PURPOSE: Cxbladder tests are urinary biomarker tests for detection of urothelial carcinoma. We developed enhanced Cxbladder tests that incorporate DNA analysis of 6 single nucleotide polymorphisms for the FGFR3 and TERT genes, in addition to the current 5 mRNA biomarkers and clinical risk factors. MATERIALS AND METHODS: Two multicenter, prospective studies were undertaken in: (1) U.S. patients with gross hematuria aged ≥18 years and (2) Singaporean patients with gross hematuria or microhematuria aged >21 years. All patients provided a midstream urine sample and underwent cystoscopy. Samples were retrospectively analyzed using enhanced Cxbladder-Triage (risk stratifies patients), enhanced Cxbladder-Detect (risk stratifies patients and detects positive patients), and the combination enhanced Cxbladder-Triage × Cxbladder-Detect. RESULTS: In the pooled cohort (N=804; gross hematuria: n=484, microhematuria: n=320), enhanced Cxbladder-Detect had a sensitivity of 97% (95% CI 89%-100%), specificity of 90% (95% CI 88%-92%), and negative predictive value of 99.7% (95% CI 99%-100%) for detection of urothelial carcinoma. Overall, 83% of patients were enhanced Cxbladder-Detect-negative (ie, needed no further work-up). Of 133 enhanced Cxbladder-Detect-positive patients, 59 had a confirmed tumor, of which 19 were low-grade noninvasive papillary carcinoma or papillary urothelial neoplasm of low malignant potential. In total, 40 tumors were high-grade Ta, T1-T4, Tis, including concomitant carcinoma in situ. Of the 74 patients with normal cystoscopy, 41 were positive by single nucleotide polymorphism analysis. Enhanced Cxbladder-Triage and enhanced Cxbladder-Detect had significantly better specificity than the first-generation Cxbladder tests (P < .001). CONCLUSIONS: This study in ethnically diverse patients with hematuria showed the analytical validity of the enhanced Cxbladder tests.
- MeSH
- cystoskopie MeSH
- dospělí MeSH
- hematurie etiologie genetika MeSH
- hodnocení rizik MeSH
- karcinom in situ * MeSH
- karcinom z přechodných buněk * diagnóza genetika moč MeSH
- lidé MeSH
- mladiství MeSH
- mutace MeSH
- nádorové biomarkery genetika moč MeSH
- nádory močového měchýře * diagnóza genetika moč MeSH
- prospektivní studie MeSH
- receptor fibroblastových růstových faktorů, typ 3 genetika MeSH
- retrospektivní studie MeSH
- senzitivita a specificita MeSH
- telomerasa * genetika MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mladiství MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
Activating mutations in the FGFR3 receptor tyrosine kinase lead to most prevalent form of genetic dwarfism in humans, the achondroplasia. Many features of the complex function of FGFR3 in growing skeleton were characterized, which facilitated identification of therapy targets, and drove progress toward treatment. In August 2021, the vosoritide was approved for treatment of achondroplasia, which is based on a stable variant of the C-natriuretic peptide. Other drugs may soon follow, as several conceptually different inhibitors of FGFR3 signaling progress through clinical trials. Here, we review the current achondroplasia therapeutics, describe their mechanisms, and illuminate motivations leading to their development. We also discuss perspectives of curing achondroplasia, and options for repurposing achondroplasia drugs for dwarfing conditions unrelated to FGFR3.
BACKGROUND: Achondroplasia (ACH) is one of the most prevalent genetic forms of short-limbed skeletal dysplasia, caused by gain-of-function mutations in the receptor tyrosine kinase FGFR3. In August 2021, the C-type natriuretic peptide (CNP) analog vosoritide was approved for the treatment of ACH. A total of six other inhibitors of FGFR3 signaling are currently undergoing clinical evaluation for ACH. This progress creates an opportunity for children with ACH, who may gain early access to the treatment by entering clinical trials before the closure of their epiphyseal growth plates and cessation of growth. Pathophysiology associated with the ACH, however, demands a long observational period before admission to the interventional trial. Public patient registries can facilitate the process by identification of patients suitable for treatment and collecting the data necessary for the trial entry. RESULTS: In 2015, we established the prospective ACH registry in the Czechia and the Slovak Republic ( http://www.achondroplasia-registry.cz ). Patient data is collected through pediatric practitioners and other relevant specialists. After informed consent is given, the data is entered to the online TrialDB system and stored in the Oracle 9i database. The initial cohort included 51 ACH children (average age 8.5 years, range 3 months to 14 years). The frequency of selected neurological, orthopedic, or ORL diagnoses is also recorded. In 2015-2021, a total of 89 measurements of heights, weights, and other parameters were collected. The individual average growth rate was calculated and showed values without exception in the lower decile for the appropriate age. Evidence of paternal age effect was found, with 58.7% of ACH fathers older than the general average paternal age and 43.5% of fathers older by two or more years. One ACH patient had orthopedic limb extension and one patient received growth hormone therapy. Low blood pressure or renal impairment were not found in any patient. CONCLUSION: The registry collected the clinical information of 51 pediatric ACH patients during its 6 years of existence, corresponding to ~ 60% of ACH patients living in the Czechia and Slovak Republic. The registry continues to collect ACH patient data with annual frequency to monitor the growth and other parameters in preparation for future therapy.
- MeSH
- achondroplazie * epidemiologie genetika MeSH
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mutace MeSH
- předškolní dítě MeSH
- prospektivní studie MeSH
- receptor fibroblastových růstových faktorů, typ 3 genetika MeSH
- registrace MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- předškolní dítě MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Česká republika MeSH
- Slovenská republika MeSH
Achondroplasia is the most prevalent genetic form of dwarfism in humans and is caused by activating mutations in FGFR3 tyrosine kinase. The clinical need for a safe and effective inhibitor of FGFR3 is unmet, leaving achondroplasia currently incurable. Here, we evaluated RBM-007, an RNA aptamer previously developed to neutralize the FGFR3 ligand FGF2, for its activity against FGFR3. In cultured rat chondrocytes or mouse embryonal tibia organ culture, RBM-007 rescued the proliferation arrest, degradation of cartilaginous extracellular matrix, premature senescence, and impaired hypertrophic differentiation induced by FGFR3 signaling. In cartilage xenografts derived from induced pluripotent stem cells from individuals with achondroplasia, RBM-007 rescued impaired chondrocyte differentiation and maturation. When delivered by subcutaneous injection, RBM-007 restored defective skeletal growth in a mouse model of achondroplasia. We thus demonstrate a ligand-trap concept of targeting the cartilage FGFR3 and delineate a potential therapeutic approach for achondroplasia and other FGFR3-related skeletal dysplasias.
- MeSH
- achondroplazie * farmakoterapie genetika MeSH
- aptamery nukleotidové * MeSH
- buněčná diferenciace MeSH
- chondrocyty MeSH
- krysa rodu rattus MeSH
- myši MeSH
- receptor fibroblastových růstových faktorů, typ 3 genetika MeSH
- vývoj kostí MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
PURPOSE OF REVIEW: Fibroblast growth factor receptor (FGFR) signalling, especially induced by FGFR3, is a crucial factor in the pathogenesis of urothelial carcinoma and was therefore extensively studied over the last decades. In this review, we summarize the most relevant findings of the past two years. RECENT FINDINGS: Recent studies support the concept that FGFR3 mediates a pathway of urothelial carcinogenesis associated with low malignant potential. FGFR3 may represent a highly accurate biomarker for diagnosis and prediction of recurrence, progression or therapy response. The pan FGFR-inhibitor erdafitinib was recently approved for urothelial carcinoma, whereas several other FGFR-targeted drugs are currently undergoing clinical trials. SUMMARY: Numerous recent studies focus on the role of FGFR3 in different urothelial carcinoma subtypes and its potential clinical application as noninvasive biomarker, as well as therapeutic target.
- MeSH
- antitumorózní látky terapeutické užití MeSH
- chinoxaliny terapeutické užití MeSH
- inhibitory proteinkinas terapeutické užití MeSH
- karcinom z přechodných buněk farmakoterapie patologie MeSH
- lidé MeSH
- lokální recidiva nádoru MeSH
- nádory močového měchýře farmakoterapie patologie MeSH
- pyrazoly terapeutické užití MeSH
- receptor fibroblastových růstových faktorů, typ 3 MeSH
- receptory fibroblastových růstových faktorů antagonisté a inhibitory terapeutické užití MeSH
- urologické nádory farmakoterapie MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- MeSH
- chondrocyty fyziologie metabolismus MeSH
- dítě MeSH
- insulinu podobný růstový faktor I farmakologie metabolismus MeSH
- lidé MeSH
- mutace MeSH
- natriuretický peptid typu C genetika MeSH
- parathormon metabolismus MeSH
- poruchy růstu * etiologie farmakoterapie genetika MeSH
- puberta MeSH
- receptor fibroblastových růstových faktorů, typ 3 genetika MeSH
- růst fyziologie MeSH
- růstová ploténka anatomie a histologie fyziologie růst a vývoj MeSH
- růstový hormon farmakologie metabolismus MeSH
- tělesná výška MeSH
- vývoj kostí fyziologie MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
- přehledy MeSH
CONTEXT: Familial short stature (FSS) is a term describing a growth disorder that is vertically transmitted. Milder forms may result from the combined effect of multiple genes; more severe short stature is suggestive of a monogenic condition. The etiology of most FSS cases has not been thoroughly elucidated to date. OBJECTIVES: To identify the genetic etiology of severe FSS in children treated with GH because of the diagnosis of small for gestational age or GH deficiency (SGA/GHD). DESIGN, SETTINGS, AND PATIENTS: Of 736 children treated with GH because of GHD/SGA, 33 with severe FSS (life-minimum height -2.5 SD or less in both the patient and shorter parent) were included in the study. The genetic etiology was known in 5 of 33 children prior to the study [ACAN (in 2], NF1, PTPN11, and SOS1). In the remaining 28 of 33, whole-exome sequencing was performed. The results were evaluated using American College of Medical Genetics and Genomics standards and guidelines. RESULTS: In 30 of 33 children (90%), we found at least one variant with potential clinical significance in genes known to affect growth. A genetic cause was elucidated in 17 of 33 (52%). Of these children, variants in growth plate-related genes were found in 9 of 17 [COL2A1, COL11A1, and ACAN (all in 2), FLNB, FGFR3, and IGF1R], and IGF-associated proteins were affected in 2 of 17 (IGFALS and HMGA2). In the remaining 6 of 17, the discovered genetic mechanisms were miscellaneous (TRHR, MBTPS2, GHSR, NF1, PTPN11, and SOS1). CONCLUSIONS: Single-gene variants are frequent among families with severe FSS, with variants affecting the growth plate being the most prevalent.
- MeSH
- dítě MeSH
- genetická predispozice k nemoci epidemiologie MeSH
- genetická variace * MeSH
- kohortové studie MeSH
- kojenec MeSH
- lidé MeSH
- lidský růstový hormon terapeutické užití MeSH
- metaloendopeptidasy genetika MeSH
- mladiství MeSH
- poruchy růstu farmakoterapie epidemiologie genetika MeSH
- předškolní dítě MeSH
- prognóza MeSH
- prospektivní studie MeSH
- receptor fibroblastových růstových faktorů, typ 3 genetika MeSH
- receptor IGF typ 1 genetika MeSH
- rodokmen MeSH
- růstová ploténka účinky léků MeSH
- sekvenování exomu metody MeSH
- stupeň závažnosti nemoci MeSH
- výsledek terapie MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Česká republika MeSH
Vertebrate primary cilium is a Hedgehog signaling center but the extent of its involvement in other signaling systems is less well understood. This report delineates a mechanism by which fibroblast growth factor (FGF) controls primary cilia. Employing proteomic approaches to characterize proteins associated with the FGF-receptor, FGFR3, we identified the serine/threonine kinase intestinal cell kinase (ICK) as an FGFR interactor. ICK is involved in ciliogenesis and participates in control of ciliary length. FGF signaling partially abolished ICK's kinase activity, through FGFR-mediated ICK phosphorylation at conserved residue Tyr15, which interfered with optimal ATP binding. Activation of the FGF signaling pathway affected both primary cilia length and function in a manner consistent with cilia effects caused by inhibition of ICK activity. Moreover, knockdown and knockout of ICK rescued the FGF-mediated effect on cilia. We provide conclusive evidence that FGF signaling controls cilia via interaction with ICK.
- MeSH
- buňky NIH 3T3 MeSH
- cilie metabolismus MeSH
- CRISPR-Cas systémy MeSH
- fibroblastové růstové faktory metabolismus MeSH
- fosforylace MeSH
- HEK293 buňky MeSH
- interakční proteinové domény a motivy MeSH
- lidé MeSH
- modely u zvířat MeSH
- myši knockoutované MeSH
- myši MeSH
- protein-serin-threoninkinasy genetika metabolismus MeSH
- proteiny hedgehog metabolismus MeSH
- proteomika MeSH
- receptor fibroblastových růstových faktorů, typ 1 metabolismus MeSH
- receptor fibroblastových růstových faktorů, typ 3 genetika metabolismus MeSH
- receptor fibroblastových růstových faktorů, typ 4 metabolismus MeSH
- receptory fibroblastových růstových faktorů genetika metabolismus MeSH
- signální transdukce MeSH
- simulace molekulového dockingu MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
Receptor tyrosine kinases (RTKs) form multiprotein complexes that initiate and propagate intracellular signals and determine the RTK-specific signalling patterns. Unravelling the full complexity of protein interactions within the RTK-associated complexes is essential for understanding of RTK functions, yet it remains an understudied area of cell biology. We describe a comprehensive approach to characterize RTK interactome. A single tag immunoprecipitation and phosphotyrosine protein isolation followed by mass-spectrometry was used to identify proteins interacting with fibroblast growth factor receptor 3 (FGFR3). A total of 32 experiments were carried out in two different cell types and identified 66 proteins out of which only 20 (30.3%) proteins were already known FGFR interactors. Using co-immunoprecipitations, we validated FGFR3 interaction with adapter protein STAM1, transcriptional regulator SHOX2, translation elongation factor eEF1A1, serine/threonine kinases ICK, MAK and CCRK, and inositol phosphatase SHIP2. We show that unappreciated signalling mediators exist for well-studied RTKs, such as FGFR3, and may be identified via proteomic approaches described here. These approaches are easily adaptable to other RTKs, enabling identification of novel signalling mediators for majority of the known human RTKs.
- MeSH
- adaptorové proteiny signální transdukční genetika metabolismus MeSH
- buňky NIH 3T3 MeSH
- cyklin-dependentní kinasy genetika metabolismus MeSH
- elongační faktor 1 genetika metabolismus MeSH
- endozomální třídící komplexy pro transport genetika metabolismus MeSH
- fosfatidylinositol-3,4,5-trisfosfát-5-fosfatasy genetika metabolismus MeSH
- fosfoproteiny genetika metabolismus MeSH
- fosforylace MeSH
- HEK293 buňky MeSH
- homeodoménové proteiny genetika metabolismus MeSH
- lidé MeSH
- mapování interakce mezi proteiny MeSH
- myši MeSH
- protein-serin-threoninkinasy genetika metabolismus MeSH
- proteomika metody MeSH
- receptor fibroblastových růstových faktorů, typ 3 genetika metabolismus MeSH
- regulace genové exprese * MeSH
- signální transdukce genetika MeSH
- stanovení celkové genové exprese MeSH
- vazba proteinů MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Familiárně malý vzrůst (FSS) je charakterizován výškou menší než -2 SD ve srovnání s průměrnou výškou pro daný věk, pohlaví a populaci, a to ve dvou nebo více po sobě jdoucích generacích. Ačkoliv v řadě individuálních případů se podstata FSS neobjasní, relativně častou příčinou jsou autosomálně dominantně dědičné poruchy růstové ploténky. Jejich klinický obraz představuje široké spektrum stavů od velmi mírně vyjádřených forem s proporcionálním malým vzrůstem až po potenciálně letální těžké formy kostních dysplazií s deformitami končetin. Poruchy růstové ploténky lze dělit podle mechanismu na molekulární úrovni – může se jednat o porušenou parakrinní signalizaci, abnormity mezibuněčné hmoty chrupavky, nebo poruchy v základních buněčných dějích. Do skupiny poruch parakrinní signalizace patří stavy spojené se změnami genů FGFR3 nebo NPR2. Změny mezibuněčné hmoty růstové chrupavky nacházíme u mutací genu ACAN, FBN1 nebo genů pro jednotlivé typy kolagenů (např. COL2A1). Heterozygotní mutace v SHOX genu jsou příčinou malé výšky u 2–15 % dětí s klinickým obrazem idiopatického malého vzrůstu. Znalost správné diagnózy je důležitá pro přesnější odhad finální výšky, pro cílené sledování s ohledem na předpokládané komplikace, pro správnou léčbu a pro možnost validního genetického poradenství. Spolupráce dětského endokrinologa, antropologa, radiologa a genetika pomáhá při diagnostice i kvalitní péči o tyto pacienty.
Familial short stature (FSS) is characterised by body height lower than -2 SD if compared with mean height for age, sex and background population, that occurs in two or more subsequent generations. Although the cause for FSS remains not clarified in many individual cases, it may result from autosomal dominantly inherited growth plate disorders. The spectrum of clinical features of growth plate disorders ranges from very mildly expressed forms with proportional short stature up to potentially lethal severe skeletal dysplasia with limb deformities. Growth plate disorders include subgroups according to underlying mechanisms at molecular level – impaired paracrine signalisation, defects of cartilaginous extracellular matrix, or defective fundamental intracellular functions. FGFR3 or NPR2 gene mutations lead to impaired paracrine signalisation. The defects of cartilaginous extracellular matrix include mutations in genes ACAN, FNB1 or in genes encoding individual types collagen (e.g. COL2A1). Heterozygous mutations of SHOX gene cause 2-15 % of idiopathic short stature. Clarification of specific diagnosis allows a more precise estimation of final body height, for targeted follow-up with regard to potential complications, for appropriate management and relevant genetic counselling. Team collaboration of paediatric endocrinologist, anthropologist, radiologist and genetician is helpful for both diagnosis and management of affected children.
- Klíčová slova
- familiárně malý vzrůst, gen NPR2, gen ACAN, kolagenopatie,
- MeSH
- genetické nemoci vrozené MeSH
- kolagen fyziologie klasifikace MeSH
- lidé MeSH
- meloreostóza genetika patofyziologie MeSH
- mutace MeSH
- osteochondrodysplazie etiologie genetika MeSH
- poruchy růstu MeSH
- protein SHOX fyziologie genetika MeSH
- receptor fibroblastových růstových faktorů, typ 3 fyziologie genetika MeSH
- růstová ploténka * abnormality růst a vývoj MeSH
- vývojové onemocnění kostí * klasifikace MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
