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Tumor heterogeneity poses a significant challenge in osteosarcoma (OS) treatment. In this regard, the "omics" era has constantly expanded our understanding of biomarkers and altered signaling pathways (i.e., PI3K/AKT/mTOR, WNT/ß-catenin, NOTCH, SHH/GLI, among others) involved in OS pathophysiology. Despite different players and complexities, many commonalities have been described, among which the nuclear factor kappa B (NF-κB) stands out. Its altered activation is pervasive in cancer, with pleiotropic action on many disease-relevant traits. Thus, in the scope of this article, we highlight the evidence of NF-κB dysregulation in OS and its integration with other cancer-related pathways while we summarize the repertoire of compounds that have been described to interfere with its action. In silico strategies were used to demonstrate that NF-κB is closely coordinated with other commonly dysregulated signaling pathways not only by functionally interacting with several of their members but also by actively participating in the regulation of their transcription. While existing inhibitors lack selectivity or act indirectly, the therapeutic potential of targeting NF-κB is indisputable, first for its multifunctionality on most cancer hallmarks, and secondly, because, as a common downstream effector of the many dysregulated pathways influencing OS aggressiveness, it turns complex regulatory networks into a simpler picture underneath molecular heterogeneity.
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PURPOSE: Our study aimed to explore real-world treatment scenarios for children and adolescents with neurotrophic tropomyosin receptor kinase (NTRK)-fused tumors, emphasizing access, responses, side effects, and outcomes. PATIENTS AND METHODS: Pooled clinical data from 17 pediatric cases (11 soft-tissue sarcomas, five brain tumors, and one neuroblastoma) treated with larotrectinib and radiologic images for 14 patients were centrally reviewed. Testing for gene fusions was prompted by poor response to treatment, tumor progression, or aggressiveness. RESULTS: Six different NTRK fusion subtypes were detected, and various payment sources for testing and medication were reported. Radiologic review revealed objective tumor responses (OR) in 11 of 14 patients: Complete responses: two; partial responses: nine; and stable disease: three cases. Grades 1 or 2 Common Terminology Criteria for Adverse Events adverse effects were reported in five patients. Regarding the entire cohort's clinical information, 15 of 17 patients remain alive (median observation time: 25 months): four with no evidence of disease and 11 alive with disease (10 without progression). One patient developed resistance to the NTRK inhibitor and died from disease progression while another patient died due to an unrelated cause. CONCLUSION: This real-world study confirms favorable agnostic tumor OR rates to larotrectinib in children with NTRK-fused tumors. Better coordination to facilitate access to medication remains a challenge, particularly in middle-income countries like Brazil.
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Inibidores de Proteínas Quinases , Pirazóis , Humanos , Criança , Masculino , Feminino , Adolescente , Pirazóis/uso terapêutico , Pré-Escolar , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Receptor trkA/genética , Receptor trkA/antagonistas & inibidores , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Sarcoma/tratamento farmacológico , Sarcoma/genética , Neuroblastoma/tratamento farmacológico , Neuroblastoma/genética , Lactente , Receptor trkB/genética , Receptor trkC/genética , Ensaios Clínicos como AssuntoRESUMO
Estrogen deficiency, long-term immobilization, and/or aging are commonly related to bone mass loss, thus increasing the risk of fractures. One option for bone replacement in injuries caused by either traumas or pathologies is the use of orthopedic cement based on polymethylmethacrylate (PMMA). Nevertheless, its reduced bioactivity may induce long-term detachment from the host tissue, resulting in the failure of the implant. In view of this problem, we developed an alternative PMMA-based porous cement (pPMMA) that favors cell invasion and improves osteointegration with better biocompatibility. The cement composition was changed by adding bioactive strontium-nanoparticles that mimic the structure of bone apatite. The nanoparticles were characterized regarding their physical-chemical properties, and their effects on osteoblasts and osteoclast cultures were assessed. Initial in vivo tests were also performed using 16 New Zealand rabbits as animal models, in which the pPMMA-cement containing the strontium nanoparticles were implanted. We showed that the apatite nanoparticles in which 90% of Ca2+ ions were substituted by Sr2+ (NanoSr 90%) upregulated TNAP activity and increased matrix mineralization. Moreover, at the molecular level, NanoSr 90% upregulated the mRNA expression levels of, Sp7, and OCN. Runx2 was increased at both mRNA and protein levels. In parallel, in vivo tests revealed that pPMMA-cement containing NanoSr 90%, upregulated two markers of bone maturation, OCN and BMP2, as well as the formation of apatite minerals after implantation in the femur of rabbits. The overall data support that strontium nanoparticles hold the potential to up-regulate mineralization in osteoblasts when associated with synthetic biomaterials.
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Osteoblastos , Estrôncio , Animais , Estrôncio/farmacologia , Estrôncio/química , Coelhos , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Osteoblastos/citologia , Nanopartículas/química , Polimetil Metacrilato/química , Polimetil Metacrilato/farmacologia , Cimentos Ósseos/farmacologia , Cimentos Ósseos/química , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , CamundongosRESUMO
Childhood cancer is considered rare, corresponding to ~3% of all malignant neoplasms in the human population. The World Health Organization (WHO) reports a universal occurrence of more than 15 cases per 100,000 inhabitants around the globe, and despite improvements in diagnosis, treatment and supportive care, one child dies of cancer every 3 min. Consequently, more efficient, selective and affordable therapeutics are still needed in order to improve outcomes and avoid long-term sequelae. Alterations in kinases' functionality is a trademark of cancer and the concept of exploiting them as drug targets has burgeoned in academia and in the pharmaceutical industry of the 21st century. Consequently, an increasing plethora of inhibitors has emerged. In the present study, the expression patterns of a selected group of kinases (including tyrosine receptors, members of the PI3K/AKT/mTOR and MAPK pathways, coordinators of cell cycle progression, and chromosome segregation) and their correlation with clinical outcomes in pediatric solid tumors were accessed through the R2: Genomics Analysis and Visualization Platform and by a thorough search of published literature. To further illustrate the importance of kinase dysregulation in the pathophysiology of pediatric cancer, we analyzed the vulnerability of different cancer cell lines against their inhibition through the Cancer Dependency Map portal, and performed a search for kinase-targeted compounds with approval and clinical applicability through the CanSAR knowledgebase. Finally, we provide a detailed literature review of a considerable set of small molecules that mitigate kinase activity under experimental testing and clinical trials for the treatment of pediatric tumors, while discuss critical challenges that must be overcome before translation into clinical options, including the absence of compounds designed specifically for childhood tumors which often show differential mutational burdens, intrinsic and acquired resistance, lack of selectivity and adverse effects on a growing organism.
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PURPOSE: While pediatric glioblastomas are molecularly distinct from adult counterparts, the activation of NF-kB is partially shared by both subsets, playing key roles in tumor propagation and treatment response. RESULTS: We show that, in vitro, dehydroxymethylepoxyquinomicin (DHMEQ) impairs growth and invasiveness. Xenograft response to the drug alone varied according to the model, being more effective in KNS42-derived tumors. In combination, SF188-derived tumors were more sensitive to temozolomide while KNS42-derived tumors responded better to the combination with radiotherapy, with continued tumor regression. CONCLUSION: Taken together, our results strengthen the potential usefulness of NF-kB inhibition in future therapeutic strategies to overcome this incurable disease.
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Glioblastoma , NF-kappa B , Criança , Humanos , NF-kappa B/metabolismo , NF-kappa B/farmacologia , Glioblastoma/tratamento farmacológico , Apoptose , Linhagem Celular TumoralRESUMO
Over the last decades, accumulating evidence has shown tumor-dependent profiles of miR-708, being either up- or downregulated, and thus, acting as a "Janus" regulator of oncogenic pathways. Herein, its functional duality was assessed through a thorough review of the literature and further validation in silico using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. In the literature, miR-708 was found with an oncogenic role in eight tumor types, while a suppressor tumor role was described in seven cancers. This double profile was also found in TCGA and GEO databases, with some tumor types having a high expression of miR-708 and others with low expression compared with non-tumor counterparts. The investigation of validated targets using miRBase, miRTarBase, and miRecords platforms, identified a total of 572 genes that appeared enriched for PI3K-Akt signaling, followed by cell cycle control, p53, Apellin and Hippo signaling, endocrine resistance, focal adhesion, and cell senescence regulations, which are all recognized contributors of tumoral phenotypes. Among these targets, a set of 15 genes shared by at least two platforms was identified, most of which have important roles in cancer cells that influence either tumor suppression or progression. In a clinical scenario, miR-708 has shown to be a good diagnostic and prognosis marker. However, its multitarget nature and opposing roles in diverse human tumors, aligned with insufficient experimental data and the lack of proper delivery strategies, hamper its potential as a sequence-directed therapeutic.
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Transtorno Dissociativo de Identidade , MicroRNAs , Neoplasias , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Neoplasias/genética , Transdução de Sinais/genéticaRESUMO
Polymethylmethacrylate (PMMA)-based cements are used for bone reparation due to their biocompatibility, suitable mechanical properties, and mouldability. However, these materials suffer from high exothermic polymerization and poor bioactivity, which can cause the formation of fibrous tissue around the implant and aseptic loosening. Herein, we tackled these problems by adding Sr2+ -substituted hydroxyapatite nanoparticles (NPs) and a porogenic compound to the formulations, thus creating a microenvironment suitable for the proliferation of osteoblasts. The NPs resembled the structure of the bone's apatite and enabled the controlled release of Sr2+ . Trends in the X-ray patterns and infrared spectra confirmed that Sr2+ replaced Ca2+ in the whole composition range of the NPs. The inclusion of an effervescent additive reduced the polymerization temperature and lead to the formation of highly porous cement exhibiting mechanical properties comparable to the trabecular bone. The formation of an opened and interconnected matrix allowed osteoblasts to penetrate the cement structure. Most importantly, the gas formation confined the NPs at the surface of the pores, guaranteeing the controlled delivery of Sr2+ within a concentration sufficient to maintain osteoblast viability. Additionally, the cement was able to form apatite when immersed into simulated body fluids, further increasing its bioactivity. Therefore, we offer a formulation of PMMA cement with improved in vitro performance supported by enhanced bioactivity, increased osteoblast viability and deposition of mineralized matrix assigned to the loading with Sr2+ -substituted hydroxyapatite NPs and the creation of an interconnected porous structure. Altogether, our results hold promise for enhanced bone reparation guided by PMMA cements.
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Nanopartículas , Polimetil Metacrilato , Apatitas/química , Cimentos Ósseos/química , Cimentos Ósseos/farmacologia , Cálcio , Teste de Materiais , Polimetil Metacrilato/química , Polimetil Metacrilato/farmacologia , Porosidade , Estrôncio/química , Estrôncio/farmacologiaRESUMO
Despite advances in the understanding of the molecular mechanisms underlying the basic biology and pathogenesis of pediatric central nervous system (CNS) malignancies, patients still have an extremely unfavorable prognosis. Over the years, a plethora of natural and synthetic compounds has emerged for the pharmacologic intervention of the NF-kB pathway, one of the most frequently dysregulated signaling cascades in human cancer with key roles in cell growth, survival, and therapy resistance. Here, we provide a review about the state-of-the-art concerning the dysregulation of this hub transcription factor in the most prevalent pediatric CNS tumors: glioma, medulloblastoma, and ependymoma. Moreover, we compile the available literature on the anti-proliferative effects of varied NF-kB inhibitors acting alone or in combination with other therapies in vitro, in vivo, and clinical trials. As the wealth of basic research data continues to accumulate, recognizing NF-kB as a therapeutic target may provide important insights to treat these diseases, hopefully contributing to increase cure rates and lower side effects related to therapy.
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Neoplasias do Sistema Nervoso Central/patologia , NF-kappa B/metabolismo , 2-Metoxiestradiol/química , 2-Metoxiestradiol/metabolismo , 2-Metoxiestradiol/uso terapêutico , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/uso terapêutico , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/metabolismo , Criança , Glioma/metabolismo , Glioma/patologia , Proteínas Hedgehog/antagonistas & inibidores , Proteínas Hedgehog/metabolismo , Humanos , Meduloblastoma/metabolismo , Meduloblastoma/patologia , NF-kappa B/antagonistas & inibidores , Proteínas Wnt/antagonistas & inibidores , Proteínas Wnt/metabolismoRESUMO
HnRNP K protein is a heterogeneous nuclear ribonucleoprotein which has been proposed to be involved in the leukemogenesis of acute promyelocytic leukemia (APL), as well as in differentiation induced by all-trans retinoic acid (ATRA). We previously demonstrated a connection between SET and hnRNP K function in head and neck squamous cell carcinoma (HNSCC) cells related to splicing processing. The objective of this study was to characterize the participation of hnRNP K and SET proteins in ATRA-induced differentiation in APL. We observed higher (5- to 40-fold) levels of hnRNP K and SET mRNA in APL patients at the diagnosis phase compared with induction and maintenance phases. hnRNP K knockdown using short-hairpin RNA led to cell death in ATRA-sensitive NB4 and resistant NB4-R2 cells by apoptosis with SET cleavage. In addition, hnRNP K knockdown increased granulocytic differentiation in APL cells, mainly in NB4-R2 with ATRA. hnRNP K knockdown had an effect similar to that of treatment with U0126 (an meiosis-specific serine/threonine protein kinase/ERK inhibitor), mainly in NB4-R2 cells. SET knockdown in APL cells revealed that apoptosis induction in cells with hnRNP K knockdown occurred by SET cleavage rather than by reduction in SET protein. Transplantation of NB4-R2 cells into nude mice confirmed that arsenic trioxide (ATO) combined with U0126 has higher potential against tumor progression when compared to ATO. Therefore, hnRNP K/SET and ERK are potential therapeutic targets for both antineoplastic leukemia therapy and relapsed APL patients with ATRA resistance.
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Leucemia Promielocítica Aguda , Animais , Trióxido de Arsênio/metabolismo , Trióxido de Arsênio/uso terapêutico , Ribonucleoproteínas Nucleares Heterogêneas Grupo K/genética , Humanos , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/metabolismo , Camundongos , Camundongos Nus , Tretinoína/metabolismo , Tretinoína/farmacologiaRESUMO
Although ependymoma (EPN) molecular subgroups have been well established by integrated high-throughput platforms, low- and middle-income countries still need low-cost techniques to promptly classify these molecular subtypes. Here, we applied low-cost methods to classify EPNs from a Brazilian cohort with 60 pediatric EPN patients. Fusion transcripts (C11orf95-RELA, YAP1-MAMLD1, and YAP1-FAM118B) were investigated in supratentorial EPN (ST-EPNs) samples through RT-PCR/Sanger sequencing and immunohistochemistry (IHC) for p65/L1CAM. qRT-PCR and IHC were used to evaluate expression profiling of CXorf67, LAMA2, NELL2, and H3K27me3 in posterior fossa EPN (PF-EPNs) samples. In silico analysis was performed using public microarray data to validate the molecular assignment PF-EPNs with LAMA2/NELL2 markers. RELA cases and YAP1-MAMLD1 fusions were identified in nine and four ST-EPNs, respectively. An additional RELA case was identified by IHC. Of note, LAMA2 and NELL2 gene expression and immunoprofiling were less accurate for classifying PF-EPNs, which were confirmed by in silico analysis. Yet, H3K27me3 staining was sufficient to classify PF-EPN subgroups. Our results emphasize the feasibility of a simplified strategy to molecularly classify EPNs in the vast majority of cases (49/60; 81.7%). A coordinated combination of simple methods can be effective to screen pediatric EPN with the available laboratory resources at most low-/mid-income countries, giving support for clinical practice in pediatric EPN. KEY MESSAGES: Low- and middle-income countries need effective low-cost approaches to promptly distinguish between EPN molecular subgroups. RT-PCR plus Sanger sequencing is able to recognize the most common types of RELA and YAP1 fusion transcripts in ST-EPNs. Genetic and protein expressions of LAMA2 and NELL2 are of limited value to accurately stratify PF-EPNs. Immunohistochemical staining for H3K27me3 may be used as a robust method to accurately diagnose PF-EPNs subgroups. A coordinated flow diagram based on these validated low-cost methods is proposed to help clinical-decision making and to reduce costs with NGS assessment outside research protocols.