Ependymomas (EPN) are central nervous system tumors comprising both aggressive and more benign molecular subtypes. However, therapy of the high-risk subtypes posterior fossa group A (PF-A) and ...supratentorial RELA-fusion positive (ST-RELA) is limited to gross total resection and radiotherapy, as effective systemic treatment concepts are still lacking. We have recently described fibroblast growth factor receptors 1 and 3 (
FGFR1/FGFR3
) as oncogenic drivers of EPN. However, the underlying molecular mechanisms and their potential as therapeutic targets have not yet been investigated in detail. Making use of transcriptomic data across 467 EPN tissues, we found that
FGFR1
and
FGFR3
were both widely expressed across all molecular groups.
FGFR3
mRNA levels were enriched in ST-RELA showing the highest expression among EPN as well as other brain tumors. We further identified high expression levels of fibroblast growth factor 1 and 2 (
FGF1
,
FGF2)
across all EPN subtypes while
FGF9
was elevated in ST-EPN. Interrogation of our EPN single-cell RNA-sequencing data revealed that
FGFR3
was further enriched in cycling and progenitor-like cell populations. Corroboratively, we found
FGFR3
to be predominantly expressed in radial glia cells in both mouse embryonal and human brain datasets. Moreover, we detected alternative splicing of the
FGFR1/3-IIIc
variant, which is known to enhance ligand affinity and FGFR signaling. Dominant-negative interruption of FGFR1/3 activation in PF-A and ST-RELA cell models demonstrated inhibition of key oncogenic pathways leading to reduced cell growth and stem cell characteristics. To explore the feasibility of therapeutically targeting FGFR, we tested a panel of FGFR inhibitors in 12 patient-derived EPN cell models revealing sensitivity in the low-micromolar to nano-molar range. Finally, we gain the first clinical evidence for the activity of the FGFR inhibitor nintedanib in the treatment of a patient with recurrent ST-RELA. Together, these preclinical and clinical data suggest FGFR inhibition as a novel and feasible approach to combat aggressive EPN.
The ageing suppressor α-klotho binds to the fibroblast growth factor receptor (FGFR). This commits FGFR to respond to FGF23, a key hormone in the regulation of mineral ion and vitamin D homeostasis. ...The role and mechanism of this co-receptor are unknown. Here we present the atomic structure of a 1:1:1 ternary complex that consists of the shed extracellular domain of α-klotho, the FGFR1c ligand-binding domain, and FGF23. In this complex, α-klotho simultaneously tethers FGFR1c by its D3 domain and FGF23 by its C-terminal tail, thus implementing FGF23-FGFR1c proximity and conferring stability. Dimerization of the stabilized ternary complexes and receptor activation remain dependent on the binding of heparan sulfate, a mandatory cofactor of paracrine FGF signalling. The structure of α-klotho is incompatible with its purported glycosidase activity. Thus, shed α-klotho functions as an on-demand non-enzymatic scaffold protein that promotes FGF23 signalling.
Fibroblast growth factor receptors (FGFRs) can act as driving oncoproteins in certain cancers, making them attractive drug targets. Here we have characterized tumour cell responses to two new ...inhibitors of FGFR1-3, AZ12908010 and the clinical candidate AZD4547, making comparisons with the well-characterized FGFR inhibitor PD173074. In a panel of 16 human tumour cell lines, the anti-proliferative activity of AZ12908010 or AZD4547 was strongly linked to the presence of deregulated FGFR signalling, indicating that addiction to deregulated FGFRs provides a therapeutic opportunity for selective intervention. Acquired resistance to targeted tyrosine kinase inhibitors is a growing problem in the clinic but has not yet been explored for FGFR inhibitors. To assess how FGFR-dependent tumour cells adapt to long-term FGFR inhibition, we generated a derivative of the KMS-11 myeloma cell line (FGFR(Y373C)) with acquired resistance to AZ12908010 (KMS-11R cells). Basal phosphorylated FGFR and FGFR-dependent downstream signalling were constitutively elevated and refractory to drug in KMS-11R cells. Sequencing of FGFR3 in KMS-11R cells revealed the presence of a heterozygous mutation at the gatekeeper residue, encoding FGFR3(V555M); consistent with this, KMS-11R cells were cross-resistant to AZD4547 and PD173074. These results define the selectivity and efficacy of two new FGFR inhibitors and identify a secondary gatekeeper mutation as a mechanism of acquired resistance to FGFR inhibitors that should be anticipated as clinical evaluation proceeds.
Cancer is a complex group of diseases initiated by abnormal cell division with the potential of spreading to other parts of the body. The advancement in the discoveries of omics and bio- and ...cheminformatics has led to the identification of drugs inhibiting putative targets including vascular endothelial growth factor (VEGF) family receptors, fibroblast growth factors (FGF), platelet derived growth factors (PDGF), epidermal growth factor (EGF), thymidine phosphorylase (TP), and neuropeptide Y4 (NY4), amongst others. Drug resistance, systemic toxicity, and drug ineffectiveness for various cancer chemo-treatments are widespread. Due to this, efficient therapeutic agents targeting two or more of the putative targets in different cancer cells are proposed as cutting edge treatments. Heterocyclic compounds, both synthetic and natural products, have, however, contributed immensely to chemotherapeutics for treatments of various diseases, but little is known about such compounds and their multimodal anticancer properties. A compendium of heterocyclic synthetic and natural product multitarget anticancer compounds, their IC
, and biological targets of inhibition are therefore presented in this review.
Persson GR, Samuelsson E, Lindahl C, Renvert S. Mechanical non‐surgical treatment of peri‐implantitis: a single‐blinded randomized longitudinal clinical study. II. Microbiological results. J Clin ...Periodontol 2010; 37: 563–573. doi: 10.1111/j.1600‐051X.2010.01561.x
Background: Peri‐implantitis is common in patients with dental implants. We performed a single‐blinded longitudinal randomized study to assess the effects of mechanical debridement on the peri‐implant microbiota in peri‐implantitis lesions.
Materials and Methods: An expanded checkerboard DNA–DNA hybridization assay encompassing 79 different microorganisms was used to study bacterial counts before and during 6 months following mechanical treatment of peri‐implantitis in 17 cases treated with curettes and 14 cases treated with an ultrasonic device. Statistics included non‐parametric tests and GLM multivariate analysis with p<0001 indicating significance and 80% power.
Results: At selected implant test sites, the most prevalent bacteria were: Fusobacterium nucleatum sp., Staphylococci sp., Aggregatibacter actinomycetemcomitans, Helicobacter pylori, and Tannerella forsythia. 30 min. after treatment with curettes, A. actinomycetemcomitans (serotype a), Lactobacillus acidophilus, Streptococcus anginosus, and Veillonella parvula were found at lower counts (p<0.001). No such differences were found for implants treated with the ultrasonic device. Inconsistent changes occurred following the first week. No microbiological differences between baseline and 6‐month samples were found for any species or between treatment study methods in peri‐implantitis.
Conclusions: Both methods failed to eliminate or reduce bacterial counts in peri‐implantitis. No group differences were found in the ability to reduce the microbiota in peri‐implantitis.
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.
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).
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.
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).
Single-gene variants are frequent among families with severe FSS, with variants affecting the growth plate being the most prevalent.
Insulin-like growth factor (IGF) signalling plays a key role in homing, progression, and treatment resistance in multiple myeloma (MM). In the extracellular environment, the majority of IGF molecules ...are bound to one of six IGF-binding proteins (IGFBP1-6), leaving a minor fraction of total IGF free and accessible for receptor activation. In MM, high IGF-receptor type 1 expression levels correlate with a poor prognosis, but the status and role of IGF and IGFBPs in the pathobiology of MM is unknown. Here we measured total IGF1, IGF2, and intact IGFBP levels in blood and bone marrow samples from MM (n = 17), monoclonal gammopathy of undetermined significance (MGUS) (n = 37), and control individuals (n = 15), using ELISA (IGFs) and 125I-IGF1 Western Ligand Blotting (IGFBPs). MGUS and MM patients displayed a significant increase in intact IGFBP-2 (2.5-3.8 fold) and decrease in intact IGFBP-3 (0.6-0.5 fold) in the circulation compared to control individuals. Further, IGFBP-2 as well as total IGFBP levels were significantly lower in bone marrow compared to circulation in MM and MGUS only, whereas IGF1, IGF2, and IGFBP-3 were equally distributed between the two compartments. In conclusion, the profound change in IGFBP profile strongly suggests an increased IGF bioavailability in the bone marrow microenvironment in MGUS and MM, despite no change in growth factor concentration.
This monograph reviews the biology of Neuregulins and their receptors and summarizes recent research, which has established crucial functions of this signaling system during development and disease.
Vascular endothelial growth factor (VEGF) is the main driver of angiogenesis and vascular permeability via VEGF receptor 2 (VEGFR2), whereas lymphangiogenesis signals are transduced by VEGFC/D via ...VEGFR3. VEGFR3 also regulates sprouting angiogenesis and blood vessel growth, but to what extent VEGFR3 signaling controls blood vessel permeability remains unknown.
To investigate the role of VEGFR3 in the regulation of VEGF-induced vascular permeability.
Long-term global
gene deletion in adult mice resulted in increased fibrinogen deposition in lungs and kidneys, indicating enhanced vascular leakage at the steady state. Short-term deletion of
in blood vascular endothelial cells increased baseline leakage in various tissues, as well as in tumors, and exacerbated vascular permeability in response to VEGF, administered via intradermal adenoviral delivery or through systemic injection of recombinant protein.
gene silencing upregulated VEGFR2 protein levels and phosphorylation in cultured endothelial cells. Consistent with elevated VEGFR2 activity, vascular endothelial cadherin showed reduced localization at endothelial cell-cell junctions in postnatal retinas after
deletion, or after
silencing in cultured endothelial cells. Furthermore, concurrent deletion of
prevented VEGF-induced excessive vascular leakage in mice lacking
.
VEGFR3 limits VEGFR2 expression and VEGF/VEGFR2 pathway activity in quiescent and angiogenic blood vascular endothelial cells, thereby preventing excessive vascular permeability.
Actinomycetes, a Gram positive bacteria, well reported as a source of antibiotics, also possess potential to control various plant pathogens, besides acting as plant growth promoting agent. Chemicals ...in different forms are extensively being used in vegetable farming, adversely affecting the environment and consumer health. Microbial agent like actinomycetes can substantially replace these harmful chemicals, and have now started finding a place as an important input in to farming practices. Only selected vegetable crops belonging to 11 different families have been explored with use of actinomycetes as biocontrol and plant growth promoting agent till now. It provides ample opportunities to vegetable researchers, to further explore with use of this very important group of microorganisms, in order to achieve even higher production level of safe vegetables. Mycostop and Actinovate are two actinomycetes based formulations globally available for use in vegetable farming as a substitute for chemical formulations. Present review article has summarized the literature available on use of actinomycetes in vegetable farming. Existing wide gap in knowledge, and potential thrust areas for future research have also been projected.
PDF
