through homologous or heterologous infection or vaccination against SARS-CoV-2 VOCs
Emerging SARS-CoV-2 variants raise concerns on protective immunity. Here the authors show that convalescent sera from people infected with Alpha, Beta, Gamma or Delta show a significant drop of Omicron-BA.1 neutralization and that vaccine-breakthrough infections with Omicron-BA.1 or Delta result in robust neutralization for both Delta and Omicron-BA.1.
- Meriem Bekliz
- , Kenneth Adea
- & Isabella Eckerle
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Article
| Open AccessClonal reconstruction from co-occurrence of vector integration sites accurately quantifies expanding clones in vivo
High transduction rates of viral vectors ensure good gene delivery; however multiple integration events can occur in the same cell. Here the authors use correlations between repeated measurements of integration site abundances to estimate their mutual similarity and identify clusters of co-occurring sites.
- Sebastian Wagner
- , Christoph Baldow
- & Ingmar Glauche
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Article
| Open AccessStructural basis for defective membrane targeting of mutant enzyme in human VLCAD deficiency
Prew et al. uncovered a structural basis for human VLCAD deficiency that arises from point mutations within the enzyme’s membrane-binding region, which was shown to fold as a putative α-helical hairpin. Helix-breaking mutations selectively disrupt membrane interaction and thus homeostatic function.
- Michelle S. Prew
- , Christina M. Camara
- & Loren D. Walensky
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Article
| Open AccessVariants in ASPH cause exertional heat illness and are associated with malignant hyperthermia susceptibility
The genetic cause(s) of malignant hyperthermia and exertional heat illness are unknown in approximately 30% of cases. To address this barrier, the authors performed genome sequencing on a large cohort of cases, identifying rare variants in ASPH, a gene encoding junctin, and validating them in animal and cell models.
- Yukari Endo
- , Linda Groom
- & James J. Dowling
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Article
| Open AccessNeonatal gene therapy achieves sustained disease rescue of maple syrup urine disease in mice
Maple syrup urine disease (MSUD) is a rare inborn error of metabolism, which is currently treated with life-long low-protein diet that can be challenging to maintain. Here the authors develop an AAV8-directed gene therapy providing sustainable disease rescue in a mouse model of MSUD.
- Clément Pontoizeau
- , Marcelo Simon-Sola
- & Manuel Schiff
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Article
| Open AccessDepletion of skeletal muscle satellite cells attenuates pathology in muscular dystrophy
Boyer et al. created genetic mouse models of muscular dystrophy in which satellite cells were selectively depleted. The depletion of satellite cells at select times was protective. Myofibers no longer had plasma membrane instability leading to tissue wasting in the muscular dystrophies.
- Justin G. Boyer
- , Jiuzhou Huo
- & Jeffery D. Molkentin
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Article
| Open AccessHomophilic ATP1A1 binding induces activin A secretion to promote EMT of tumor cells and myofibroblast activation
Direct contact between tumour cells and fibroblasts influences tumour cell behaviour. Here the authors show that pancreatic cancer cells and fibroblasts directly interact via homophilic ATP1A1 binding, which induces fibroblasts to secrete activin A to promote epithelial-mesenchymal transition of tumour cells and myofibroblast activation.
- Yi-Ing Chen
- , Chin-Chun Chang
- & Wen-Hwa Lee
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Article
| Open AccessADAMTS4-specific MR probe to assess aortic aneurysms in vivo using synthetic peptide libraries
New biomarkers are required to improve the assessment of aortic wall integrity and risk of rupture. Here the authors report the development of an imaging probe for ADAMTS4, which they test in an abdominal aortic aneurysm mouse model and show in vivo prediction of aneurysm and rupture.
- Jan O. Kaufmann
- , Julia Brangsch
- & Marcus R. Makowski
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Article
| Open AccessEngineered Cas12i2 is a versatile high-efficiency platform for therapeutic genome editing
Cas12i is a genome editing platform with compact size that fits in AAV vector with short 43-mer gRNA, absence of tracrRNA, ability to process pre-crRNA, and high specificity. Here the authors present an unbiased mutational scanning approach to engineer Cas12i, which shows low activity in mammalian cells, and identify single substitutions that significantly improve indel activity.
- Colin McGaw
- , Anthony J. Garrity
- & Shaorong Chong
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Article
| Open AccessLipid droplet degradation by autophagy connects mitochondria metabolism to Prox1-driven expression of lymphatic genes and lymphangiogenesis
Autophagy is essential to endothelial cell homeostasis. Here the authors show that lipophagy in LEC supports fatty acid oxidation to sustain a mitochondrial-Prox1 gene expression circuit and promote response of LEC to lymphangiogenic mediators.
- Odeta Meçe
- , Diede Houbaert
- & Patrizia Agostinis
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| Open AccessMultimodal CEA-targeted fluorescence and radioguided cytoreductive surgery for peritoneal metastases of colorectal origin
Imaging of tumor burden during surgery can lead to better tumor resection. Here, the authors develop a fluorescent probe that binds to carcinoembryonic antigen, expressed on colorectal cancer cells, and describe the results of their phase I clinical trial.
- Jan Marie de Gooyer
- , Fortuné M. K. Elekonawo
- & Johannes H. W. de Wilt
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| Open AccessDual functions of microRNA-17 in maintaining cartilage homeostasis and protection against osteoarthritis
Osteoarthritic (OA) is characterized by progressive destruction of joint cartilage. Here, the authors show that microRNA-17 plays a dual role in maintaining cartilage homeostasis and in the prevention of osteoarthritis, by targeting hypoxia-inducible factor-1α as well as multiple matrix-degrading enzymes.
- Yun Zhang
- , Shuaijun Li
- & Lei Cui