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BACKGROUND: Sarcomas represent an extensive group of malignant diseases affecting mesodermal tissues. Among sarcomas, the clinical management of chondrosarcomas remains a complex challenge, as high-grade tumours do not respond to current therapies. Mutations in the isocitrate dehydrogenase (IDH) 1 and 2 genes are among the most common mutations detected in chondrosarcomas and may represent a therapeutic opportunity. The presence of mutated IDH (mIDH) enzymes results in the accumulation of the oncometabolite 2-HG leading to molecular alterations that contribute to drive tumour growth. METHODS: We developed a personalized medicine strategy based on the targeted NGS/Sanger sequencing of sarcoma samples (n = 6) and the use of matched patient-derived cell lines as a drug-testing platform. The anti-tumour potential of IDH mutations found in two chondrosarcoma cases was analysed in vitro, in vivo and molecularly (transcriptomic and DNA methylation analyses). FINDINGS: We treated several chondrosarcoma models with specific mIDH1/2 inhibitors. Among these treatments, only the mIDH2 inhibitor enasidenib was able to decrease 2-HG levels and efficiently reduce the viability of mIDH2 chondrosarcoma cells. Importantly, oral administration of enasidenib in xenografted mice resulted in a complete abrogation of tumour growth. Enasidenib induced a profound remodelling of the transcriptomic landscape not associated to changes in the 5 mC methylation levels and its anti-tumour effects were associated with the repression of proliferative pathways such as those controlled by E2F factors. INTERPRETATION: Overall, this work provides preclinical evidence for the use of enasidenib to treat mIDH2 chondrosarcomas. FUNDING: Supported by the Spanish Research Agency/FEDER (grants PID2022-142020OB-I00; PID2019-106666RB-I00), the ISC III/FEDER (PI20CIII/00020; DTS18CIII/00005; CB16/12/00390; CB06/07/1009; CB19/07/00057); the GEIS group (GEIS-62); and the PCTI (Asturias)/FEDER (IDI/2021/000027).
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Aminopiridinas , Neoplasias Ósseas , Condrossarcoma , Sarcoma , Triazinas , Humanos , Animais , Camundongos , Medicina de Precisão , Condrossarcoma/tratamento farmacológico , Condrossarcoma/genética , Isocitrato Desidrogenase/genética , Mutação , Neoplasias Ósseas/genéticaRESUMO
After only Alzheimer's disease (AD), Parkinson's disease (PD) is the second most prevalent neurodegenerative disease. The incidence of this disease increases with age, especially for those above 70 years old. There are many risk factors that are well-established in the contribution to the development of PD, such as age, gender, ethnicity, rapid eye movement sleep disorder, high consumption of dairy products, traumatic brain injury, genetics, and pesticides/herbicides. Interestingly, smoking, consumption of caffeine, and physical activities are the protective factors of PD. A deficiency of dopamine in the substantia nigra of the brainstem is the main pathology. This, subsequently, alters the neurotransmitter, causing an imbalance between excitatory and inhibitory signals. In addition, genetics is also involved in the pathogenesis of the disease. As a result, patients exhibit characteristic motor symptoms such as tremors, stiffness, bradykinesia, and postural instability, along with non-motor symptoms, including dementia, urinary incontinence, sleeping disturbances, and orthostatic hypotension. PD may resemble other diseases; therefore, it is important to pay attention to the diagnosis criteria. Parkinson's disease dementia can share common features with AD; this can include behavioral as well as psychiatric symptoms, in addition to the pathology being protein aggregate accumulation in the brain. For PD management, the administration of pharmacological treatment depends on the motor symptoms experienced by the patients. Non-pharmacological treatment plays a role as adjuvant therapy, while surgical management is indicated in chronic cases. This paper aims to review the etiology, risk factors, protective factors, pathophysiology, signs and symptoms, associated conditions, and management of PD.
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Osteosarcoma (OS) is an aggressive bone cancer with poor prognosis, largely due to the limited effectiveness of current treatments such as doxorubicin (DX). Developing ways to overcome DX resistance is a significant clinical challenge. Here, we used two DX-resistant models to study the potential of Cold Plasma Treated Medium (PTM) to prevent DX resistance in OS. During the acquisition of the resistant phenotype upon long-term DX exposure, OS resistant cells became less proliferative, overexpressed the drug resistance-related efflux pump MDR1 and displayed a concomitant loss of SOD2 or GPX1. According to the reduced expression of these antioxidant enzymes, PTM treatment produced higher levels of oxidative express and was more effective in eradicating DX-resistant cells. Moreover, PTM reduced the expression of MDR1, thus sensitizing resistant cells to DX. These findings uncover new vulnerabilities of DX-resistant cells related with their inability to cope with excessive oxidative stress and their dependence on MDR1 that can be exploited using PTM-based treatments to provide new therapeutic approaches for the management of drug resistance in OS.
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Neoplasias Ósseas , Osteossarcoma , Gases em Plasma , Humanos , Gases em Plasma/farmacologia , Gases em Plasma/uso terapêutico , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Doxorrubicina/metabolismo , Osteossarcoma/tratamento farmacológico , Osteossarcoma/genética , Osteossarcoma/metabolismo , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Resistencia a Medicamentos Antineoplásicos , Linhagem Celular TumoralRESUMO
Osteosarcoma (OS) remains a dismal malignancy in children and young adults, with poor outcome for metastatic and recurrent disease. Immunotherapies in OS are not as promising as in some other cancer types due to intra-tumor heterogeneity and considerable off-target expression of the potentially targetable proteins. Here we show that chimeric antigen receptor (CAR) T cells could successfully target an isoform of alkaline phosphatase, ALPL-1, which is highly and specifically expressed in primary and metastatic OS. The target recognition element of the second-generation CAR construct is based on two antibodies, previously shown to react against OS. T cells transduced with these CAR constructs mediate efficient and effective cytotoxicity against ALPL-positive cells in in vitro settings and in state-of-the-art in vivo orthotopic models of primary and metastatic OS, without unexpected toxicities against hematopoietic stem cells or healthy tissues. In summary, CAR-T cells targeting ALPL-1 show efficiency and specificity in treating OS in preclinical models, paving the path for clinical translation.
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Neoplasias Ósseas , Osteossarcoma , Criança , Humanos , Imunoterapia Adotiva , Linfócitos T , Imunoterapia , Osteossarcoma/terapia , Neoplasias Ósseas/terapia , Linhagem Celular Tumoral , Fosfatase AlcalinaRESUMO
Osteosarcomas are frequently associated to a poor prognosis and a modest response to current treatments. EC-8042 is a well-tolerated mithramycin analog that has demonstrated an efficient ability to eliminate tumor cells, including cancer stem cell subpopulations (CSC), in sarcomas. In transcriptomic and protein expression analyses, we identified NOTCH1 signaling as one of the main pro-stemness pathways repressed by EC-8042 in osteosarcomas. Overexpression of NOTCH-1 resulted in a reduced anti-tumor effect of EC-8042 in CSC-enriched 3D tumorspheres cultures. On the other hand, the depletion of the NOTCH-1 downstream target HES-1 was able to enhance the action of EC-8042 on CSCs. Moreover, HES1 depleted cells failed to recover after treatment withdrawal and showed reduced tumor growth potential in vivo. In contrast, mice xenografted with NOTCH1-overexpressing cells responded worse than parental cells to EC-8042. Finally, we found that active NOTCH1 levels in sarcoma patients was associated to advanced disease and lower survival. Overall, these data highlight the relevant role that NOTCH1 signaling plays in mediating stemness in osteosarcoma. Moreover, we demonstrate that EC-8042 is powerful inhibitor of NOTCH signaling and that the anti-CSC activity of this mithramycin analog highly rely on its ability to repress this pathway.
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Neoplasias Ósseas , Osteossarcoma , Animais , Camundongos , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Células-Tronco Neoplásicas/metabolismo , Osteossarcoma/patologia , Plicamicina/farmacologia , Receptor Notch1/metabolismo , Receptores Notch/metabolismoRESUMO
Treatment of head and neck squamous cell carcinomas (HNSCC), the sixth most frequent cancer worldwide, remains challenging. miRNA dysregulation is closely linked to tumorigenesis and tumor progression, thus emerging as suitable targets for cancer treatment. Transcriptomic analysis of TCGA HNSCC dataset revealed that miR-301a expression levels significantly increased in primary tumors, as compared to patient-matched normal tissue. This prompted us to investigate its pathobiological role and potential as new therapeutic target using different preclinical HNSCC models. miR-301a overexpression in HNSCC-derived cell lines led to enhanced proliferation and invasion, whereas miR-301 inhibition reduced these effects. In vivo validation was performed using an orthotopic mouse model. Results concordantly showed that the mitotic counts, the percentage of infiltration depth and Ki67 proliferative index were significantly augmented in the subgroup of mice harboring miR-301a-overexpressing tumors. Further mechanistic characterization revealed PI3K/PTEN/AKT and MEK/ERK pathways as central signaling nodes responsible for mediating the oncogenic activity of miR-301a observed in HNSCC cells. Notably, pharmacological disruption of PI3K and ERK signals with BYL-719 and PD98059, respectively, was effective to completely revert/abolish miR-301a-promoted tumor cell growth and invasion. Altogether, these findings demonstrate that miR-301a dysregulation plays an oncogenic role in HNSCC, thus emerging as a candidate therapeutic target for this disease. Importantly, available PI3K and ERK inhibitors emerge as promising anti-tumor agents to effectively target miR-301a-mediated signal circuit hampering growth-promoting and pro-invasive functions.
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Neoplasias de Cabeça e Pescoço , MicroRNAs , Animais , Camundongos , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Sistema de Sinalização das MAP Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Neoplasias de Cabeça e Pescoço/genética , Linhagem Celular Tumoral , MicroRNAs/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Proliferação de Células/genética , Regulação Neoplásica da Expressão GênicaRESUMO
Osteosarcoma (OS) is a malignant type of bone cancer that arises in periods of increased bone formation. Curative strategies for these types of tumors have remained essentially unchanged for decades and the overall survival for most advanced cases is still dismally low. This is in part due to the existence of drug resistant Cancer Stem Cells (CSC) with progenitor properties that are responsible for tumor relapse and metastasis. In the quest for therapeutic alternatives for OS, Cold Atmospheric Plasmas and Plasma-Treated Liquids (PTL) have come to the limelight as a source of Reactive Oxygen and Nitrogen Species displaying selectivity towards a variety of cancer cell lines. However, their effects on CSC subpopulations and in vivo tumor growth have been barely studied to date. By employing bioengineered 3D tumor models and in vivo assays, here we show that low doses of PTL increase the levels of pro-stemness factors and the self-renewal ability of OS cells, coupled to an enhanced in vivo tumor growth potential. This could have critical implications to the field. By proposing a combined treatment, our results demonstrate that the deleterious pro-stemness signals mediated by PTL can be abrogated when this is combined with the STAT3 inhibitor S3I-201, resulting in a strong suppression of in vivo tumor growth. Overall, our study unveils an undesirable stem cell-promoting function of PTL in cancer and supports the use of combinatorial strategies with STAT3 inhibitors as an efficient treatment for OS avoiding critical side effects. We anticipate our work to be a starting point for wider studies using relevant 3D tumor models to evaluate the effects of plasma-based therapies on tumor subpopulations of different cancer types. Furthermore, combination with STAT3 inhibition or other suitable cancer type-specific targets can be relevant to consolidate the development of the field.
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Neoplasias Ósseas , Osteossarcoma , Gases em Plasma , Humanos , Linhagem Celular Tumoral , Gases em Plasma/farmacologia , Proliferação de Células , Osteossarcoma/tratamento farmacológico , Osteossarcoma/genética , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Células-Tronco Neoplásicas/metabolismo , ApoptoseRESUMO
Drug resistance is a major problem in cancer treatment, as it limits the effectiveness of pharmacological agents and can lead to disease progression. Cold atmospheric plasma (CAP) is a technology that uses ionized gas (plasma) to generate reactive oxygen and nitrogen species (RONS) that can kill cancer cells. CAP is a novel approach for overcoming drug resistance in cancer. In recent years, there has been a growing interest in using CAP to enhance the effectiveness of chemotherapy drugs. In this review, we discuss the mechanisms behind this phenomenon and explore its potential applications in cancer treatment. Going through the existing literature on CAP and drug resistance in cancer, we highlight the challenges and opportunities for further research in this field. Our review suggests that CAP could be a promising option for overcoming drug resistance in cancer and warrants further investigation.
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Fundamento: el VIH/sida es un problema de salud caracterizado por un severo compromiso de la inmunidad; esta entidad constituye factor de riesgo para el desarrollo de las principales causas de muerte a nivel mundial. Objetivo: proponer un modelo para capacitar sobre percepción de riesgo sobre el VIH/sida a jóvenes del Consultorio Médico 41 del área de salud Manicaragua. Métodos: se realizó un estudio observacional, descriptivo, transversal en el Consultorio Médico 41 del área de salud Manicaragua en la provincia de Villa Clara. Se aplicaron métodos teóricos: histórico-lógico, análisis síntesis, inducción-deducción, sistémico-estructural y modelación; empíricos: el cuestionario a jóvenes y la historieta de conflictos; matemáticos-estadísticos para el análisis de los datos. Resultados: las insuficiencias más frecuentes en la percepción de riesgo estuvieron relacionadas con las carencias en la información, la comprensión y la toma de decisiones para la prevención de salud. Se ofrece un modelo para la capacitación en percepción de riesgo ante el VIH/sida el cual fue valorado por criterios de especialistas. Conclusiones: el modelo posibilita la adquisición de conductas promotoras de la salud sexual, comprender y predecir cómo puede responderse a los peligros ante la enfermedad, contribuir al cambio de intención y comportamiento, y a asumir actitudes de protección. Fue valorado como aceptado por los especialistas consultados.
Background: HIV/AIDS is a health problem characterized by a severe compromise of immunity; this entity constitutes a risk factor for the development of the main causes of death worldwide. Objective: to propose a model to train young people from the Doctor´s office 41 in the Manicaragua health area on risk perception on HIV/AIDS. Methods: an observational, descriptive, cross-sectional study was carried out in the Doctor´s office 41 of the Manicaragua health area in the province of Villa Clara. Theoretical methods were applied: historical-logical, analysis synthesis, induction-deduction, systemic-structural and modeling; empirical ones: the questionnaire for young people and the conflict story; mathematical-statisticians for data analysis. Results: the most frequent deficiencies in risk perception were related to deficiencies in information, understanding and decision-making for health prevention. A model for training in risk perception to face HIV/AIDS is offered, which was assessed by specialist criteria. Conclusions: the model enables the acquisition of behaviors that promote sexual health, understanding and predicting how to respond to the dangers of the disease, contributing to the change of intention and behavior, and assuming protective attitudes. It was valued as accepted by the specialists consulted.
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Medicina do Comportamento , Indicadores de Qualidade de Vida , Medicina ComunitáriaRESUMO
Hunter syndrome is a rare disorder in which affected patients have significant airway abnormalities (macroglossia, small mouth opening, and supraglottic narrowing) that complicate their management. Deposition of glycosaminoglycans in the heart leads to cardiomyopathy, and cardiac valve dysplasia that can lead to valvular stenosis or regurgitation or both, necessitating valve replacement. Management of patients with Hunter syndrome is complex and needs a multidisciplinary team approach. Mechanical valve replacement is a suitable treatment option.
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Bone sarcomas have not shown a significant improvement in survival for decades, due, in part, to the development of resistance to current systemic treatments, such as doxorubicin. To better understand those mechanisms mediating drug-resistance we generated three osteosarcoma and one chondrosarcoma cell lines with a stable doxorubicin-resistant phenotype, both in vitro and in vivo. These resistant strains include a pioneer model generated from a patient-derived chondrosarcoma line. The resistant phenotype was characterized by a weaker induction of apoptosis and DNA damage after doxorubicin treatment and a lower migratory capability. In addition, all resistant lines expressed higher levels of ABC pumps; meanwhile, no clear trends were found in the expression of anti-apoptotic and stem cell-related factors. Remarkably, upon the induction of resistance, the proliferation potential was reduced in osteosarcoma lines but enhanced in the chondrosarcoma model. The exposure of resistant lines to other anti-tumor drugs revealed an increased response to cisplatin and/or methotrexate in some models. Finally, the ability to retain the resistant phenotype in vivo was confirmed in an osteosarcoma model. Altogether, this work evidenced the co-existence of common and case-dependent phenotypic traits and mechanisms associated with the development of resistance to doxorubicin in bone sarcomas.
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Antineoplásicos , Neoplasias Ósseas , Condrossarcoma , Osteossarcoma , Antineoplásicos/farmacologia , Apoptose , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Linhagem Celular Tumoral , Condrossarcoma/tratamento farmacológico , Condrossarcoma/genética , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Osteossarcoma/tratamento farmacológico , Osteossarcoma/genética , Osteossarcoma/metabolismoRESUMO
Sarcomas are mesenchymal cancers which often show an aggressive behavior and patient survival largely depends on an early detection. In last years, much attention has been given to the fact that cancer patients release specific odorous volatile organic compounds (VOCs) that can be efficiently detected by properly trained sniffer dogs. Here, we have evaluated for the first time the ability of sniffer dogs (n = 2) to detect osteosarcoma cell cultures and patient samples. One of the two dogs was successfully trained to discriminate osteosarcoma patient-derived primary cells from mesenchymal stem/stromal cells (MSCs) obtained from healthy individuals. After the training phase, the dog was able to detect osteosarcoma specific odor cues in a different panel of 6 osteosarcoma cell lines with sensitivity and specificity rates between 95 and 100%. Moreover, the same VOCs were also detected by the sniffer dog in saliva samples from osteosarcoma patients (n = 2) and discriminated from samples from healthy individuals with a similar efficacy. Altogether, these results indicate that there are common odor profiles shared by cultures of osteosarcoma cells and body fluid samples from patients and provide a first proof of concept about the potential of canine odor detection as a non-invasive screening method to detect osteosarcomas.
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Neoplasias Ósseas , Osteossarcoma , Sarcoma , Compostos Orgânicos Voláteis , Animais , Neoplasias Ósseas/diagnóstico , Neoplasias Ósseas/veterinária , Cães , Humanos , Odorantes , Osteossarcoma/diagnóstico , Osteossarcoma/veterinária , Olfato , Cães TrabalhadoresRESUMO
BACKGROUND: Sarcomas comprise a group of aggressive malignancies with very little treatment options beyond standard chemotherapy. Reposition of approved drugs represents an attractive approach to identify effective therapeutic compounds. One example is mithramycin (MTM), a natural antibiotic which has demonstrated a strong antitumour activity in several tumour types, including sarcomas. However, its widespread use in the clinic was limited by its poor toxicity profile. RESULTS: In order to improve the therapeutic index of MTM, we have loaded MTM into newly developed nanocarrier formulations. First, polylactide (PLA) polymeric nanoparticles (NPs) were generated by nanoprecipitation. Also, liposomes (LIP) were prepared by ethanol injection and evaporation solvent method. Finally, MTM-loaded hydrogels (HG) were obtained by passive loading using a urea derivative non-peptidic hydrogelator. MTM-loaded NPs and LIP display optimal hydrodynamic radii between 80 and 105 nm with a very low polydispersity index (PdI) and encapsulation efficiencies (EE) of 92 and 30%, respectively. All formulations show a high stability and different release rates ranging from a fast release in HG (100% after 30 min) to more sustained release from NPs (100% after 24 h) and LIP (40% after 48 h). In vitro assays confirmed that all assayed MTM formulations retain the cytotoxic, anti-invasive and anti-stemness potential of free MTM in models of myxoid liposarcoma, undifferentiated pleomorphic sarcoma and chondrosarcoma. In addition, whole genome transcriptomic analysis evidenced the ability of MTM, both free and encapsulated, to act as a multi-repressor of several tumour-promoting pathways at once. Importantly, the treatment of mice bearing sarcoma xenografts showed that encapsulated MTM exhibited enhanced therapeutic effects and was better tolerated than free MTM. CONCLUSIONS: Overall, these novel formulations may represent an efficient and safer MTM-delivering alternative for sarcoma treatment.
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Plicamicina/análogos & derivados , Plicamicina/farmacologia , Plicamicina/uso terapêutico , Sarcoma/patologia , Animais , Antibacterianos/uso terapêutico , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Condrossarcoma/tratamento farmacológico , Composição de Medicamentos , Feminino , Humanos , Hidrogéis/química , Hidrogéis/uso terapêutico , Lipossomos , Camundongos , Camundongos Nus , Nanopartículas/química , Nanopartículas/uso terapêutico , Poliésteres/química , Poliésteres/uso terapêutico , Sarcoma/tratamento farmacológicoRESUMO
Bone sarcomas are commonly characterized by a high degree of intra-tumor heterogeneity, which in part is due to the presence of subpopulations of tumor cells presenting stem cell properties. Similar to normal stem cells, these cancer stem cells (CSCs) display a drug resistant phenotype and therefore are responsible for relapses and tumor dissemination. Drug resistance in bone sarcomas could be enhanced/modulated during tumor evolution though the acquisition of (epi)-genetic alterations and the adaptation to changing microenvironments, including drug treatments. Here we summarize findings supporting the involvement of pro-stemness signaling in the development of drug resistance in bone sarcomas. This include the activation of well-known pro-stemness pathways (Wnt/ß-Cat, NOTCH or JAT/STAT pathways), changes in the metabolic and autophagic activities, the alteration of epigenetic pathways, the upregulation of specific non-coding RNAs and the crosstalk with different microenvironmental factors. This altered signaling is expected to be translated to the clinic in the form of biomarkers of response and new therapies able to overcome drug resistance.
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Sarcomas are aggressive tumors which often show a poor response to current treatments. As a promising therapeutic alternative, we focused on mithramycin (MTM), a natural antibiotic with a promising anti-tumor activity but also a relevant systemic toxicity. Therefore, the encapsulation of MTM in nano-delivery systems may represent a way to increase its therapeutic window. Here, we designed novel transfersomes and PLGA polymeric micelles by combining different membrane components (phosphatidylcholine, Span 60, Tween 20 and cholesterol) to optimize the nanoparticle size, polydispersity index (PDI) and encapsulation efficiency (EE). Using both thin film hydration and the ethanol injection methods we obtained MTM-loaded transferosomes displaying an optimal hydrodynamic diameter of 100-130 nm and EE values higher than 50%. Additionally, we used the emulsion/solvent evaporation method to synthesize polymeric micelles with a mean size of 228 nm and a narrow PDI, capable of encapsulating MTM with EE values up to 87%. These MTM nano-delivery systems mimicked the potent anti-tumor activity of free MTM, both in adherent and cancer stem cell-enriched tumorsphere cultures of myxoid liposarcoma and chondrosarcoma models. Similarly to free MTM, nanocarrier-delivered MTM efficiently inhibits the signaling mediated by the pro-oncogenic factor SP1. In summary, we provide new formulations for the efficient encapsulation of MTM which may constitute a safer delivering alternative to be explored in future clinical uses.
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The ionic gelation method was used to study the effect of the crosslinking agent, sodium tripolyphosphate on average particle size (Dp) and zeta potential (ζp) of chitosan microparticles (CSMP) unloaded and loaded with trans-cinnamaldehyde (TCIN). The obtained values of Dp and ζp trend as 117.6⯱â¯0.4â¯≤â¯Dpâ¯≤â¯478.5⯱â¯3.5â¯nm and +27.8⯱â¯1.3â¯≤â¯Î¶pâ¯≤â¯+103.5⯱â¯4.2â¯mV, respectively. The entrapment efficiency of TCIN in CSMP was 9.1⯱â¯2.0% and 71.5⯱â¯2.9% was released after 360â¯min (pHâ¯=â¯6.5) which reveals a potential anti-cancer activity in acidic environment. Cytotoxicity of TCIN in DMSO (0-50⯵M) was evaluated on MDCK and HeLa cell lines and exhibited low effect at either 24 or 48â¯h of exposure; whereas TCIN-loaded CSMP (0-50⯵M) showed, after 24â¯h of exposure, 67.6⯱â¯7.0 and 64.5⯱â¯3.9% cytotoxicity for MDCK and HeLa cell lines, respectively. At 48â¯h of exposure, TCIN-loaded CSMP achieved 81.1⯱â¯0.26 and 77.9⯱â¯4.2% cytotoxicity for MDCK and HeLa cell lines, respectively.
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Acroleína/análogos & derivados , Antineoplásicos Fitogênicos/administração & dosagem , Quitosana/química , Microesferas , Acroleína/administração & dosagem , Acroleína/toxicidade , Animais , Antineoplásicos Fitogênicos/toxicidade , Proliferação de Células/efeitos dos fármacos , Reagentes de Ligações Cruzadas/química , Cães , Liberação Controlada de Fármacos , Células HeLa , Humanos , Hidrogéis/química , Células Madin Darby de Rim CaninoRESUMO
Edible coatings are safe, legal, and sensory acceptable for food applications and they can be incorporated as natural additives due to their antimicrobial activity, thickening capacity, nutrient content, and bioactive agents for protecting seafood from physical, chemical, and microbiological damage that affects its shelf-life. This study aimed to evaluate the effect of the guar gum bioactive coating with thyme oil on the quality of tilapia fish fillets for 15 days of storage at 4 °C, as a means to extend shelf-life. pH, moisture, ash, fat, color, thiobarbituric acid reactive substances (TBARS), total volatile basic nitrogen (TVB-N), microbiological, and sensory examinations were investigated, and the results were analyzed by analysis of variance. The treatments were control (uncoated, UC), GGC (coated with guar gum, GGC), and guar gum combined with thyme oil (GGCTH). Tilapia fillets were stored at 4 °C, the safe temperature for refrigerated storage for 15 days. GGCTH had a slower increase of pH after 15 days of storage in comparison with GGC and UC (p < 0.05). GGC and GGCTH resulted in lower and lowest lightness (L*; p < 0.05) values, lower and lowest redness (a*; p < 0.01) values, and greater and greatest yellowness (b*; p < 0.05) values compared to UC, respectively. UC reduced shear force at 5 (0.37 kgf), 10 (0.32 kgf), and 15 (0.30 kgf) days post-storage in comparison with GGC (0.43, 0.43, and 0.43 kgf) and GGCTH (0.43, 0.44, and 0.44 kgf), respectively. There was less (p < 0.05) deterioration, as well as differences in textural and sensorial variables between uncoated and coated fish fillets. The microbiological analyses demonstrated that there was greater microbial growth in the uncoated fillets than in the coated ones. It was concluded that this bioactive coating with thyme oil retards microbial colonization of fish and reduces degradability of quality variables, therefore, it is a reliable and effective alternative to extend the shelf-life of tilapia fillets.
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Sarcomas are mesenchymal cancers with poor prognosis, representing about 20% of all solid malignancies in children, adolescents, and young adults. Radio- and chemoresistance are common features of sarcomas warranting the search for novel prognostic and predictive markers. GARP/LRRC32 is a TGF-ß-activating protein that promotes immune escape and dissemination in various cancers. However, if GARP affects the tumorigenicity and treatment resistance of sarcomas is not known. We show that GARP is expressed by human osteo-, chondro-, and undifferentiated pleomorphic sarcomas and is associated with a significantly worse clinical prognosis. Silencing of GARP in bone sarcoma cell lines blocked their proliferation and induced apoptosis. In contrast, overexpression of GARP promoted their growth in vitro and in vivo and increased their resistance to DNA damage and cell death induced by etoposide, doxorubicin, and irradiation. Our data suggest that GARP could serve as a marker with therapeutic, prognostic, and predictive value in sarcoma. We propose that targeting GARP in bone sarcomas could reduce tumour burden while simultaneously improving the efficacy of chemo- and radiotherapy.
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Neoplasias Ósseas/metabolismo , Proteínas de Membrana/metabolismo , Osteossarcoma/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Criança , Pré-Escolar , Feminino , Xenoenxertos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Pessoa de Meia-Idade , Osteossarcoma/patologia , Prognóstico , Adulto JovemRESUMO
Sarcomas are heterogeneous and clinically challenging soft tissue and bone cancers. Although constituting only 1% of all human malignancies, sarcomas represent the second most common type of solid tumors in children and adolescents and comprise an important group of secondary malignancies. More than 100 histological subtypes have been characterized to date, and many more are being discovered due to molecular profiling. Owing to their mostly aggressive biological behavior, relative rarity, and occurrence at virtually every anatomical site, many sarcoma subtypes are in particular difficult-to-treat categories. Current multimodal treatment concepts combine surgery, polychemotherapy (with/without local hyperthermia), irradiation, immunotherapy, and/or targeted therapeutics. Recent scientific advancements have enabled a more precise molecular characterization of sarcoma subtypes and revealed novel therapeutic targets and prognostic/predictive biomarkers. This review aims at providing a comprehensive overview of the latest advances in the molecular biology of sarcomas and their effects on clinical oncology; it is meant for a broad readership ranging from novices to experts in the field of sarcoma.
Assuntos
Neoplasias Ósseas , Osteossarcoma , Sarcoma , Neoplasias de Tecidos Moles , Adolescente , Criança , Humanos , Medicina Molecular , Sarcoma/genética , Sarcoma/terapiaRESUMO
B-cell acute lymphoblastic leukemia (ALL; B-ALL) is the most common pediatric cancer, and high hyperdiploidy (HyperD) identifies the most common subtype of pediatric B-ALL. Despite HyperD being an initiating oncogenic event affiliated with childhood B-ALL, the mitotic and chromosomal defects associated with HyperD B-ALL (HyperD-ALL) remain poorly characterized. Here, we have used 54 primary pediatric B-ALL samples to characterize the cellular-molecular mechanisms underlying the mitotic/chromosome defects predicated to be early pathogenic contributors in HyperD-ALL. We report that HyperD-ALL blasts are low proliferative and show a delay in early mitosis at prometaphase, associated with chromosome-alignment defects at the metaphase plate leading to robust chromosome-segregation defects and nonmodal karyotypes. Mechanistically, biochemical, functional, and mass-spectrometry assays revealed that condensin complex is impaired in HyperD-ALL cells, leading to chromosome hypocondensation, loss of centromere stiffness, and mislocalization of the chromosome passenger complex proteins Aurora B kinase (AURKB) and Survivin in early mitosis. HyperD-ALL cells show chromatid cohesion defects and an impaired spindle assembly checkpoint (SAC), thus undergoing mitotic slippage due to defective AURKB and impaired SAC activity, downstream of condensin complex defects. Chromosome structure/condensation defects and hyperdiploidy were reproduced in healthy CD34+ stem/progenitor cells upon inhibition of AURKB and/or SAC. Collectively, hyperdiploid B-ALL is associated with a defective condensin complex, AURKB, and SAC.