RESUMEN
Asparaginase (ASNase) is an important anti-leukaemic drug in the treatment of childhood acute lymphoblastic leukaemia (ALL) and non-Hodgkin lymphoma (NHL). A substantial proportion of patients develop hypersensitivity reactions with anti-ASNase neutralising antibodies, resulting in allergic reactions or silent inactivation (SI), and characterised by inactivation and rapid clearance of ASNase. We report results of a prospective, real-time therapeutic drug monitoring of pegylated Escherichia coli (PEG-)ASNase and Erwinia ASNase in children treated for ALL and NHL in Belgium. Erwinia ASNase was given as second-line after hypersensitivity to PEG-ASNase. In total, 286 children were enrolled in the PEG-ASNase cohort. Allergy was seen in 11·2% and SI in 5·2% of patients. Of the 42 patients treated with Erwinia ASNase, 7·1% experienced allergy and 2·4% SI. The median trough PEG-ASNase activity was high in all patients without hypersensitivity. After Erwinia administration significantly more day 3 samples had activities <100 IU/l (62·5% vs. 10% at day 2 (D2)). The median D2 activity was significantly higher for intramuscular (IM; 347 IU/l) than for intravenous Erwinia administrations (159 IU/l). This prospective, multicentre study shows that monitoring of ASNase activity during treatment of children with ALL and NHL is feasible and informative. Treatment with Erwinia ASNase warrants close monitoring and optimally adherence to a 2-day interval of IM administrations.
Asunto(s)
Asparaginasa/metabolismo , Erwinia/metabolismo , Linfoma no Hodgkin/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Adolescente , Bélgica , Niño , Preescolar , Escherichia coli , Femenino , Humanos , Lactante , Masculino , Estudios ProspectivosRESUMEN
On June 28, 2018, the Committee for Advanced Therapies and the Committee for Medicinal Products for Human Use adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Yescarta for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma and primary mediastinal large B-cell lymphoma, after two or more lines of systemic therapy. Yescarta, which was designated as an orphan medicinal product and included in the European Medicines Agency's Priority Medicines scheme, was granted an accelerated review timetable. The active substance of Yescarta is axicabtagene ciloleucel, an engineered autologous T-cell immunotherapy product whereby a patient's own T cells are harvested and genetically modified ex vivo by retroviral transduction using a retroviral vector to express a chimeric antigen receptor (CAR) comprising an anti-CD19 single chain variable fragment linked to CD28 costimulatory domain and CD3-zeta signaling domain. The transduced anti-CD19 CAR T cells are expanded ex vivo and infused back into the patient, where they can recognize and eliminate CD19-expressing cells. The benefits of Yescarta as studied in ZUMA-1 phase II (NCT02348216) were an overall response rate per central review of 66% (95% confidence interval, 56%-75%) at a median follow-up of 15.1 months in the intention to treat population and a complete response rate of 47% with a significant duration. The most common adverse events were cytokine release syndrome, neurological adverse events, infections, pyrexia, diarrhea, nausea, hypotension, and fatigue. IMPLICATIONS FOR PRACTICE: Yescarta (axicabtagene ciloleucel) was the first chimeric antigen receptor T-cell therapy to be submitted for evaluation to the European Medicines Agency and admitted into the "priority medicine" scheme; it was granted accelerated assessment on the basis of anticipated clinical benefit in relapsed/refractory diffuse large B-cell lymphoma, a condition of unmet medical need. Indeed, Yescarta showed an overall response rate of 66% and a complete response rate of 47% with a significant duration and a manageable toxicity that compared very favorably with historical controls. Here the analysis of benefits and risks is presented, and specific challenges with this important novel product are highlighted, providing further insights and reflections for future medical research.
Asunto(s)
Linfoma de Células B Grandes Difuso , Receptores Quiméricos de Antígenos , Adulto , Antígenos CD19/uso terapéutico , Productos Biológicos , Humanos , Inmunoterapia Adoptiva , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Receptores Quiméricos de Antígenos/genéticaRESUMEN
The multifunctional AMPK-activated protein kinase (AMPK) is an evolutionarily conserved energy sensor that plays an important role in cell proliferation, growth, and survival. It remains unclear whether AMPK functions as a tumor suppressor or a contextual oncogene. This is because although on one hand active AMPK inhibits mammalian target of rapamycin (mTOR) and lipogenesis--two crucial arms of cancer growth--AMPK also ensures viability by metabolic reprogramming in cancer cells. AMPK activation by two indirect AMPK agonists AICAR and metformin (now in over 50 clinical trials on cancer) has been correlated with reduced cancer cell proliferation and viability. Surprisingly, we found that compared with normal tissue, AMPK is constitutively activated in both human and mouse gliomas. Therefore, we questioned whether the antiproliferative actions of AICAR and metformin are AMPK independent. Both AMPK agonists inhibited proliferation, but through unique AMPK-independent mechanisms and both reduced tumor growth in vivo independent of AMPK. Importantly, A769662, a direct AMPK activator, had no effect on proliferation, uncoupling high AMPK activity from inhibition of proliferation. Metformin directly inhibited mTOR by enhancing PRAS40's association with RAPTOR, whereas AICAR blocked the cell cycle through proteasomal degradation of the G2M phosphatase cdc25c. Together, our results suggest that although AICAR and metformin are potent AMPK-independent antiproliferative agents, physiological AMPK activation in glioma may be a response mechanism to metabolic stress and anticancer agents.
Asunto(s)
Ciclo Celular/fisiología , Proteínas Quinasas/efectos de los fármacos , Serina-Treonina Quinasas TOR/fisiología , Quinasas de la Proteína-Quinasa Activada por el AMP , Animales , Neoplasias Encefálicas/enzimología , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Glioblastoma/enzimología , Glioblastoma/metabolismo , Glioblastoma/patología , Humanos , Lipogénesis/efectos de los fármacos , Metformina/farmacología , Ratones , Ratones Noqueados , Proteínas Quinasas/genéticaRESUMEN
Since its establishment as a pediatric subspecialty oncology has become the near exclusive domain of specialized tertiary centers. This has greatly aided progress in the field with formation of exemplary and highly focused international consortia that have continued to streamline clinical research efforts. Recently, the rate of progress in terms of further improvements in overall outcome has paradoxically slowed. Novel strategies are therefore needed to assure continued advances. On the one hand, international and global consortia of subspecialists will continue to focus on the development of much needed improved therapies for those disease groups that have not yet seen their prognosis brighten, and on the other hand, there is a trend to invest in the development of joint-care initiatives that assure cost-effective access to standard therapy for all. This will require closer involvement of the general pediatrician in certain aspects of cancer care in its broadest sense. We hope the upcoming series will aid this process by highlighting selected topics in pediatric oncology that are likely to gain even more relevance for the general pediatrician in the years to come. They include: screening strategies for cancer predisposition syndromes; molecular diagnosis and risk-adjustment of therapy for acute leukemia in childhood; an overview of new agents in clinical development; and the impact of cancer treatment on fertility and available preservation options.
Asunto(s)
Educación Médica/normas , Oncología Médica/educación , Pediatría/educación , Médicos , Niño , HumanosRESUMEN
AMP-activated protein kinase (AMPK) is an evolutionarily conserved cellular switch that activates catabolic pathways and turns off anabolic processes. In this way, AMPK activation can restore the perturbation of cellular energy levels. In physiological situations, AMPK senses energy deficiency (in the form of an increased AMP/ATP ratio), but it is also activated by metabolic insults, such as glucose or oxygen deprivation. Metformin, one of the most widely prescribed anti-diabetic drugs, exerts its actions by AMPK activation. However, while the functions of AMPK as a metabolic regulator are fairly well understood, its actions in neuronal cells only recently gained attention. This review will discuss newly emerged functions of AMPK in neuroprotection and neurodegeneration. Additionally, recent views on the role of AMPK in autophagy, an important catabolic process that is also involved in neurodegeneration and cancer, will be highlighted.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Autofagia , Supervivencia Celular , Neuronas/citología , Neuronas/enzimología , Proteínas Quinasas Activadas por AMP/química , Proteínas Quinasas Activadas por AMP/genética , Animales , Evolución Molecular , Humanos , Transducción de SeñalRESUMEN
Understanding how the genome empowers the nervous system to express behaviors remains a critical challenge in behavioral genetics. The startle response is an attractive behavioral model for studies on the relationship between genes, brain, and behavior, as the ability to respond rapidly to harmful changes in the environment is a universal survival trait. Drosophila melanogaster provides a powerful system in which genetic studies on individuals with controlled genetic backgrounds and reared under controlled environmental conditions can be combined with neuroanatomical studies to analyze behaviors. In a screen of 720 lines of D. melanogaster, carrying single P[GT1] transposon insertions, we found 267 lines that showed significant changes in startle-induced locomotor behavior. Excision of the transposon reversed this effect in five lines out of six tested. We infer that most of the 267 lines show mutant effects on startle-induced locomotion that are caused by the transposon insertions. We selected a subset of 15 insertions in the same genetic background in autosomal genes with strong mutant effects and crossed them to generate all 105 possible nonreciprocal double heterozygotes. These hybrids revealed an extensive network of epistatic interactions on the behavioral trait. In addition, we observed changes in neuroanatomy that were caused by these 15 mutations, individually and in their double heterozygotes. We find that behavioral and neuroanatomical phenotypes are determined by a common set of genes that are organized as partially overlapping genetic networks.
Asunto(s)
Drosophila melanogaster/genética , Epistasis Genética , Redes Reguladoras de Genes/fisiología , Locomoción/genética , Fenómenos Fisiológicos del Sistema Nervioso , Reflejo de Sobresalto/genética , Animales , Elementos Transponibles de ADN , Drosophila melanogaster/fisiología , Locomoción/fisiología , Mutación , Reflejo de Sobresalto/fisiologíaRESUMEN
Lysosomal storage is the most common cause of neurodegenerative brain disease in preadulthood. However, the underlying cellular mechanisms that lead to neuronal dysfunction are unknown. Here, we report that loss of Drosophila benchwarmer (bnch), a predicted lysosomal sugar carrier, leads to carbohydrate storage in yolk spheres during oogenesis and results in widespread accumulation of enlarged lysosomal and late endosomal inclusions. At the bnch larval neuromuscular junction, we observe similar inclusions and find defects in synaptic vesicle recycling at the level of endocytosis. In addition, loss of bnch slows endosome-to-lysosome trafficking in larval garland cells. In adult bnch flies, we observe age-dependent synaptic dysfunction and neuronal degeneration. Finally, we find that loss of bnch strongly enhances tau neurotoxicity in a dose-dependent manner. We hypothesize that, in bnch, defective lysosomal carbohydrate efflux leads to endocytic defects with functional consequences in synaptic strength, neuronal viability, and tau neurotoxicity.
Asunto(s)
Metabolismo de los Hidratos de Carbono , Proteínas Portadoras/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/embriología , Lisosomas/metabolismo , Degeneración Nerviosa/metabolismo , Malformaciones del Sistema Nervioso/metabolismo , Animales , Supervivencia Celular/genética , Modelos Animales de Enfermedad , Drosophila melanogaster/genética , Drosophila melanogaster/ultraestructura , Endocitosis/genética , Endosomas/metabolismo , Endosomas/patología , Endosomas/ultraestructura , Femenino , Enfermedad del Almacenamiento de Glucógeno/genética , Enfermedad del Almacenamiento de Glucógeno/metabolismo , Enfermedad del Almacenamiento de Glucógeno/fisiopatología , Larva/crecimiento & desarrollo , Larva/metabolismo , Larva/ultraestructura , Lisosomas/patología , Lisosomas/ultraestructura , Masculino , Proteínas de la Membrana , Microscopía Electrónica de Transmisión , Degeneración Nerviosa/genética , Degeneración Nerviosa/fisiopatología , Malformaciones del Sistema Nervioso/genética , Malformaciones del Sistema Nervioso/fisiopatología , Unión Neuromuscular/metabolismo , Unión Neuromuscular/patología , Unión Neuromuscular/ultraestructura , Oogénesis/genética , Transporte de Proteínas/genética , Saco Vitelino/metabolismo , Saco Vitelino/ultraestructura , Proteínas tau/toxicidadRESUMEN
The third multistakeholder Paediatric Strategy Forum organised by ACCELERATE and the European Medicines Agency focused on immune checkpoint inhibitors for use in combination therapy in children and adolescents. As immune checkpoint inhibitors, both as monotherapy and in combinations have shown impressive success in some adult malignancies and early phase trials in children of single agent checkpoint inhibitors have now been completed, it seemed an appropriate time to consider opportunities for paediatric studies of checkpoint inhibitors used in combination. Among paediatric patients, early clinical studies of checkpoint inhibitors used as monotherapy have demonstrated a high rate of activity, including complete responses, in Hodgkin lymphoma and hypermutant paediatric tumours. Activity has been very limited, however, in more common malignancies of childhood and adolescence. Furthermore, apart from tumour mutational burden, no other predictive biomarker for monotherapy activity in paediatric tumours has been identified. Based on these observations, there is collective agreement that there is no scientific rationale for children to be enrolled in new monotherapy trials of additional checkpoint inhibitors with the same mechanism of action of agents already studied (e.g. anti-PD1, anti-PDL1 anti-CTLA-4) unless additional scientific knowledge supporting a different approach becomes available. This shared perspective, based on scientific evidence and supported by paediatric oncology cooperative groups, should inform companies on whether a paediatric development plan is justified. This could then be proposed to regulators through the available regulatory tools. Generally, an academic-industry consensus on the scientific merits of a proposal before submission of a paediatric investigational plan would be of great benefit to determine which studies have the highest probability of generating new insights. There is already a rationale for the evaluation of combinations of checkpoint inhibitors with other agents in paediatric Hodgkin lymphoma and hypermutated tumours in view of the activity shown as single agents. In paediatric tumours where no single agent activity has been observed in multiple clinical trials of anti-PD1, anti-PDL1 and anti-CTLA-4 agents as monotherapy, combinations of checkpoint inhibitors with other treatment modalities should be explored when a scientific rationale indicates that they could be efficacious in paediatric cancers and not because these combinations are being evaluated in adults. Immunotherapy in the form of engineered proteins (e.g. monoclonal antibodies and T cell engaging agents) and cellular products (e.g. CAR T cells) has great therapeutic potential for benefit in paediatric cancer. The major challenge for developing checkpoint inhibitors for paediatric cancers is the lack of neoantigens (based on mutations) and corresponding antigen-specific T cells. Progress critically depends on understanding the immune macroenvironment and microenvironment and the ability of the adaptive immune system to recognise paediatric cancers in the absence of high neoantigen burden. Future clinical studies of checkpoint inhibitors in children need to build upon strong biological hypotheses that take into account the distinctive immunobiology of childhood cancers in comparison to that of checkpoint inhibitor responsive adult cancers.
Asunto(s)
Antineoplásicos/uso terapéutico , Desarrollo de Medicamentos , Agencias Gubernamentales/organización & administración , Inmunoterapia/métodos , Evaluación de Necesidades , Neoplasias/tratamiento farmacológico , Planificación de Atención al Paciente/organización & administración , Antígeno B7-H1/antagonistas & inhibidores , Antígeno CTLA-4/antagonistas & inhibidores , Niño , Quimioterapia Combinada , Humanos , Neoplasias/patología , PronósticoRESUMEN
Exploring mechanisms that govern neuronal responses to metabolic stress is essential for the development of therapeutic strategies aimed at treatment of neuronal injury and disease. AMP-activated protein kinase (AMPK) is a key enzyme regulating cellular energy homeostasis that responds to changes in cellular energy levels by promoting energy-restorative and inhibiting energy-consumptive processes. Recent studies have suggested that AMPK might have a neuroprotective function. However, the existing evidence is contradictory and almost exclusively derived from in vitro studies based on drug treatments and metabolic stress models. To tackle these issues in vivo, we used the Drosophila visual system. In this report, we describe a novel Drosophila mutant, alicorn (alc), encoding the single beta regulatory subunit of AMPK. Loss of alc using the eyFlp system causes severe early-onset progressive nonapoptotic neurodegeneration in the retina, the optic lobe, and the antennae, as well as behavioral and neurophysiological defects. Retinal degeneration occurs immediately after normal neuronal differentiation, can be enhanced by exposure to light, and can be prevented by blocking photoreceptor excitation. Furthermore, AMPK is required for proper viability of differentiated photoreceptors by mechanisms unrelated to polarity events that AMPK controls in epithelial tissues. In conclusion, AMPK does not affect photoreceptor development but is crucial to maintaining integrity of mature neurons under conditions of increased activity and provides protection from excitotoxicity.
Asunto(s)
Proteínas de Drosophila/fisiología , Complejos Multienzimáticos/fisiología , Neuronas/metabolismo , Proteínas Serina-Treonina Quinasas/fisiología , Degeneración Retiniana/enzimología , Degeneración Retiniana/prevención & control , Proteínas Quinasas Activadas por AMP , Secuencia de Aminoácidos , Animales , Animales Modificados Genéticamente , Drosophila , Proteínas de Drosophila/biosíntesis , Proteínas de Drosophila/genética , Femenino , Datos de Secuencia Molecular , Complejos Multienzimáticos/biosíntesis , Complejos Multienzimáticos/genética , Mutación , Proteínas Serina-Treonina Quinasas/biosíntesis , Proteínas Serina-Treonina Quinasas/genética , Degeneración Retiniana/genéticaRESUMEN
AMP-activated protein kinase (AMPK) constitutes a molecular hub for cellular metabolic control, common to all eukaryotic cells. Numerous reports have established how AMPK responds to changes in the AMP:ATP ratio as a measure of cellular energy levels. In this way, it integrates control over a number of metabolic enzymes and adapts cellular processes to the current energy status in various cell types, such as muscle and liver cells. The role of AMPK in the development, function, and maintenance of the nervous system, on the other hand, has only recently gained attention. Neurons, while highly metabolically active, have poor capacity for nutrient storage and are thus sensitive to energy fluctuations. Recent reports demonstrate that AMPK may have neuroprotective properties and is activated in neurons by resveratrol but also by metabolic stress in the form of ischemia/hypoxia and glucose deprivation. Novel studies on AMPK also implicate neuronal activity as a critical factor in neurodegeneration. Here we discuss the latest advances in the knowledge of AMPK's role in the metabolic control and survival of excitable cells.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Encéfalo/enzimología , Metabolismo Energético/fisiología , Neuronas/enzimología , Animales , Química Encefálica , Supervivencia Celular/fisiología , Citoprotección/efectos de los fármacos , Citoprotección/fisiología , Humanos , Hipoxia-Isquemia Encefálica/enzimología , Hipoxia-Isquemia Encefálica/fisiopatología , Estrés Fisiológico/fisiologíaRESUMEN
During sensory organ precursor divisions in Drosophila, the numb gene product segregates asymmetrically into one of the two daughter cells, to which it confers a specific fate by inhibiting Notch signaling. In this issue of Developmental Cell, Berdnik et al. show that Numb recruits alpha-Adaptin and that this physical interaction plays a role in downregulating Notch, presumably by stimulating endocytosis of Notch.
Asunto(s)
Tipificación del Cuerpo/fisiología , Proteínas Portadoras/metabolismo , Diferenciación Celular/fisiología , Linaje de la Célula/fisiología , Endocitosis/fisiología , Hormonas Juveniles/metabolismo , Proteínas de la Membrana/metabolismo , Células Madre/metabolismo , Subunidades alfa de Complejo de Proteína Adaptadora , Animales , Proteínas Portadoras/genética , Proteínas de Drosophila , Drosophila melanogaster/citología , Drosophila melanogaster/embriología , Drosophila melanogaster/metabolismo , Hormonas Juveniles/genética , Proteínas de la Membrana/genética , Receptores Notch , Órganos de los Sentidos/citología , Órganos de los Sentidos/embriología , Órganos de los Sentidos/metabolismo , Células Madre/citologíaRESUMEN
Understanding how genotypic variation influences variation in brain structures and behavioral phenotypes represents a central challenge in behavioral genetics. In Drosophila melanogaster, the neuralized (neur) gene plays a key role in development of the nervous system. Different P-element insertional mutations of neur allow the development of viable and fertile adults with profoundly altered behavioral phenotypes that depend on the exact location of the inserted P element. The neur mutants exhibit reduced responsiveness to noxious olfactory and mechanosensory stimulation and increased aggression when limited food is presented after a period of food deprivation. These behavioral phenotypes are correlated with distinct structural changes in integrative centers in the brain, the mushroom bodies, and the ellipsoid body of the central complex. Transcriptional profiling of neur mutants revealed considerable overlap among ensembles of coregulated genes in the different mutants, but also distinct allele-specific differences. The diverse phenotypic effects arising from nearby P-element insertions in neur provide a new appreciation of the concept of allelic effects on phenotype, in which the wild type and null mutant are at the extreme ends of a continuum of pleiotropic allelic effects.
Asunto(s)
Conducta , Encéfalo/anatomía & histología , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/fisiología , Ubiquitina-Proteína Ligasas/metabolismo , Alelos , Empalme Alternativo/genética , Animales , Elementos Transponibles de ADN , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Femenino , Regulación del Desarrollo de la Expresión Génica , Genes de Insecto , Masculino , Mutagénesis Insercional , Mutación/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
Objective: Pediatric cancer is a life-threatening disease that poses significant challenges to the ill child and his/her parents. Among the studies investigating risk and protective factors for the individual and relationship adjustment of parents being confronted with pediatric cancer, couple factors - such as dyadic coping - gained little research attention. Therefore, the aim of the current study was to explore the association between dyadic coping and individual/relationship outcomes of parents in the context of pediatric cancer. Methods: Participants were 59 couples of children diagnosed with leukemia or Non-Hodgkin lymphoma. Time since diagnosis varied from diagnosis to 20 months. Both parents completed the DCI-short, DASS21, PIP, and MMQ. Results: Positive dyadic coping (i.e., supportive and common dyadic coping) and negative dyadic coping proved to be related to individual and relational outcomes of parents facing cancer in their child. In addition, while men and women reported to be equally satisfied with their partner and their sexual relationship, women reported higher levels of individual maladjustment. Conclusion: Our findings led to the conclusion that dyadic coping is important for both individual as well as relationship outcomes of parents when facing a diagnosis of cancer in their child. When meeting with families, both partners should be invited as a unit in order to best capture couple level experiences. Also, clinicians should be sensitive to relational and sexual issues besides individual issues, taking into account evidence-based standards for psychosocial care in pediatric oncology.
RESUMEN
OBJECTIVES: Childhood cancer is a life-threatening disease that poses significant challenges to the life of the diagnosed child and his/her family members. Based on the ABCX-model, the aim of the current study was to explore the association between family functioning, cancer appraisal and the individual adjustment of patients, parents and siblings. METHODS: Participants were 60 children with leukemia or non-Hodgkin lymphoma, 172 parents and 78 siblings (115 families). Time since diagnosis varied from zero to 33 months. Patients, parents and siblings completed the Family Environment Scale (FES), Perceived Stress Scale, Situation-Specific Emotional Reactions Questionnaire and Pediatric Quality of Life Inventory/Maudsley Marital Questionnaire. RESULTS: Family functioning and the appraisal of the cancer diagnosis proved to be related to patients', parents' and siblings' cancer-related emotions and quality of life post-diagnosis. In addition, family members differed in their perception of some family functioning domains, the appraisal of the cancer diagnosis, positive feelings and quality of life. DISCUSSION: Our findings led to the conclusion that family functioning and the appraisal of the cancer diagnosis are important for the individual adjustment of patients, parents and siblings when facing a diagnosis of cancer in the child. Differences across members within one family and differences between families speak to the need of screening all family members and intervening at the level of individual as well as the family unit.
RESUMEN
OBJECTIVES: Pediatric cancer is a life-threatening disease that poses significant challenges to the life of all family members (diagnosed child, parents, and siblings) and the family as a whole. To date, limited research has investigated family adjustment when facing pediatric cancer. The aim of the current study was to explore the role of protective factors at the individual (parental psychological flexibility), intrafamilial (dyadic coping) and contextual level (network support) in explaining family adjustment as perceived by parents of children with leukemia or non-Hodgkin lymphoma. In addition, we were interested to see whether these protective factors could be predictive for family adjustment at a later time point. METHOD: Participants were 70 mothers and 53 fathers (80 families) of children with leukemia or non-Hodgkin lymphoma. Mean time since diagnosis was 5.26 (T1) and 18.86 (T2) months post-diagnosis. Parents completed the Acceptance and Action Questionnaire II (to assess psychological flexibility), Dyadic Coping Inventory, a network support questionnaire, Impact on Family Scale and the Family Adjustment Scale. Both concurrent and prospective association models were tested. RESULTS: Psychological flexibility, dyadic coping and network support proved to be cross-sectionally and positively related to parents' perception of family adjustment post-diagnosis; psychological flexibility and dyadic coping proved to predict better family adjustment over time. CONCLUSION: Our findings led to the conclusion that protective factors at all three levels (individual, intrafamilial and contextual) are important for explaining family adjustment as perceived by parents facing a diagnosis of cancer in their child. Interventions targeting the individual, couple, as well as family level are warranted to enhance family adjustment.
RESUMEN
Dendritic cell-based and other vaccination strategies that use the patient's own immune system for the treatment of cancer are gaining momentum. Most studies of therapeutic cancer vaccination have been performed in adults. However, since cancer is one of the leading causes of death among children past infancy in the Western world, the hope is that this form of active specific immunotherapy can play an important role in the pediatric population as well. Since children have more vigorous and adaptable immune systems than adults, therapeutic cancer vaccines are expected to have a better chance of creating protective immunity and preventing cancer recurrence in pediatric patients. Moreover, in contrast to conventional cancer treatments such as chemotherapy, therapeutic cancer vaccines are designed to specifically target tumor cells and not healthy cells or tissues. This reduces the likelihood of side effects, which is an important asset in this vulnerable patient population. In this review, we present an overview of the different therapeutic cancer vaccines that have been studied in the pediatric population, with a main focus on dendritic cell-based strategies. In addition, new approaches that are currently being investigated in clinical trials are discussed to provide guidance for further improvement and optimization of pediatric cancer vaccines.
RESUMEN
Paediatric Strategy Forums have been created by the multistakeholder organisation, ACCELERATE, and the European Medicines Agency to facilitate dialogue between all relevant stakeholders and suggest strategies in critical areas of paediatric oncology drug development. As there are many medicines being developed for B-cell malignancies in adults but comparatively few in children with these malignancies, a Paediatric Strategy Forum was held to discuss the best approach to develop these products for children. It was concluded that as current frontline therapy is highly successful, despite associated acute toxicity, de-escalation of this or substitution of presently used drugs with new medicines can only be undertaken when there is an effective salvage regimen, which is currently not available. Therefore priority should be given to developing treatment for patients with relapsed and refractory mature B-cell lymphomas. The consensus of the clinicians attending the meeting was that CAR T-cells, T-cell engagers and antibody drug conjugates (excluding those with a vinca alkaloid-like drug) presently have the greatest probability of providing benefit in relapse in view of their mechanism of action. However, as producing autologous CAR T-cells currently takes at least 4 weeks, they are not products which could be quickly employed initially at relapse in rapidly progressing mature B-cell malignancies but only for the consolidation phase of the treatment. Global, industry-supported, academic-sponsored studies testing compounds from different pharmaceutical companies simultaneously should be considered in rare populations, and it was proposed that an international working group be formed to develop an overarching clinical trials strategy for these disease groups. Future Forums are planned for other relevant paediatric oncologic diseases with a high unmet medical need and relevant molecular targets.
Asunto(s)
Antineoplásicos/uso terapéutico , Desarrollo de Medicamentos , Linfoma de Células B/tratamiento farmacológico , Adolescente , Adulto , Linfocitos B/efectos de los fármacos , Niño , Europa (Continente) , Agencias Gubernamentales , Humanos , Evaluación de Necesidades , América del Norte , Planificación de Atención al PacienteRESUMEN
Behaviors are complex traits influenced by multiple pleiotropic genes. Understanding the mechanisms that give rise to complex behaviors requires an understanding of how variation in transcriptional regulation shapes nervous system development and how variation in brain structure influences an organism's ability to respond to its environment. To begin to address this problem, we used olfactory behavior in Drosophila melanogaster as a model and showed that a hypomorphic transposon-mediated mutation of the early developmental gene Semaphorin-5c (Sema-5c) results in aberrant behavioral responses to the repellant odorant benzaldehyde. We fine mapped this effect to the Sema-5c locus using deficiency mapping, phenotypic reversion through P-element excision, and transgenic rescue. Morphometric analysis of this Sema-5c allele reveals subtle neuroanatomical changes in the brain with a reduction in the size of the ellipsoid body. High-density oligonucleotide expression microarrays identified 50 probe sets with altered transcriptional regulation in the Sema-5c background and quantitative complementation tests identified epistatic interactions between nine of these coregulated genes and the transposon-disrupted Sema-5c gene. Our results demonstrate how hypomorphic mutation of an early developmental gene results in genomewide transcriptional consequences and alterations in brain structure accompanied by profound impairment of adult behavior.
Asunto(s)
Proteínas de Drosophila/genética , Drosophila melanogaster/fisiología , Regulación del Desarrollo de la Expresión Génica , Glicoproteínas de Membrana/genética , Semaforinas/genética , Olfato/fisiología , Envejecimiento/fisiología , Animales , Animales Modificados Genéticamente , Anticuerpos Monoclonales , Reacción de Prevención , Conducta Animal , Benzaldehídos , Moléculas de Adhesión Celular Neuronal/inmunología , Cruzamientos Genéticos , Drosophila melanogaster/genética , Drosophila melanogaster/crecimiento & desarrollo , Mutación , OdorantesRESUMEN
BACKGROUND: Market forces may not be sufficient to stimulate research and development of medicines for small patient populations, such as children and patients with rare diseases. Both the European Union Orphan and Paediatric Regulations were introduced to address the unmet public health needs of these smaller patient populations through the use of incentives, rewards and obligations. Developers for new medicines for rare diseases must agree a paediatric investigation plan (PIP) or waiver with the European Medicines Agency's (EMA) Paediatric Committee (PDCO), and can also apply for an orphan designation (OD) from the EMA's Committee of Orphan Medicinal Products (COMP). The scope of both the OD and the PIP (or waiver) is defined by the agreed condition. OBJECTIVES: The aim of this study was to analyse the approach of PDCO and COMP in defining the appropriate condition for a PIP or OD, respectively, in order to investigate potential challenges in the paediatric development of orphan medicines which have to meet the requirements of both legislations. METHODS: A comparative analysis of PIP conditions and OD conditions was performed for medicines that have been reviewed by both Committees. RESULTS: We found that in the substantial majority of cases there is no divergence between the conclusions of COMP and PDCO with regard to the condition for which a medicine is to be developed. CONCLUSION: These findings demonstrate that a collaborative approach allows both Regulations to work synergistically to foster pharmaceutical development for rare diseases in childhood.
Asunto(s)
Desarrollo de Medicamentos/legislación & jurisprudencia , Producción de Medicamentos sin Interés Comercial/legislación & jurisprudencia , Enfermedades Raras/tratamiento farmacológico , Niño , Industria Farmacéutica/legislación & jurisprudencia , Europa (Continente) , Unión Europea , Humanos , Legislación de MedicamentosRESUMEN
BACKGROUND: The identification of the function of all genes that contribute to specific biological processes and complex traits is one of the major challenges in the postgenomic era. One approach is to employ forward genetic screens in genetically tractable model organisms. In Drosophila melanogaster, P element-mediated insertional mutagenesis is a versatile tool for the dissection of molecular pathways, and there is an ongoing effort to tag every gene with a P element insertion. However, the vast majority of P element insertion lines are viable and fertile as homozygotes and do not exhibit obvious phenotypic defects, perhaps because of the tendency for P elements to insert 5' of transcription units. Quantitative genetic analysis of subtle effects of P element mutations that have been induced in an isogenic background may be a highly efficient method for functional genome annotation. RESULTS: Here, we have tested the efficacy of this strategy by assessing the extent to which screening for quantitative effects of P elements on sensory bristle number can identify genes affecting neural development. We find that such quantitative screens uncover an unusually large number of genes that are known to function in neural development, as well as genes with yet uncharacterized effects on neural development, and novel loci. CONCLUSIONS: Our findings establish the use of quantitative trait analysis for functional genome annotation through forward genetics. Similar analyses of quantitative effects of P element insertions will facilitate our understanding of the genes affecting many other complex traits in Drosophila.