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INTRODUCTION: Atypical (WHO grade II) and malignant meningiomas (WHO Grade III) are a rare subset of primary intracranial tumors. Given their relatively high recurrence rate after surgical resection and radiotherapy, there has been a recent push to explore other adjuvant treatment options for these treatment-refractory tumors. Recent advances in molecular sequencing of tumors have elucidated new pathways and drug targets which are currently being studied. This article provides a thorough overview of novel investigational therapeutics including targeted therapy, immunotherapy, and new technological modalities for atypical and malignant meningiomas. METHODS: We performed a comprehensive review of the available literature regarding preclinical and clinical evidence for emerging treatments for high grade meningiomas from 1980 to 2020 including contemporaneous clinical trials. RESULTS: There is encouraging preclinical evidence regarding the efficacy of the emerging treatments discussed in this article. Several clinical trials are currently recruiting patients to translate targeted molecular therapy for meningiomas. Several clinical studies have suggested a clinical benefit of combinatorial treatment for these treatment-refractory tumors. CONCLUSION: With numerous active clinical trials for high grade meningiomas, a meaningful improvement in the outcomes for these tumors may be on the horizon.
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Neoplasias Meníngeas , Meningioma , Humanos , Neoplasias Meníngeas/terapia , Meningioma/terapia , Pronóstico , Radioterapia Adyuvante , Estudios Retrospectivos , Terapias en InvestigaciónRESUMEN
Huntington disease (HD) is an autosomal dominant neurodegenerative disorder caused by expanded CAG repeats in the huntingtin gene (HTT). Although mutant HTT is expressed during embryonic development and throughout life, clinical HD usually manifests later in adulthood. A number of studies document neurodevelopmental changes associated with mutant HTT, but whether these are reversible under therapy remains unclear. Here, we identify very early behavioral, molecular, and cellular changes in preweaning transgenic HD rats and mice. Reduced ultrasonic vocalization, loss of prepulse inhibition, and increased risk taking are accompanied by disturbances of dopaminergic regulation in vivo, reduced neuronal differentiation capacity in subventricular zone stem/progenitor cells, and impaired neuronal and oligodendrocyte differentiation of mouse embryo-derived neural stem cells in vitro. Interventional treatment of this early phenotype with the histone deacetylase inhibitor (HDACi) LBH589 led to significant improvement in behavioral changes and markers of dopaminergic neurotransmission and complete reversal of aberrant neuronal differentiation in vitro and in vivo. Our data support the notion that neurodevelopmental changes contribute to the prodromal phase of HD and that early, presymptomatic intervention using HDACi may represent a promising novel treatment approach for HD.
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Diferenciación Celular/efectos de los fármacos , Enfermedad de Huntington/fisiopatología , Ácidos Hidroxámicos/farmacología , Indoles/farmacología , Neuronas/efectos de los fármacos , Animales , Animales Modificados Genéticamente , Diferenciación Celular/genética , Diferenciación Celular/fisiología , Modelos Animales de Enfermedad , Femenino , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Proteína Huntingtina/genética , Enfermedad de Huntington/genética , Ventrículos Laterales/patología , Masculino , Ratones Transgénicos , Mutación , Neuronas/metabolismo , Neuronas/fisiología , Panobinostat , RatasRESUMEN
The cardioprotective activity of ALM-802 compound was demonstrated in model experiments simulating postinfarction chronic heart failure in rats forming in 90 days after anterior transmural myocardial infarction. ALM-802 decreased the left ventricle and improved its inotropic function (p=0.038). This effect was observed in case of systematic administration of ALM-802 over 28 days (starting from day 91 after infarction modeling). This is apparently the minimum time for the cardioprotective effect of ALM-802 to prevent or treat the resulting heart failure, because short-term systematic therapy (15 days) produced no positive effect.
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Ventrículos Cardíacos/metabolismo , Infarto del Miocardio/metabolismo , Animales , Enfermedad Crónica , Modelos Animales de Enfermedad , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/metabolismo , Masculino , Infarto del Miocardio/genética , RatasRESUMEN
Mitochondrial diseases are extremely heterogeneous genetic conditions characterized by faulty oxidative phosphorylation (OXPHOS). OXPHOS deficiency can be the result of mutation in mtDNA genes, encoding either proteins (13 subunits of the mitochondrial complexes I, III, IV and V) or the tRNA and rRNA components of the in situ mtDNA translation. The remaining mitochondrial disease genes are in the nucleus, encoding proteins with a huge variety of functions, from structural subunits of the mitochondrial complexes, to factors involved in their formation and regulation, components of the mtDNA replication and expression machinery, biosynthetic enzymes for the biosynthesis or incorporation of prosthetic groups, components of the mitochondrial quality control and proteostasis, enzymes involved in the clearance of toxic compounds, factors involved in the formation of the lipid milieu, etc. These different functions represent potential targets for 'general' therapeutic interventions, as they may be adapted to a number of different mitochondrial conditions. This is in contrast with 'tailored', personalized therapeutic approaches, such as gene therapy, cell therapy and organ replacement, that can be useful only for individual conditions. This review will present the most recent concepts emerged from preclinical work and the attempts to translate them into the clinics. The common notion that mitochondrial disorders have no cure is currently challenged by a massive effort of scientists and clinicians, and we do expect that thanks to this intensive investigation work and tangible results for the development of strategies amenable to the treatment of patients with these tremendously difficult conditions are not so far away.
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Enfermedades Mitocondriales/terapia , Animales , Antioxidantes/uso terapéutico , Terapia Genética , Humanos , Mitocondrias/efectos de los fármacos , Mitocondrias/genética , Mitocondrias/metabolismo , Enfermedades Mitocondriales/tratamiento farmacológico , Enfermedades Mitocondriales/genética , Enfermedades Mitocondriales/metabolismo , Nucleótidos/uso terapéutico , Investigación Biomédica TraslacionalRESUMEN
Prodrug-carboxypeptidase G2 (e.g., ZD2767P+CPG2) can realize a targeted treatment where the specific advantage is a lack of CPG2 analogues in humans, but it is limited by low efficacy. Here ultrasound was employed to enhance ZD2767P+CPG2 (i.e., ZD2767P+CPG2+US) against chemoresistant human ovarian cancer cells. The release dynamics of ZD2767D (activated drug) by CPG2 were investigated. The in vitro efficacy was explored in SKOV3 and SKOV3/DDP (cisplatin-resistant subline) cells; spectrophotometry was established to quantify ZD2767P and ZD2767D, and then intracellular pharmacokinetics were evaluated. The in vivo efficacy was validated in both subcutaneous and orthotopic tumors. With insonation, the ZD2767D concentration was increased during an early period. Insonation synergized ZD2767P+CPG2 to enhance cell death and apoptosis, and efficacies in SKOV3 and SKOV3/DDP cells were similar. Intracellular pharmacokinetics of ZD2767D were nonproportional, and insonation increased the peak level, area under the level vs time curve, and mean residence time. In subcutaneous xenografts, ZD2767P+CPG2 and ZD2767P+CPG2+US resulted in volume-inhibitory rates of 20.4% and 26.5% in SKOV3 tumors and 36.8% and 81.6% in SKOV3/DDP tumors, respectively. In the orthotopic tumor model, the survival time in group ZD2767P+CPG2 or ZD2767P+CPG2+US was prolonged compared with group control, in SKOV3 (33.0 ± 3.5 or 39.2 ± 1.8 vs 25.0 ± 1.6 days, p < 0.0001) and SKOV3/DDP (16.2 ± 4.8 or 22.3 ± 7.3 vs 8.7 ± 3.9 days, p = 0.0015) tumors. These data indicated that ZD2767P+CPG2+US was effective against resistant ovarian cancer cells.
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Compuestos de Mostaza Nitrogenada/química , gamma-Glutamil Hidrolasa/química , gamma-Glutamil Hidrolasa/uso terapéutico , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Daño del ADN/efectos de los fármacos , Daño del ADN/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Proteína HMGB1/genética , Proteína HMGB1/metabolismo , Humanos , Ratones , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismoRESUMEN
Mycobacterium abscessus is a non-tuberculous mycobacterium notoriously known for causing severe, chronic infections. Treatment of these infections is challenging due to either intrinsic or acquired resistance of M. abscessus to multiple antibiotics. Despite prolonged poly-antimicrobial therapy, treatment of M. abscessus infections often fails, leading to progressive morbidity and eventual mortality. Great research efforts are invested in finding new therapeutic options for M. abscessus. Clofazimine and rifabutin are known anti-mycobacterial antibiotics, repurposed for use against M. abscessus. Novel antimicrobials active against M. abscessus include delamanid, pretomanid and PIPD1 and the recently approved beta-lactamase inhibitors avibactam, relebactam and vaborbactam. Previously unused antimicrobial combinations, e.g. vancomycin-clarithromycin and dual beta-lactam therapy, have been shown to have synergistic effect against M. abscessus in experimental models, suggesting their possible use in multiple-drug regimens. Finally, engineered phage therapy has been reported to be clinically successful in a severe case of disseminated M. abscessus infection. While many of these experimental therapeutics have shown activity against M. abscessus in vitro, as well as in intracellular and/or animal models, most have little if any evidence of effect in human infections. Clinical studies of M. abscesssus treatments are needed to reliably determine the value of their incorporation in therapeutic regimens.
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Infecciones por Mycobacterium no Tuberculosas/terapia , Mycobacterium abscessus/efectos de los fármacos , Terapias en Investigación , Administración por Inhalación , Animales , Antibacterianos/uso terapéutico , Ensayos Clínicos como Asunto , Evaluación Preclínica de Medicamentos , Drogas en Investigación/uso terapéutico , Humanos , Ratones , Infecciones por Mycobacterium no Tuberculosas/tratamiento farmacológico , Óxido Nítrico/administración & dosificación , Óxido Nítrico/uso terapéutico , Terapia de Fagos , Pez CebraRESUMEN
New health technologies are rapidly emerging from various areas of bioscience research, such as gene editing, regenerative medicine and synthetic biology. These technologies raise promising medical possibilities but also a range of ethical considerations. Apart from the issues involved in considering whether novel health technologies can or should become part of mainstream medical treatment once established, the process of research translation to develop such therapies itself entails particular ethical concerns. In this paper I use synthetic biology as an example of a new and largely unexplored area of health technology to consider the ways in which novel health technologies are likely to emerge and the ethical challenges these will present. I argue that such developments require us to rethink conventional attitudes towards clinical research, the roles of doctors/researchers and patients/participants with respect to research, and the relationship between science and society; and that a broader framework is required to address the plurality of stakeholder roles and interests involved in the development of treatments based on novel technologies.
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Investigación Biomédica/ética , Biología Sintética/ética , Biología Sintética/organización & administración , Terapias en Investigación/ética , Investigación Biomédica Traslacional/organización & administración , Actitud , Investigación Biomédica/organización & administración , Ética Médica , Humanos , Internacionalidad , Turismo Médico/ética , Aceptación de la Atención de Salud , Participación del Paciente , Médicos/ética , Rol Profesional , Investigadores/ética , Medición de Riesgo , Investigación Biomédica Traslacional/éticaRESUMEN
Epilepsy is a major risk factor for autism spectrum disorder (ASD) and complicates clinical manifestations and management of ASD significantly. Tuberous sclerosis complex (TSC), caused by TSC1 or TSC2 mutations, is one of the medical conditions most commonly associated with ASD and has become an important model to examine molecular pathways associated with ASD. Previous research showed reversal of autism-like social deficits in Tsc1 +/- and Tsc2 +/- mouse models by mammalian target of rapamycin (mTOR) inhibitors. However, at least 70 % of individuals with TSC also have epilepsy, known to complicate the severity and treatment responsiveness of the behavioural phenotype. No previous study has examined the impact of seizures on neurocognitive reversal by mTOR inhibitors. Adult Tsc2 +/- (Eker)-rats express social deficits similar to Tsc2 +/- mice, with additive social deficits from developmental status epilepticus (DSE). DSE was induced by intraperitoneal injection with kainic acid at post-natal days P7 and P14 (n = 12). The experimental group that modelled TSC pathology carried the Tsc2 +/- (Eker)-mutation and was challenged with DSE. The wild-type controls had not received DSE (n = 10). Four-month-old animals were analysed for social behaviour (T1), then treated three times during 1 week with 1 mg/kg everolimus and finally retested in the post-treatment behavioural analysis (T2). In the experimental group, both social interaction and social cognition were impaired at T1. After treatment at T2, behaviour in the experimental group was indistinguishable from controls. The mTOR inhibitor, everolimus, reversed social deficit behaviours in the Tsc2 haploinsufficiency plus DSE animal model to control levels.
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Trastorno del Espectro Autista/complicaciones , Trastorno del Espectro Autista/genética , Everolimus/uso terapéutico , Trastorno de la Conducta Social/tratamiento farmacológico , Trastorno de la Conducta Social/etiología , Estado Epiléptico/complicaciones , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Proteínas Supresoras de Tumor/deficiencia , Animales , Animales Recién Nacidos , Peso Corporal/genética , Modelos Animales de Enfermedad , Haploinsuficiencia/genética , Relaciones Interpersonales , Locomoción/efectos de los fármacos , Locomoción/genética , Ratas , Ratas Transgénicas , Reconocimiento en Psicología/efectos de los fármacos , Reconocimiento en Psicología/fisiología , Proteína 2 del Complejo de la Esclerosis Tuberosa , Proteínas Supresoras de Tumor/genéticaRESUMEN
Chronic pancreatitis (CP) is a progressive inflammatory disease of the pancreas. The currently available treatment of CP is aimed at controlling symptoms and managing complications. Unfortunately, no specific treatment is available to halt the progression of the disease process because the pathophysiological perturbations in CP are not well understood. In this review, we discuss various therapeutic targets and investigational agents acting on these targets. Among these, therapies modulating immune cells and those acting on pancreatic stellate cells appear promising and may translate into clinical benefit in near future. However, these experimental therapies are mostly in animal models and they do not recapitulate all aspects of human disease. Still they may be beneficial in developing effective therapeutic modalities to curb inflammation in chronic pancreatitis.
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Inmunoterapia/métodos , Pancreatitis Crónica/terapia , Animales , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Humanos , Células Estrelladas Pancreáticas , Pancreatitis Crónica/inmunología , Pancreatitis Crónica/fisiopatologíaRESUMEN
Eye diseases caused by amoebae from the genus Acanthamoeba are usually chronic and severe, and their treatment is prolonged and not very effective. The difficulties associated with therapy have led to attempts at finding alternative treatment methods. Particularly popular is searching for cures among drugs made of plants. However, no substances with total efficacy in treating Acanthamoeba keratitis have been identified.Results of our semi in vivo studies of tea tree oil simulating eyeball infection demonstrated 100% effectiveness in the case of both trophozoites and cysts of amoebae from the genus Acanthamoeba. The action of tea tree oil indicates that this is the first substance with a potential ability to quickly and effectively remove the amoebae from the eye. Tea tree oil has the ability to penetrate tissues, which allows it to destroy amoebae in both the shallow and deep layers of the cornea. The present research into the use of tea tree oil in the therapy of Acanthamoeba infection is the first study of this type in parasitology. It offers tremendous potential for effective treatment of Acanthamoeba keratitis and other diseases caused by these protozoa.
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Queratitis por Acanthamoeba/tratamiento farmacológico , Acanthamoeba/efectos de los fármacos , Melaleuca/química , Aceite de Árbol de Té/farmacología , Acanthamoeba/fisiología , Queratitis por Acanthamoeba/parasitología , Animales , Córnea/parasitología , Evaluación Preclínica de Medicamentos , Humanos , Ratones , Ratones Endogámicos BALB C , Aceites de Plantas/farmacología , Resultado del TratamientoRESUMEN
Mitochondrial disorders are an important group of genetic conditions characterized by impaired oxidative phosphorylation. Mitochondrial disorders come with an impressive variability of symptoms, organ involvement, and clinical course, which considerably impact the quality of life and quite often shorten the lifespan expectancy. Although the last 20 years have witnessed an exponential increase in understanding the genetic and biochemical mechanisms leading to disease, this has not resulted in the development of effective therapeutic approaches, amenable of improving clinical course and outcome of these conditions to any significant extent. Therapeutic options for mitochondrial diseases still remain focused on supportive interventions aimed at relieving complications. However, new therapeutic strategies have recently been emerging, some of which have shown potential efficacy at the pre-clinical level. This review will present the state of the art on experimental therapy for mitochondrial disorders.
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Enfermedades Mitocondriales/terapia , Transporte de Electrón , Humanos , Enfermedades Mitocondriales/metabolismo , Enfermedades Mitocondriales/patología , Fosforilación OxidativaRESUMEN
The treatment of acanthamoebiasis is a great problem. Most cerebral invasions end with death, and the treatment of ocular invasions is usually long-lasting and not very effective. Numerous plant extracts and substances isolated from plants, which are effective against trophozoites or cysts, have been studied in the treatment of acanthamoebiasis. However, no agents that are simultaneously effective against both developing forms of amoebae have been discovered yet. It seems that such a plant which fulfils both tasks is Artemisia annua L. Our studies showed that water, alcohol and chloroform extracts from the herb A. annua L. can be applied in general and local treatment or in combined therapy with antibiotics in the treatment of acanthamoebiasis. Extracts from this plant show not only in vitro but also in vivo effects. Studies carried out on experimental animals infected with amoebae show that the application of these extracts significantly prolongs the survival of the animals.
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Queratitis por Acanthamoeba/tratamiento farmacológico , Amoeba/efectos de los fármacos , Artemisia annua/química , Encefalitis/tratamiento farmacológico , Extractos Vegetales/farmacología , Neumonía/tratamiento farmacológico , Animales , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificaciónRESUMEN
The recent Ebola outbreak in West Africa began in the spring of 2014 and has since caused the deaths of over 6,000 people. Since there are no approved treatments or prevention modalities specifically targeted at Ebola Virus Disease (EVD), debate has focused on whether unproven interventions should be offered to Ebola patients outside of clinical trials. Those engaged in the debate have responded rapidly to a complex and evolving crisis, however, and this debate has not provided much opportunity for in-depth analysis. Additionally, the existing literature on access to unproven therapies has focused on contexts like HIV/AIDS and oncology, which are very different than the Ebola epidemic. In this paper, we examine the ethical issues surrounding access to unproven therapies in the context of the recent Ebola outbreak to yield new insights about this controversial and unsettled issue. We argue first that, in this context, the interests of patients in obtaining access to unproven therapies are not fully aligned with the interests of their providers and drug developers. Second, we focus on the resource constraints facing providers, funders, and patients and conclude that they often counsel against the use of unproven interventions against EVD.
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Ensayos de Uso Compasivo/ética , Brotes de Enfermedades , Fiebre Hemorrágica Ebola/epidemiología , Fiebre Hemorrágica Ebola/terapia , Asignación de Recursos/ética , Experimentación Humana Terapéutica/ética , África Occidental/epidemiología , Ensayos Clínicos como Asunto , Brotes de Enfermedades/prevención & control , Ética en Investigación , Fiebre Hemorrágica Ebola/prevención & control , Humanos , Relaciones Médico-Paciente/éticaRESUMEN
Neuronal ceroid lipofuscinoses are a group of fatal progressive neurodegenerative diseases predominantly affecting children. Identification of mutations that cause neuronal ceroid lipofuscinosis, and subsequent functional and pathological studies of the affected genes, underpins efforts to investigate disease mechanisms and identify and test potential therapeutic strategies. These functional studies and pre-clinical trials necessitate the use of model organisms in addition to cell and tissue culture models as they enable the study of protein function within a complex organ such as the brain and the testing of therapies on a whole organism. To this end, a large number of disease models and genetic tools have been identified or created in a variety of model organisms. In this review, we will discuss the ethical issues associated with experiments using model organisms, the factors underlying the choice of model organism, the disease models and genetic tools available, and the contributions of those disease models and tools to neuronal ceroid lipofuscinosis research. This article is part of a Special Issue entitled: The Neuronal Ceroid Lipofuscinoses or Batten Disease.
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Modelos Animales de Enfermedad , Proteínas de la Membrana/genética , Lipofuscinosis Ceroideas Neuronales/genética , Lipofuscinosis Ceroideas Neuronales/patología , Animales , HumanosRESUMEN
This year marks the 35th anniversary of Professor Walter Wahli's discovery of the PPARs (Peroxisome Proliferator-Activated Receptors) family of nuclear hormone receptors. To mark the occasion, the editors of the scientific periodical Biomolecules decided to publish a special issue in his honor. This paper summarizes what is known about PPARs and shows how trends have changed and how research on PPARs has evolved. The article also highlights the importance of PPARs and what role they play in various diseases and ailments. The paper is in a mixed form; essentially it is a review article, but it has been enriched with the results of our experiments. The selection of works was subjective, as there are more than 200,000 publications in the PubMed database alone. First, all papers done on an animal model were discarded at the outset. What remained was still far too large to describe directly. Therefore, only papers that were outstanding, groundbreaking, or simply interesting were described and briefly commented on.
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Receptores Activados del Proliferador del Peroxisoma , Animales , Humanos , Receptores Activados del Proliferador del Peroxisoma/metabolismo , Investigación Biomédica/historia , Historia del Siglo XXRESUMEN
KEY POINTS: SinoNasal Microbiota Transfer (SNMT) was safe with immediate benefit in all recipients, with sustained improvement in two of three recipients for up to 180 days. The addition of antimicrobial photodynamic therapy worsened chronic rhinosinusitis. These promising SNMT results warrant further study of safety and efficacy.
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Microbiota , Rinitis , Sinusitis , Humanos , Sinusitis/microbiología , Sinusitis/terapia , Rinitis/microbiología , Rinitis/terapia , Enfermedad Crónica , Persona de Mediana Edad , Masculino , Femenino , Adulto , Senos Paranasales/microbiología , Resultado del Tratamiento , Anciano , RinosinusitisRESUMEN
Background: Huntington's disease (HD) is a neurodegenerative disorder characterized by motor, cognitive, and psychiatric dysfunction caused by a mutant huntingtin protein. Compromised metabolic activity resulting from systemic administration of the mitochondrial toxin, 3-nitropropionic acid (3-NP), is known to mimic the pathology of HD and induce HD-like symptoms in rats. N-hexanoic-Tyr-Ile-(6)-amino hexanoic amide (PNB-0408), also known as Dihexa, has been shown to have neuroprotective and procognitive properties in animal models of Alzheimer's and Parkinson's diseases. Given the mechanism of action and success in other neurodegenerative diseases, we felt it an appropriate compound to investigate further for HD. Objective: The present study was designed to test if PNB-0408, an angiotensin IV analog, could attenuate 3-NP-induced HD-like symptoms in rats and serve as a potential therapeutic agent. Methods: Forty male Wistar rats were randomized into three groups consisting of a "vehicle" group, a "3-NP" group, and a "3-NPâ+âPNB-0408" group. PNB-0408 was administered along with chronic exposure to 3-NP. Animal body weight, motor function, and cognitive abilities were measured for five weeks, before euthanasia and histopathological analysis. Results: Exposure to 3-NP decreased the amount of weight rats gained, impaired spatial learning and memory consolidation, and led to marked motor dysfunction. From our observations and analysis, PNB-0408 did not protect rats from the deficits induced by 3-NP neurotoxicity. Conclusions: Our findings suggest that PNB-0408 may not be an efficacious treatment strategy for preventing 3-NP-induced HD-like symptoms in a preclinical model. These data highlight the need for further research of this compound in alternate models and/or alternative approaches to managing this disorder.
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Angiotensina II/análogos & derivados , Enfermedad de Huntington , Fármacos Neuroprotectores , Ratas , Masculino , Animales , Ratas Wistar , Enfermedad de Huntington/inducido químicamente , Enfermedad de Huntington/tratamiento farmacológico , Enfermedad de Huntington/metabolismo , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Nitrocompuestos/toxicidad , Nitrocompuestos/uso terapéutico , Propionatos/toxicidad , Propionatos/uso terapéutico , Modelos Animales de EnfermedadRESUMEN
Subsequently to the publication of the above article, an interested reader drew to the authors' attention that two pairs of the culture plate images in Fig. 4A-C on p. 60 appeared to be the same, although the images were shown in different orientations; moreover, the 'NC/0 and DEX+miR132' and 'DEX and miR132' pairings of images in the scratch-wound assay experiments shown in Fig. 4B also appeared to be overlapping, such that these were apparently derived from the same original source where the results of differently performed experiments were intended to have been portrayed. After reexamining their original data, the authors have realized that some of the data in Fig. 4A and B were inadvertently assembled incorrectly. The revised version of Fig. 4, showing all the correct data for the culture plate images in Fig. 4A-C (specifically, the images fifth along on the right for Fig. 4B and C have been revised) and the correct images for 'NC/0' and 'DEX/0' in Fig. 4D is shown on on the next page. The authors are grateful to the Editor of International Journal of Oncology for allowing them this opportunity to publish a Corrigendum, and all the authors agree with its publication. Furthermore, the authors apologize to the readership for any inconvenience caused. [International Journal of Oncology 54: 5364, 2019; DOI: 10.3892/ijo.2018.4616].
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Several lines of evidence suggest that a characteristic of the neuropathology of Alzheimer's disease (AD) is the aggregation of the amyloid beta peptides (Aß), fragments of the human amyloid precursor protein (hAPP). The dominating species are the Aß40 and Aß42 fragments with 40 and 42 amino acids, respectively. Aß initially forms soluble oligomers that continue to expand to protofibrils, suggestively the neurotoxic intermediates, and thereafter turn into insoluble fibrils that are markers of the disease. Using the powerful tool of pharmacophore simulation, we selected small molecules not known to possess central nervous system (CNS) activity but that might interact with Aß aggregation, from the NCI Chemotherapeutic Agents Repository, Bethesda, MD. We assessed the activity of these compounds on Aß aggregation using the thioflavin T fluorescence correlation spectroscopy (ThT-FCS) assay. Förster resonance energy transfer-based fluorescence correlation spectroscopy (FRET-FCS) was used to characterize the dose-dependent activity of selected compounds at an early stage of Aß aggregation. Transmission electron microscopy (TEM) confirmed that the interfering substances block fibril formation and identified the macrostructures of Aß aggregates formed in their presence. We first found three compounds generating protofibrils with branching and budding never observed in the control. One compound generated a two-dimensional sheet structure and another generated a double-stranded filament. Importantly, these compounds generating protofibrils with altered macrostructure protected against Aß-induced toxicity in a cell model while showing no toxicity in a model of cognition in normal mice. The data suggest that the active compounds act as decoys turning the aggregation into nontoxic trajectories and pointing toward novel approaches to therapy.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Animales , Humanos , Ratones , Péptidos beta-Amiloides/metabolismo , Fragmentos de Péptidos/metabolismo , Enfermedad de Alzheimer/metabolismo , Microscopía Electrónica de Transmisión , Precursor de Proteína beta-AmiloideRESUMEN
Glioblastoma (GBM) is one of the most aggressive (grade IV) gliomas characterized by a high rate of recurrence, resistance to therapy and a grim survival prognosis. The long-awaited improvement in GBM patients' survival rates essentially depends on advances in the development of new therapeutic approaches. Recent preclinical studies show that nanoscale materials could greatly contribute to the improvement of diagnosis and management of brain cancers. In the current review, we will discuss how specific features of glioma pathobiology can be employed for designing efficient targeting approaches. Moreover, we will summarize the main evidence for the potential of the IL-13R alpha 2 receptor (IL13α2R) targeting in GBM early diagnosis and experimental therapy.