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1.
Cell ; 187(10): 2521-2535.e21, 2024 May 09.
Artículo en Inglés | MEDLINE | ID: mdl-38697107

RESUMEN

Cancer immunotherapy remains limited by poor antigenicity and a regulatory tumor microenvironment (TME). Here, we create "onion-like" multi-lamellar RNA lipid particle aggregates (LPAs) to substantially enhance the payload packaging and immunogenicity of tumor mRNA antigens. Unlike current mRNA vaccine designs that rely on payload packaging into nanoparticle cores for Toll-like receptor engagement in immune cells, systemically administered RNA-LPAs activate RIG-I in stromal cells, eliciting massive cytokine/chemokine response and dendritic cell/lymphocyte trafficking that provokes cancer immunogenicity and mediates rejection of both early- and late-stage murine tumor models. In client-owned canines with terminal gliomas, RNA-LPAs improved survivorship and reprogrammed the TME, which became "hot" within days of a single infusion. In a first-in-human trial, RNA-LPAs elicited rapid cytokine/chemokine release, immune activation/trafficking, tissue-confirmed pseudoprogression, and glioma-specific immune responses in glioblastoma patients. These data support RNA-LPAs as a new technology that simultaneously reprograms the TME while eliciting rapid and enduring cancer immunotherapy.


Asunto(s)
Inmunoterapia , Lípidos , ARN , Microambiente Tumoral , Animales , Perros , Femenino , Humanos , Ratones , Antígenos de Neoplasias/inmunología , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/inmunología , Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/uso terapéutico , Línea Celular Tumoral , Citocinas/metabolismo , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Glioblastoma/terapia , Glioblastoma/inmunología , Glioma/terapia , Glioma/inmunología , Inmunoterapia/métodos , Ratones Endogámicos C57BL , Neoplasias/terapia , Neoplasias/inmunología , ARN/química , ARN/uso terapéutico , ARN Mensajero/metabolismo , ARN Mensajero/genética , Lípidos/química
2.
Cell ; 168(5): 817-829.e15, 2017 02 23.
Artículo en Inglés | MEDLINE | ID: mdl-28215705

RESUMEN

Investigating therapeutic "outliers" that show exceptional responses to anti-cancer treatment can uncover biomarkers of drug sensitivity. We performed preclinical trials investigating primary murine acute myeloid leukemias (AMLs) generated by retroviral insertional mutagenesis in KrasG12D "knockin" mice with the MEK inhibitor PD0325901 (PD901). One outlier AML responded and exhibited intrinsic drug resistance at relapse. Loss of wild-type (WT) Kras enhanced the fitness of the dominant clone and rendered it sensitive to MEK inhibition. Similarly, human colorectal cancer cell lines with increased KRAS mutant allele frequency were more sensitive to MAP kinase inhibition, and CRISPR-Cas9-mediated replacement of WT KRAS with a mutant allele sensitized heterozygous mutant HCT116 cells to treatment. In a prospectively characterized cohort of patients with advanced cancer, 642 of 1,168 (55%) with KRAS mutations exhibited allelic imbalance. These studies demonstrate that serial genetic changes at the Kras/KRAS locus are frequent in cancer and modulate competitive fitness and MEK dependency.


Asunto(s)
Antineoplásicos/uso terapéutico , Benzamidas/uso terapéutico , Neoplasias Colorrectales/genética , Difenilamina/análogos & derivados , Sistema de Señalización de MAP Quinasas , Proteínas Proto-Oncogénicas p21(ras)/genética , Animales , Antineoplásicos/farmacología , Benzamidas/farmacología , Línea Celular Tumoral , Evolución Clonal , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Difenilamina/farmacología , Difenilamina/uso terapéutico , Resistencia a Antineoplásicos , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Ratones , Mutación , Retroviridae
3.
Curr Oncol Rep ; 25(8): 847-855, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37160547

RESUMEN

PURPOSE OF REVIEW: Correlative studies should leverage clinical trial frameworks to conduct biospecimen analyses that provide insight into the bioactivity of the intervention and facilitate iteration toward future trials that further improve patient outcomes. In pediatric cellular immunotherapy trials, correlative studies enable deeper understanding of T cell mobilization, durability of immune activation, patterns of toxicity, and early detection of treatment response. Here, we review the correlative science in adoptive cell therapy (ACT) for childhood central nervous system (CNS) tumors, with a focus on existing chimeric antigen receptor (CAR) and T cell receptor (TCR)-expressing T cell therapies. RECENT FINDINGS: We highlight long-standing and more recently understood challenges for effective alignment of correlative data and offer practical considerations for current and future approaches to multi-omic analysis of serial tumor, serum, and cerebrospinal fluid (CSF) biospecimens. We highlight the preliminary success in collecting serial cytokine and proteomics from patients with CNS tumors on ACT clinical trials.


Asunto(s)
Neoplasias del Sistema Nervioso Central , Receptores Quiméricos de Antígenos , Humanos , Niño , Inmunoterapia Adoptiva , Neoplasias del Sistema Nervioso Central/terapia , Receptores de Antígenos de Linfocitos T/genética , Linfocitos T
4.
Acta Neuropathol ; 141(5): 771-785, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33619588

RESUMEN

Recent genomic studies have shed light on the biology and inter-tumoral heterogeneity underlying pineal parenchymal tumors, in particular pineoblastomas (PBs) and pineal parenchymal tumors of intermediate differentiation (PPTIDs). Previous reports, however, had modest sample sizes and lacked the power to integrate molecular and clinical findings. The different proposed molecular group structures also highlighted a need to reach consensus on a robust and relevant classification system. We performed a meta-analysis on 221 patients with molecularly characterized PBs and PPTIDs. DNA methylation profiles were analyzed through complementary bioinformatic approaches and molecular subgrouping was harmonized. Demographic, clinical, and genomic features of patients and samples from these pineal tumor groups were annotated. Four clinically and biologically relevant consensus PB groups were defined: PB-miRNA1 (n = 96), PB-miRNA2 (n = 23), PB-MYC/FOXR2 (n = 34), and PB-RB1 (n = 25). A final molecularly distinct group, designated PPTID (n = 43), comprised histological PPTID and PBs. Genomic and transcriptomic profiling allowed the characterization of oncogenic drivers for individual tumor groups, specifically, alterations in the microRNA processing pathway in PB-miRNA1/2, MYC amplification and FOXR2 overexpression in PB-MYC/FOXR2, RB1 alteration in PB-RB1, and KBTBD4 insertion in PPTID. Age at diagnosis, sex predilection, and metastatic status varied significantly among tumor groups. While patients with PB-miRNA2 and PPTID had superior outcome, survival was intermediate for patients with PB-miRNA1, and dismal for those with PB-MYC/FOXR2 or PB-RB1. Reduced-dose CSI was adequate for patients with average-risk, PB-miRNA1/2 disease. We systematically interrogated the clinical and molecular heterogeneity within pineal parenchymal tumors and proposed a consensus nomenclature for disease groups, laying the groundwork for future studies as well as routine use in tumor diagnostic classification and clinical trial stratification.


Asunto(s)
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Glándula Pineal/patología , Pinealoma/genética , Pinealoma/patología , Adolescente , Adulto , Niño , Preescolar , Estudios de Cohortes , Metilación de ADN , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Transcriptoma , Adulto Joven
5.
Pediatr Blood Cancer ; 68(2): e28756, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33025730

RESUMEN

BACKGROUND: Central nervous system (CNS) malignancies are the most common solid tumors among children, and novel therapies are needed to help improve survival. Pomalidomide is an immunomodulatory agent that displays antiangiogenic and cytotoxic activity, making it an appropriate candidate to explore in pediatric CNS tumors. METHODS: A phase 1 first in pediatric trial of pomalidomide was conducted in children with recurrent, progressive, and refractory CNS tumors. The primary objective was to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) when given orally once daily for 21 consecutive days of a 28-day cycle. Once the MTD was established, 12 additional patients were enrolled on expansion cohorts based on age and steroid use. RESULTS: Twenty-nine children were enrolled and 25 were evaluable for dose-limiting toxicity (DLT). The MTD was 2.6 mg/m2 (dose level 2). Four DLTs were observed in three patients at dose level 3 (3.4 mg/m2 ) includeding grade 3 diarrhea, grade 3 thrombocytopenia, grade 3 lung infection, and grade 4 neutropenia. The most common adverse events were grade 1 and 2 myelosuppression. One patient with an oligodendroglioma had stable disease for nine cycles, and a second patient with an anaplastic pleomorphic xanthoastrocytoma achieved a sustained partial response. Immunologic analyses suggested that pomalidomide triggers immunomodulation. CONCLUSIONS: The MTD of pomalidomide is 2.6 mg/m2 . It was well tolerated, and immune correlates showed a serum immune response. These data led to an industry-sponsored phase 2 trial of pomalidomide monotherapy in children with recurrent brain tumors (NCT03257631).


Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Talidomida/análogos & derivados , Adolescente , Inhibidores de la Angiogénesis/farmacocinética , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Neoplasias del Sistema Nervioso Central/mortalidad , Neoplasias del Sistema Nervioso Central/patología , Niño , Preescolar , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Inmunomodulación/efectos de los fármacos , Masculino , Talidomida/farmacocinética , Talidomida/uso terapéutico , Adulto Joven
6.
Pediatr Blood Cancer ; 68(4): e28879, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33405376

RESUMEN

BACKGROUND: Disruption of cell-cycle regulators is a potential therapeutic target for brain tumors in children and adolescents. The aim of this study was to determine the maximum tolerated dose (MTD) and describe toxicities related to palbociclib, a selective cyclin-dependent kinase 4/6 (CDK4/6) inhibitor in pediatric patients with progressive/refractory brain tumors with intact retinoblastoma protein. METHODS: Palbociclib was administered orally starting at 50 mg/m2 daily for the first 21 days of a 28-day course. Dose escalation was according to the Rolling-6 statistical design in less heavily (stratum I) and heavily pretreated (stratum II) patients, and MTD was determined separately for each group. Pharmacokinetic studies were performed during the first course, and pharmacodynamic studies were conducted to evaluate relationships between drug levels and toxicities. RESULTS: A total of 21 patients were enrolled on stratum I and 14 patients on stratum II. The MTD for both strata was 75 mg/m2 . Palbociclib absorption (mean Tmax between 4.9 and 6.6 h) and elimination (mean half-life between 11.3 and 19.5 h) were assessed. The most common toxicity was myelosuppression. Higher palbociclib exposure was associated with grade 3/4 neutropenia and leukopenia. Dose limiting toxicities included grade 4 neutropenia and grade 3 thrombocytopenia and dehydration. No patients had an objective response to palbociclib therapy. CONCLUSIONS: Palbociclib was safely administered to children and adolescents at a dosage of 75 mg/m2 for 21 consecutive days followed by seven days of rest in both strata. Future studies will establish its optimal utilization in pediatric patients with brain tumors.


Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Piperazinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridinas/uso terapéutico , Adolescente , Adulto , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Neoplasias Encefálicas/patología , Niño , Preescolar , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Piperazinas/efectos adversos , Piperazinas/farmacocinética , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacocinética , Piridinas/efectos adversos , Piridinas/farmacocinética , Adulto Joven
7.
Acta Neuropathol ; 139(2): 223-241, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31820118

RESUMEN

Pineoblastomas (PBs) are rare, aggressive pediatric brain tumors of the pineal gland with modest overall survival despite intensive therapy. We sought to define the clinical and molecular spectra of PB to inform new treatment approaches for this orphan cancer. Tumor, blood, and clinical data from 91 patients with PB or supratentorial primitive neuroectodermal tumor (sPNETs/CNS-PNETs), and 2 pineal parenchymal tumors of intermediate differentiation (PPTIDs) were collected from 29 centres in the Rare Brain Tumor Consortium. We used global DNA methylation profiling to define a core group of PB from 72/93 cases, which were delineated into five molecular sub-groups. Copy number, whole exome and targeted sequencing, and miRNA expression analyses were used to evaluate the clinico-pathologic significance of each sub-group. Tumors designated as group 1 and 2 almost exclusively exhibited deleterious homozygous loss-of-function alterations in miRNA biogenesis genes (DICER1, DROSHA, and DGCR8) in 62 and 100% of group 1 and 2 tumors, respectively. Recurrent alterations of the oncogenic MYC-miR-17/92-RB1 pathway were observed in the RB and MYC sub-group, respectively, characterized by RB1 loss with gain of miR-17/92, and recurrent gain or amplification of MYC. PB sub-groups exhibited distinct clinical features: group 1-3 arose in older children (median ages 5.2-14.0 years) and had intermediate to excellent survival (5-year OS of 68.0-100%), while Group RB and MYC PB patients were much younger (median age 1.3-1.4 years) with dismal survival (5-year OS 37.5% and 28.6%, respectively). We identified age < 3 years at diagnosis, metastatic disease, omission of upfront radiation, and chr 16q loss as significant negative prognostic factors across all PBs. Our findings demonstrate that PB exhibits substantial molecular heterogeneity with sub-group-associated clinical phenotypes and survival. In addition to revealing novel biology and therapeutics, molecular sub-grouping of PB can be exploited to reduce treatment intensity for patients with favorable biology tumors.


Asunto(s)
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Glándula Pineal , Pinealoma/genética , Pinealoma/patología , Adolescente , Adulto , Factores de Edad , Neoplasias Encefálicas/mortalidad , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , Lactante , Masculino , MicroARNs/metabolismo , Mutación/genética , Pinealoma/mortalidad , Sistema de Registros , Tasa de Supervivencia , Adulto Joven
8.
J Med Internet Res ; 22(12): e18418, 2020 12 16.
Artículo en Inglés | MEDLINE | ID: mdl-33325832

RESUMEN

BACKGROUND: Despite excellent prediction performance, noninterpretability has undermined the value of applying deep-learning algorithms in clinical practice. To overcome this limitation, attention mechanism has been introduced to clinical research as an explanatory modeling method. However, potential limitations of using this attractive method have not been clarified to clinical researchers. Furthermore, there has been a lack of introductory information explaining attention mechanisms to clinical researchers. OBJECTIVE: The aim of this study was to introduce the basic concepts and design approaches of attention mechanisms. In addition, we aimed to empirically assess the potential limitations of current attention mechanisms in terms of prediction and interpretability performance. METHODS: First, the basic concepts and several key considerations regarding attention mechanisms were identified. Second, four approaches to attention mechanisms were suggested according to a two-dimensional framework based on the degrees of freedom and uncertainty awareness. Third, the prediction performance, probability reliability, concentration of variable importance, consistency of attention results, and generalizability of attention results to conventional statistics were assessed in the diabetic classification modeling setting. Fourth, the potential limitations of attention mechanisms were considered. RESULTS: Prediction performance was very high for all models. Probability reliability was high in models with uncertainty awareness. Variable importance was concentrated in several variables when uncertainty awareness was not considered. The consistency of attention results was high when uncertainty awareness was considered. The generalizability of attention results to conventional statistics was poor regardless of the modeling approach. CONCLUSIONS: The attention mechanism is an attractive technique with potential to be very promising in the future. However, it may not yet be desirable to rely on this method to assess variable importance in clinical settings. Therefore, along with theoretical studies enhancing attention mechanisms, more empirical studies investigating potential limitations should be encouraged.


Asunto(s)
Aprendizaje Profundo/normas , Diabetes Mellitus/epidemiología , Algoritmos , Investigación Empírica , Humanos , Reproducibilidad de los Resultados , República de Corea , Proyectos de Investigación
9.
J Transl Med ; 17(1): 321, 2019 09 23.
Artículo en Inglés | MEDLINE | ID: mdl-31547819

RESUMEN

BACKGROUND: Medulloblastoma (MB), the most common pediatric brain cancer, presents with a poor prognosis in a subset of patients with high risk disease, or at recurrence, where current therapies are ineffective. Cord blood (CB) natural killer (NK) cells may be promising off-the-shelf effector cells for immunotherapy due to their recognition of malignant cells without the need for a known target, ready availability from multiple banks, and their potential to expand exponentially. However, they are currently limited by immune suppressive cytokines secreted in the MB tumor microenvironment including Transforming Growth Factor ß (TGF-ß). Here, we address this challenge in in vitro models of MB. METHODS: CB-derived NK cells were modified to express a dominant negative TGF-ß receptor II (DNRII) using retroviral transduction. The ability of transduced CB cells to maintain function in the presence of medulloblastoma-conditioned media was then assessed. RESULTS: We observed that the cytotoxic ability of nontransduced CB-NK cells was reduced in the presence of TGF-ß-rich, medulloblastoma-conditioned media (21.21 ± 1.19% killing at E:T 5:1 in the absence vs. 14.98 ± 2.11% in the presence of medulloblastoma-conditioned media, n = 8, p = 0.02), but was unaffected in CB-derived DNRII-transduced NK cells (21.11 ± 1.84% killing at E:T 5:1 in the absence vs. 21.81 ± 3.37 in the presence of medulloblastoma-conditioned media, n = 8, p = 0.85. We also observed decreased expression of CCR2 in untransduced NK cells (mean CCR2 MFI 826 ± 117 in untransduced NK + MB supernatant from mean CCR2 MFI 1639.29 ± 215 in no MB supernatant, n = 7, p = 0.0156), but not in the transduced cells. Finally, we observed that CB-derived DNRII-transduced NK cells may protect surrounding immune cells by providing a cytokine sink for TGF-ß (decreased TGF-ß levels of 610 ± 265 pg/mL in CB-derived DNRII-transduced NK cells vs. 1817 ± 342 pg/mL in untransduced cells; p = 0.008). CONCLUSIONS: CB NK cells expressing a TGF-ß DNRII may have a functional advantage over unmodified NK cells in the presence of TGF-ß-rich MB, warranting further investigation on its potential applications for patients with medulloblastoma.


Asunto(s)
Neoplasias Cerebelosas/inmunología , Células Asesinas Naturales/inmunología , Meduloblastoma/inmunología , Factor de Crecimiento Transformador beta/metabolismo , Línea Celular Tumoral , Regulación hacia Abajo , Sangre Fetal/citología , Humanos , Células Asesinas Naturales/trasplante , Pruebas de Neutralización , Receptores CCR2/metabolismo , Trasplante Homólogo
11.
Acta Neuropathol ; 136(2): 227-237, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-30019219

RESUMEN

Posterior fossa ependymoma comprise three distinct molecular variants, termed PF-EPN-A (PFA), PF-EPN-B (PFB), and PF-EPN-SE (subependymoma). Clinically, they are very disparate and PFB tumors are currently being considered for a trial of radiation avoidance. However, to move forward, unraveling the heterogeneity within PFB would be highly desirable. To discern the molecular heterogeneity within PFB, we performed an integrated analysis consisting of DNA methylation profiling, copy-number profiling, gene expression profiling, and clinical correlation across a cohort of 212 primary posterior fossa PFB tumors. Unsupervised spectral clustering and t-SNE analysis of genome-wide methylation data revealed five distinct subtypes of PFB tumors, termed PFB1-5, with distinct demographics, copy-number alterations, and gene expression profiles. All PFB subtypes were distinct from PFA and posterior fossa subependymomas. Of the five subtypes, PFB4 and PFB5 are more discrete, consisting of younger and older patients, respectively, with a strong female-gender enrichment in PFB5 (age: p = 0.011, gender: p = 0.04). Broad copy-number aberrations were common; however, many events such as chromosome 2 loss, 5 gain, and 17 loss were enriched in specific subtypes and 1q gain was enriched in PFB1. Late relapses were common across all five subtypes, but deaths were uncommon and present in only two subtypes (PFB1 and PFB3). Unlike the case in PFA ependymoma, 1q gain was not a robust marker of poor progression-free survival; however, chromosome 13q loss may represent a novel marker for risk stratification across the spectrum of PFB subtypes. Similar to PFA ependymoma, there exists a significant intertumoral heterogeneity within PFB, with distinct molecular subtypes identified. Even when accounting for this heterogeneity, extent of resection remains the strongest predictor of poor outcome. However, this biological heterogeneity must be accounted for in future preclinical modeling and personalized therapies.


Asunto(s)
Variaciones en el Número de Copia de ADN/genética , Ependimoma/clasificación , Ependimoma/genética , Neoplasias Infratentoriales/clasificación , Neoplasias Infratentoriales/genética , Adolescente , Adulto , Factores de Edad , Niño , Estudios de Cohortes , Metilación de ADN/genética , Ependimoma/patología , Ependimoma/cirugía , Femenino , Perfilación de la Expresión Génica , Humanos , Neoplasias Infratentoriales/patología , Neoplasias Infratentoriales/cirugía , Estimación de Kaplan-Meier , Masculino , Análisis por Micromatrices , Persona de Mediana Edad , Adulto Joven
12.
Pediatr Blood Cancer ; 65(2)2018 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-29090526

RESUMEN

BACKGROUND: We conducted a phase II study of oral capecitabine rapidly disintegrating tablets given concurrently with radiation therapy (RT) to assess progression-free survival (PFS) in children with newly diagnosed diffuse intrinsic pontine gliomas (DIPG). PATIENTS AND METHODS: Children 3-17 years with newly diagnosed DIPG were eligible. Capecitabine, 650 mg/m2 /dose BID (maximum tolerated dose [MTD] in children with concurrent radiation), was administered for 9 weeks starting the first day of RT. Following a 2-week break, three courses of capecitabine, 1,250 mg/m2 /dose BID for 14 days followed by a 7-day rest, were administered. As prospectively designed, 10 evaluable patients treated at the MTD on the phase I trial were included in the phase II analyses. The design was based on comparison of the PFS distribution to a contemporary historical control (n = 140) with 90% power to detect a 15% absolute improvement in the 1-year PFS with a type-1 error rate, α = 0.10. RESULTS: Forty-four patients were evaluable for the phase II objectives. Capecitabine and RT was well tolerated with low-grade palmar plantar erythrodyesthesia, increased alanine aminotransferase, cytopenias, and vomiting the most commonly reported toxicities. Findings were significant for earlier progression with 1-year PFS of 7.21% (SE = 3.47%) in the capecitabine-treated cohort versus 15.59% (SE = 3.05%) in the historical control (P = 0.007), but there was no difference for overall survival (OS) distributions (P = 0.30). Tumor enhancement at diagnosis was associated with shorter PFS and OS. Capecitabine was rapidly absorbed and converted to its metabolites. CONCLUSION: Capecitabine did not improve the outcome for children with newly diagnosed DIPG.


Asunto(s)
Neoplasias del Tronco Encefálico/terapia , Capecitabina/administración & dosificación , Quimioradioterapia , Glioma/terapia , Administración Oral , Adolescente , Neoplasias del Tronco Encefálico/diagnóstico , Niño , Preescolar , Femenino , Estudios de Seguimiento , Glioma/diagnóstico , Humanos , Masculino , Estudios Prospectivos , Comprimidos
13.
Sensors (Basel) ; 18(5)2018 May 05.
Artículo en Inglés | MEDLINE | ID: mdl-29734744

RESUMEN

Glucose sensing in diabetes diagnosis and therapy is of great importance due to the prevalence of diabetes in the world. Furthermore, glucose sensing is also critical in the food and drug industries. Sensing glucose has been accomplished through various strategies, such as electrochemical or optical methods. Novel transducers made with nanomaterials that integrate fluorescent techniques have allowed for the development of advanced glucose sensors with superior sensitivity and convenience. In this review, glucose sensing by fluorescent nanobiosensor systems is discussed. Firstly, typical fluorescence emitting/interacting nanomaterials utilized in various glucose assays are discussed. Secondly, strategies for integrating fluorescent nanomaterials and biological sensing elements are reviewed and discussed. In summary, this review highlights the applicability of fluorescent nanomaterials, which makes them ideal for glucose sensing. Insight on the future direction of fluorescent nanobiosensor systems is also provided.


Asunto(s)
Técnicas Biosensibles , Colorantes Fluorescentes/química , Glucosa/análisis , Nanoestructuras/química , Complejos de Coordinación/química , Transferencia Resonante de Energía de Fluorescencia , Grafito/química , Humanos
14.
Acta Neuropathol ; 133(1): 5-12, 2017 01.
Artículo en Inglés | MEDLINE | ID: mdl-27858204

RESUMEN

Multiple independent genomic profiling efforts have recently identified clinically and molecularly distinct subgroups of ependymoma arising from all three anatomic compartments of the central nervous system (supratentorial brain, posterior fossa, and spinal cord). These advances motivated a consensus meeting to discuss: (1) the utility of current histologic grading criteria, (2) the integration of molecular-based stratification schemes in future clinical trials for patients with ependymoma and (3) current therapy in the context of molecular subgroups. Discussion at the meeting generated a series of consensus statements and recommendations from the attendees, which comment on the prognostic evaluation and treatment decisions of patients with intracranial ependymoma (WHO Grade II/III) based on the knowledge of its molecular subgroups. The major consensus among attendees was reached that treatment decisions for ependymoma (outside of clinical trials) should not be based on grading (II vs III). Supratentorial and posterior fossa ependymomas are distinct diseases, although the impact on therapy is still evolving. Molecular subgrouping should be part of all clinical trials henceforth.


Asunto(s)
Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/terapia , Ependimoma/metabolismo , Ependimoma/terapia , Animales , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Consenso , Manejo de la Enfermedad , Ependimoma/genética , Ependimoma/patología , Humanos , Estadificación de Neoplasias
15.
Blood ; 124(26): 3947-55, 2014 Dec 18.
Artículo en Inglés | MEDLINE | ID: mdl-25361812

RESUMEN

Oncogenic NRAS mutations are highly prevalent in acute myeloid leukemia (AML). Genetic analysis supports the hypothesis that NRAS mutations cooperate with antecedent molecular lesions in leukemogenesis, but have limited independent prognostic significance. Using short hairpin RNA-mediated knockdown in human cell lines and primary mouse leukemias, we show that AML cells with NRAS/Nras mutations are dependent on continued oncogene expression in vitro and in vivo. Using the Mx1-Cre transgene to inactivate a conditional mutant Nras allele, we analyzed hematopoiesis and hematopoietic stem and progenitor cells (HSPCs) under normal and stressed conditions and found that HSPCs lacking Nras expression are functionally equivalent to normal HSPCs in the adult mouse. Treating recipient mice transplanted with primary Nras(G12D) AMLs with 2 potent allosteric mitogen-activated protein kinase kinase (MEK) inhibitors (PD0325901 or trametinib/GlaxoSmithKline 1120212) significantly prolonged survival and reduced proliferation but did not induce apoptosis, promote differentiation, or drive clonal evolution. The phosphatidylinositol 3-kinase inhibitor GDC-0941 was ineffective as a single agent and did not augment the activity of PD0325901. All mice ultimately succumbed to progressive leukemia. Together, these data validate oncogenic N-Ras signaling as a therapeutic target in AML and support testing combination regimens that include MEK inhibitors.


Asunto(s)
Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Quinasas Quinasa Quinasa PAM/metabolismo , Proteínas de Unión al GTP Monoméricas/metabolismo , Mutación , Animales , Apoptosis , Línea Celular Tumoral , Proliferación Celular , Supervivencia Celular , Genes ras , Células Madre Hematopoyéticas/citología , Humanos , Sistema de Señalización de MAP Quinasas , Ratones , Ratones Endogámicos C57BL , Proteínas de Unión al GTP Monoméricas/genética , Inhibidores de Proteínas Quinasas/química , ARN Interferente Pequeño/metabolismo , Transducción de Señal , Células Madre/citología , Transgenes
16.
Pediatr Blood Cancer ; 63(3): 547-50, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26488903

RESUMEN

A 3-year-old boy with sickle cell anemia (SCA) presented with progressive daily emesis and was found to have an anaplastic ependymoma. Radiation therapy and chemotherapy are usually employed after subtotal resections of anaplastic ependymomas, although the benefits from chemotherapy are unclear. To mitigate the risks of adjuvant treatment in this patient at risk for SCA-associated vasculopathy, renal impairment, and other end-organ damage, proton beam irradiation without chemotherapy was chosen. Scheduled packed red blood cell transfusions were instituted to maintain sickle hemoglobin levels less than 30%. This case highlights treatment complexities for malignant brain tumors in patients predisposed to treatment-related adverse effects.


Asunto(s)
Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/terapia , Neoplasias Encefálicas/complicaciones , Ependimoma/complicaciones , Neoplasias Encefálicas/diagnóstico , Preescolar , Ependimoma/diagnóstico , Humanos , Imagen por Resonancia Magnética , Masculino
17.
J Pediatr Hematol Oncol ; 38(4): 249-60, 2016 05.
Artículo en Inglés | MEDLINE | ID: mdl-26989915

RESUMEN

Great progress has been made in many areas of pediatric oncology. However, tumors of the central nervous system (CNS) remain a significant challenge. A recent explosion of data has led to an opportunity to understand better the molecular basis of these diseases and is already providing a foundation for the pursuit of rationally chosen therapeutics targeting relevant molecular pathways. The molecular biology of pediatric brain tumors is shifting from a singular focus on basic scientific discovery to a platform upon which insights are being translated into therapies.


Asunto(s)
Neoplasias del Sistema Nervioso Central , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/terapia , Neoplasias del Sistema Nervioso Central/patología , Neoplasias del Sistema Nervioso Central/terapia , Niño , Glioma , Humanos , Meduloblastoma , Biología Molecular/métodos , Biología Molecular/tendencias
18.
J Neurooncol ; 123(1): 85-91, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25859842

RESUMEN

Co-expression of ERBB2 and ERBB4, reported in 75% of pediatric ependymomas, correlates with worse overall survival. Lapatinib, a selective ERBB1 and ERBB2 inhibitor has produced prolonged disease stabilization in patients with ependymoma in a phase I study. Bevacizumab exposure in ependymoma xenografts leads to ablation of tumor self-renewing cells, arresting growth. Thus, we conducted an open-label, phase II study of bevacizumab and lapatinib in children with recurrent ependymomas. Patients ≤ 21 years of age with recurrent ependymoma received lapatinib orally twice daily (900 mg/m(2)/dose to the first 10 patients, and then 700 mg/m(2)/dose) and bevacizumab 10 mg/kg intravenously on days 1 and 15 of a 28-day course. Lapatinib serum trough levels were analyzed prior to each course. Total and phosphorylated VEGFR2 expression was measured in peripheral blood mononuclear cells (PBMCs) before doses 1 and 2 of bevacizumab and 24-48 h following dose 2 of bevacizumab. Twenty-four patients with a median age of 10 years (range 2-21 years) were enrolled; 22 were eligible and 20 evaluable for response. Thirteen had anaplastic ependymoma. There were no objective responses; 4 patients had stable disease for ≥ 4 courses (range 4-14). Grade 3 toxicities included rash, elevated ALT, and diarrhea. Grade 4 toxicities included peri-tracheostomy hemorrhage (n = 1) and elevated creatinine phosphokinase (n = 1). The median lapatinib pre-dose trough concentration was 3.72 µM. Although the combination of bevacizumab and lapatinib was well tolerated in children with recurrent ependymoma, it proved ineffective.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Ependimoma/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Terapia Recuperativa , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Bevacizumab/administración & dosificación , Niño , Preescolar , Ependimoma/patología , Femenino , Estudios de Seguimiento , Humanos , Lapatinib , Masculino , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Pronóstico , Quinazolinas/administración & dosificación , Tasa de Supervivencia , Distribución Tisular , Adulto Joven
20.
Blood ; 119(4): 1032-5, 2012 Jan 26.
Artículo en Inglés | MEDLINE | ID: mdl-22144181

RESUMEN

The palmitoylation/depalmitoylation cycle of posttranslational processing is a potential therapeutic target for selectively inhibiting the growth of hematologic cancers with somatic NRAS mutations. To investigate this question at the single-cell level, we constructed murine stem cell virus vectors and assayed the growth of myeloid progenitors. Whereas cells expressing oncogenic N-Ras(G12D) formed cytokine-independent colonies and were hypersensitive to GM-CSF, mutations within the N-Ras hypervariable region induced N-Ras mislocalization and attenuated aberrant progenitor growth. Exposing transduced hematopoietic cells and bone marrow from Nras and Kras mutant mice to the acyl protein thioesterase inhibitor palmostatin B had similar effects on protein localization and colony growth. Importantly, palmostatin B-mediated inhibition was selective for Nras mutant cells, and we mapped this activity to the hypervariable region. These data support the clinical development of depalmitoylation inhibitors as a novel class of rational therapeutics in hematologic malignancies with NRAS mutations.


Asunto(s)
Antineoplásicos/farmacología , Inhibidores Enzimáticos/farmacología , Células Madre Hematopoyéticas/efectos de los fármacos , Lipoilación/efectos de los fármacos , Palmitoil-CoA Hidrolasa/antagonistas & inhibidores , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Sustitución de Aminoácidos , Animales , Línea Celular Transformada , Cruzamientos Genéticos , Neoplasias Hematológicas/tratamiento farmacológico , Células Madre Hematopoyéticas/metabolismo , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Mutantes , Terapia Molecular Dirigida , Proteínas Mutantes/metabolismo , Concentración Osmolar , Transporte de Proteínas , Proteínas Proto-Oncogénicas p21(ras)/genética
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