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[This corrects the article DOI: 10.3389/fnagi.2020.575990.].
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PURPOSE: Pyruvate kinase M2 (PKM2) catalyzes the final step in glycolysis, a key process of cancer metabolism. PKM2 is preferentially expressed by glioblastoma (GBM) cells with minimal expression in healthy brain. We describe the development, validation, and translation of a novel PET tracer to study PKM2 in GBM. We evaluated 1-((2-fluoro-6-[18F]fluorophenyl)sulfonyl)-4-((4-methoxyphenyl)sulfonyl)piperazine ([18F]DASA-23) in cell culture, mouse models of GBM, healthy human volunteers, and patients with GBM. EXPERIMENTAL DESIGN: [18F]DASA-23 was synthesized with a molar activity of 100.47 ± 29.58 GBq/µmol and radiochemical purity >95%. We performed initial testing of [18F]DASA-23 in GBM cell culture and human GBM xenografts implanted orthotopically into mice. Next, we produced [18F]DASA-23 under FDA oversight, and evaluated it in healthy volunteers and a pilot cohort of patients with glioma. RESULTS: In mouse imaging studies, [18F]DASA-23 clearly delineated the U87 GBM from surrounding healthy brain tissue and had a tumor-to-brain ratio of 3.6 ± 0.5. In human volunteers, [18F]DASA-23 crossed the intact blood-brain barrier and was rapidly cleared. In patients with GBM, [18F]DASA-23 successfully outlined tumors visible on contrast-enhanced MRI. The uptake of [18F]DASA-23 was markedly elevated in GBMs compared with normal brain, and it identified a metabolic nonresponder within 1 week of treatment initiation. CONCLUSIONS: We developed and translated [18F]DASA-23 as a new tracer that demonstrated the visualization of aberrantly expressed PKM2 for the first time in human subjects. These results warrant further clinical evaluation of [18F]DASA-23 to assess its utility for imaging therapy-induced normalization of aberrant cancer metabolism.
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Neoplasias Encefálicas , Glioblastoma , Animais , Neoplasias Encefálicas/patologia , Compostos de Diazônio , Glioblastoma/patologia , Glicólise , Humanos , Camundongos , Tomografia por Emissão de Pósitrons/métodos , Piruvato Quinase/metabolismo , Ácidos SulfanílicosRESUMO
Ageing is characterized by the development of persistent pro-inflammatory responses that contribute to atherosclerosis, metabolic syndrome, cancer and frailty1-3. The ageing brain is also vulnerable to inflammation, as demonstrated by the high prevalence of age-associated cognitive decline and Alzheimer's disease4-6. Systemically, circulating pro-inflammatory factors can promote cognitive decline7,8, and in the brain, microglia lose the ability to clear misfolded proteins that are associated with neurodegeneration9,10. However, the underlying mechanisms that initiate and sustain maladaptive inflammation with ageing are not well defined. Here we show that in ageing mice myeloid cell bioenergetics are suppressed in response to increased signalling by the lipid messenger prostaglandin E2 (PGE2), a major modulator of inflammation11. In ageing macrophages and microglia, PGE2 signalling through its EP2 receptor promotes the sequestration of glucose into glycogen, reducing glucose flux and mitochondrial respiration. This energy-deficient state, which drives maladaptive pro-inflammatory responses, is further augmented by a dependence of aged myeloid cells on glucose as a principal fuel source. In aged mice, inhibition of myeloid EP2 signalling rejuvenates cellular bioenergetics, systemic and brain inflammatory states, hippocampal synaptic plasticity and spatial memory. Moreover, blockade of peripheral myeloid EP2 signalling is sufficient to restore cognition in aged mice. Our study suggests that cognitive ageing is not a static or irrevocable condition but can be reversed by reprogramming myeloid glucose metabolism to restore youthful immune functions.
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Envelhecimento/metabolismo , Disfunção Cognitiva/prevenção & controle , Células Mieloides/metabolismo , Adulto , Idoso , Envelhecimento/efeitos dos fármacos , Envelhecimento/genética , Animais , Respiração Celular , Células Cultivadas , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/genética , Dinoprostona/metabolismo , Metabolismo Energético , Glucose/metabolismo , Glicogênio/biossíntese , Glicogênio/metabolismo , Humanos , Inflamação/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Transtornos da Memória/tratamento farmacológico , Camundongos , Microglia/efeitos dos fármacos , Microglia/imunologia , Microglia/metabolismo , Mitocôndrias/metabolismo , Células Mieloides/imunologia , Receptores de Prostaglandina E Subtipo EP2/antagonistas & inibidores , Receptores de Prostaglandina E Subtipo EP2/deficiência , Receptores de Prostaglandina E Subtipo EP2/genética , Receptores de Prostaglandina E Subtipo EP2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Memória Espacial/efeitos dos fármacosRESUMO
Stroke is the leading cause of serious long-term disability, significantly reducing mobility in almost half of the affected patients aged 65 years and older. There are currently no proven neurorestorative treatments for chronic stroke. To address the complex problem of restoring function in ischemic brain tissue, stem cell transplantation-based therapies have emerged as potential restorative therapies. Aligning with the major cell types found within the ischemic brain, stem-cell-based clinical trials for ischemic stroke have fallen under three broad cell lineages: hematopoietic, mesenchymal, and neural. In this review article, we will discuss the scientific rationale for transplanting cells from each of these lineages and provide an overview of published and ongoing trials using this framework.
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BACKGROUND: Gadolinium-based contrast agents (GBCAs) used to enhance magnetic resonance imaging (MRI) scans have been linked to tissue deposition, including in the brain. The management of indolent tumors such as meningiomas requires frequent MRI scans to monitor for interval growth. Given concern regarding GBCA deposition, we sought to determine if noncontrast MRI scans in patients with asymptomatic meningiomas were equivalent to GBCA-enhanced MRI scans in surveillance monitoring. METHODS: This institutional review board-approved retrospective chart review included 106 MRI sequences from 18 patients. Inclusion criteria were adult patients with asymptomatic meningiomas who received baseline contrast-enhanced and noncontrast axial brain MRI scan. Exclusion criteria included the following: 1) baseline or follow-up axial images were not available for review, 2) baseline scan was obtained without contrast, and 3) diagnosis of meningioma was uncertain. Percent tumor growth was measured by comparing cross-sectional area at maximum tumor diameter from the earliest and most recent scans. For each patient, change in tumor size over time was compared using T1 + contrast, T2, and T2 fluid-attenuated inversion recovery (FLAIR) sequences. These were compared with a qualitative consensus reading by a neurosurgeon and a neuroradiologist. RESULTS: Measured change of greater than 10% was taken to represent tumor growth. In 17 out of 18 patients, measurement of noncontrast studies (T2 and T2 FLAIR) matched consensus. For one patient, imaging on T2 suggested 11% growth, whereas T2 FLAIR and overall consensus was stability. CONCLUSIONS: Our study provides evidence that noncontrasted MRI scans are equivalent to contrast-weighted MRI scans to follow change in tumor size over time in asymptomatic meningiomas.
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Imageamento por Ressonância Magnética , Neoplasias Meníngeas/patologia , Meningioma/patologia , Meningioma/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Encéfalo/patologia , Meios de Contraste , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Neoplasias Meníngeas/cirurgia , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de TempoRESUMO
Glioblastoma multiforme (GBM) is a highly aggressive malignant brain tumor with fatal outcome. Tumor-associated macrophages and microglia (TAMs) have been found to be major tumor-promoting immune cells in the tumor microenvironment. Hence, modulation and reeducation of tumor-associated macrophages and microglia in GBM is considered a promising antitumor strategy. Resident microglia and invading macrophages have been shown to have distinct origin and function. Whereas yolk sac-derived microglia reside in the brain, blood-derived monocytes invade the central nervous system only under pathological conditions like tumor formation. We recently showed that disruption of the SIRPα-CD47 signaling axis is efficacious against various brain tumors including GBM primarily by inducing tumor phagocytosis. However, most effects are attributed to macrophages recruited from the periphery but the role of the brain resident microglia is unknown. Here, we sought to utilize a model to distinguish resident microglia and peripheral macrophages within the GBM-TAM pool, using orthotopically xenografted, immunodeficient, and syngeneic mouse models with genetically color-coded macrophages (Ccr2RFP) and microglia (Cx3cr1GFP). We show that even in the absence of phagocytizing macrophages (Ccr2RFP/RFP), microglia are effector cells of tumor cell phagocytosis in response to anti-CD47 blockade. Additionally, macrophages and microglia show distinct morphological and transcriptional changes. Importantly, the transcriptional profile of microglia shows less of an inflammatory response which makes them a promising target for clinical applications.
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Neoplasias Encefálicas/imunologia , Antígeno CD47/imunologia , Glioblastoma/imunologia , Microglia/imunologia , Proteínas de Neoplasias/imunologia , Neoplasias Experimentais/imunologia , Fagocitose , Receptores Imunológicos/imunologia , Transdução de Sinais/imunologia , Animais , Neoplasias Encefálicas/patologia , Antígeno CD47/genética , Glioblastoma/genética , Glioblastoma/patologia , Macrófagos/imunologia , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos Transgênicos , Microglia/patologia , Monócitos/imunologia , Monócitos/patologia , Proteínas de Neoplasias/genética , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Receptores Imunológicos/genética , Transdução de Sinais/genéticaRESUMO
OBJECTIVE: Children with neural tube defects (NTDs) require timely surgical intervention coupled with long-term management by multiple highly trained specialty healthcare teams. In resource-limited settings, outcomes are greatly affected by the lack of coordinated care. The purpose of this study was to characterize outcomes of spina bifida patients treated at Mulago National Referral Hospital (MNRH) through follow-up phone surveys. METHODS: All children presenting to MNRH with NTDs between January 1, 2014, and August 31, 2015, were eligible for this study. For those with a documented telephone number, follow-up phone surveys were conducted with the children's caregivers to assess mortality, morbidity, follow-up healthcare, and access to medical resources. RESULTS: Of the 201 patients, the vast majority (n = 185, 92%) were diagnosed with myelomeningocele. The median age at presentation was 6 days, the median length of stay was 20 days, and the median time to surgery was 10 days. Half of the patients had documented surgeries, with 5% receiving multiple procedures (n = 102, 51%): 80 defect closures (40%), 32 ventriculoperitoneal shunts (15%), and 1 endoscopic third ventriculostomy (0.5%). Phone surveys were completed for 53 patients with a median time to follow-up of 1.5 years. There were no statistically significant differences in demographics between the surveyed and nonrespondent groups. The 1-year mortality rate was 34% (n = 18). At the time of survey, 91% of the survivors (n = 30) have received healthcare since their initial discharge from MNRH, with 67% (n = 22) returning to MNRH. Hydrocephalus was diagnosed in 29 patients (88%). Caregivers reported physical deficits in 39% of patients (n = 13), clubfoot in 18% (n = 6), and bowel or bladder incontinence in 12% (n = 4). The surgical complication rate was 2.5%. Glasgow Outcome Scale-Extended pediatric revision scores were correlated with upper good recovery in 58% (n = 19) of patients, lower good recovery in 30% (n = 10), and moderate disability in 12% of patients (n = 4). Only 5 patients (15%) reported access to home health resources postdischarge. CONCLUSIONS: This study is the first to characterize the outcomes of children with NTDs that were treated at Uganda's national referral hospital. There is a great need for improved access to and coordination of care in antenatal, perioperative, and long-term settings to improve morbidity and mortality.
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Defeitos do Tubo Neural/cirurgia , Pré-Escolar , Feminino , Seguimentos , Humanos , Hidrocefalia/etiologia , Lactente , Recém-Nascido , Tempo de Internação , Masculino , Meningomielocele/cirurgia , Defeitos do Tubo Neural/complicações , Defeitos do Tubo Neural/mortalidade , Administração dos Cuidados ao Paciente , Encaminhamento e Consulta , Centros de Atenção Terciária , UgandaRESUMO
As embryonic stem cell-derived neural progenitors (NPs) have the potential to be used in cell replacement therapy, an understanding of the signaling mechanisms that regulate their terminal differentiation is imperative. In previous studies, we discovered the presence of functional mu opioid receptors (MOR) and kappa opioid receptors (KOR) in mouse embryonic stem cells and NPs. Here, MOR and KOR immunoreactivity was detected in NP-derived oligodendrocytes during three stages of their maturation in vitro. Moreover, we examined the modulation of retinoic acid-induced NP differentiation to astrocytes and neurons by mu, [D-ala(2), mephe(4), gly-ol(5)] enkephalin, or kappa, U69, 593, opioids. Both opioid agonists inhibited NP-derived neurogenesis and astrogenesis via their corresponding receptors as determined by immunocytochemistry. By administering selective inhibitors, we found that opioid inhibition of NP-derived astrogenesis was driven via extracellular-signal regulated kinase (ERK), while the p38 mitogen-activated protein kinase pathway was implicated in opioid attenuation of neurogenesis. In addition, mu and kappa opioids stimulated oligodendrogenesis from NP-derived NG2(+) oligodendrocyte progenitors via both ERK and p38 signaling pathways. Accordingly, both opioids induced ERK phosphorylation in NG2(+) cells. These results indicate that small molecules, such as MOR and KOR agonists may play a modulatory role in NP terminal differentiation.