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Diffuse Intrinsic Pontine Gliomas (DIPGs) are deadly paediatric brain tumours where needle biopsies help guide diagnosis and targeted therapies. To address spatial heterogeneity, here we analyse 134 specimens from various neuroanatomical structures of whole autopsy brains from nine DIPG patients. Evolutionary reconstruction indicates histone 3 (H3) K27M—including H3.2K27M—mutations potentially arise first and are invariably associated with specific, high-fidelity obligate partners throughout the tumour and its spread, from diagnosis to end-stage disease, suggesting mutual need for tumorigenesis. These H3K27M ubiquitously-associated mutations involve alterations in TP53 cell-cycle ( TP53/PPM1D ) or specific growth factor pathways ( ACVR1/PIK3R1 ). Later oncogenic alterations arise in sub-clones and often affect the PI3K pathway. Our findings are consistent with early tumour spread outside the brainstem including the cerebrum. The spatial and temporal homogeneity of main driver mutations in DIPG implies they will be captured by limited biopsies and emphasizes the need to develop therapies specifically targeting obligate oncohistone partnerships. Diffuse Intrinsic Pontine Gliomas are diagnosed by sampling a small portion of the tumour. Here, using multiple samples from tumours, the authors analyse the spatial and temporal distribution of driver mutations revealing that H3K27M mutations arise first in tumorigenesis followed by a specific invariable sequence of driver mutations, which are homogeneously distributed across the tumour mass.

It is assumed that anti-CTLA-4 antibodies cause tumor rejection by blocking negative signaling from B7-CTLA-4 interactions. Surprisingly, at concentrations considerably higher than plasma levels achieved by clinically effective dosing, the anti-CTLA-4 antibody Ipilimumab blocks neither B7 trans-endocytosis by CTLA-4 nor CTLA-4 binding to immobilized or cell-associated B7. Consequently, Ipilimumab does not increase B7 on dendritic cells (DCs) from either CTLA4 gene humanized ( Ctla4 h/h ) or human CD34 + stem cell-reconstituted NSG™ mice. In Ctla4 h/m mice expressing both human and mouse CTLA4 genes, anti-CTLA-4 antibodies that bind to human but not mouse CTLA-4 efficiently induce Treg depletion and Fc receptor-dependent tumor rejection. The blocking antibody L3D10 is comparable to the non-blocking Ipilimumab in causing tumor rejection. Remarkably, L3D10 progenies that lose blocking activity during humanization remain fully competent in inducing Treg depletion and tumor rejection. Anti-B7 antibodies that effectively block CD4 T cell activation and de novo CD8 T cell priming in lymphoid organs do not negatively affect the immunotherapeutic effect of Ipilimumab. Thus, clinically effective anti-CTLA-4 mAb causes tumor rejection by mechanisms that are independent of checkpoint blockade but dependent on the host Fc receptor. Our data call for a reappraisal of the CTLA-4 checkpoint blockade hypothesis and provide new insights for the next generation of safe and effective anti-CTLA-4 mAbs.

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 β (TGF-β). Here, we address this challenge in in vitro models of MB. Methods CB-derived NK cells were modified to express a dominant negative TGF-β 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-β-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-β (decreased TGF-β 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-β DNRII may have a functional advantage over unmodified NK cells in the presence of TGF-β-rich MB, warranting further investigation on its potential applications for patients with medulloblastoma.

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.

Models of attention demonstrated the existence of top-down, bottom-up, and history-driven attentional mechanisms, controlled by partially segregated networks of brain areas. However, few studies have examined the specific deficits in those attentional mechanisms in intellectual disability within the same experimental setting. The aim of the current study was to specify the attentional deficits in intellectual disability in top-down, bottom-up, and history-driven processing of multisensory stimuli, and gain insight into effective attentional cues that could be utilized in cognitive training programs for intellectual disability. The performance of adults with mild to moderate intellectual disability (n = 20) was compared with that of typically developing controls (n = 20) in a virtual reality visual search task. The type of a spatial cue that could aid search performance was manipulated to be either endogenous or exogenous in different sensory modalities (visual, auditory, tactile). The results identified that attentional deficits in intellectual disability are overall more pronounced in top-down rather than in bottom-up processing, but with different magnitudes across cue types: The auditory or tactile endogenous cues were much less effective than the visual endogenous cue in the intellectual disability group. Moreover, the history-driven processing in intellectual disability was altered, such that a reversed priming effect was observed for immediate repetitions of the same cue type. These results suggest that the impact of intellectual disability on attentional processing is specific to attentional mechanisms and cue types, which has theoretical as well as practical implications for developing effective cognitive training programs for the target population.

Pediatric central nervous system tumors are the most common solid malignancies in childhood, and aggressive therapy often leads to long-term sequelae in survivors, making these tumors challenging to treat. Immunotherapy has revolutionized prospects for many cancer types in adults, but the intrinsic complexity of treating pediatric patients and the scarcity of clinical studies of children to inform effective approaches have hampered the development of effective immunotherapies in pediatric settings. Here, we review recent advances and ongoing challenges in pediatric brain cancer immunotherapy, as well as considerations for efficient clinical translation of efficacious immunotherapies into pediatric settings.

Pediatric brain tumors are the leading cause of cancer-related death in children. Recent advances in sequencing techniques, and collaborative efforts to encode the mutational landscape of various tumor subtypes, have resulted in the identification of recurrent mutations that may present as actionable targets in these tumors. A number of molecularly targeted agents are approved or in development for the treatment of various tumor types in adult patients. Similarly, these agents are increasingly being incorporated into pediatric clinical trials, allowing for a targeted approach to treatment. However, due to the genetic heterogeneity of these tumors, focused clinical trials in pediatric patients are challenging and regulatory hurdles may delay access to therapeutic compounds that are in regular use in adult patients. The tumor site-agnostic clinical development of TRK inhibitors for pediatric solid tumors is a current example of how the combination of genetic testing and innovative clinical trial design can accelerate the clinical development of targeted agents for pediatric patients.

We describe a case of novel use of trametinib in treating arrythmia without concomitant cardiomyopathy. Our patient is a two-year-old female born with Costello syndrome due to heterozygous mutations in the HRAS gene c34 G > T p (G12C). Shortly after birth, she was diagnosed with multifocal atrial tachyarrhythmia. Her imaging studies have shown no hypertrophy or CHD. There was poor arrhythmia control despite triple antiarrhythmic therapy. Trametinib, a MEK1 and MEK2 inhibitor, was used in treating her isolated atrial arrythmia, allowing her to wean off other antiarrhythmics. Other case reports have shown trametinib to benefit certain RASopathy patients with lymphatic abnormalities, hypertrophic cardiomyopathy, and concurrent arrhythmias. This case demonstrates effective treatment of isolated arrhythmia without cardiomyopathy, broadening the potential indications for use of trametinib in certain RASopathy patients.

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. 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. 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. 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. 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.

Bioluminescence resonance energy transfer (BRET) techniques offer a high degree of sensitivity, reliability and ease of use for their application to sensing biomolecules. BRET is a distance dependent, non-radiative energy transfer, which uses a bioluminescent protein to excite an acceptor through the resonance energy transfer. A BRET sensor can quickly detect the change of a target biomolecule quantitatively without an external electromagnetic field, e.g., UV light, which normally can damage tissue. Having been developed quite recently, this technique has evolved rapidly. Here, different bioluminescent proteins have been reviewed. In addition to a multitude of bioluminescent proteins, this manuscript focuses on the recent development of BRET sensors by utilizing quantum dots. The special size-dependent properties of quantum dots have made the BRET sensing technique attractive for the real-time monitoring of the changes of target molecules and bioimaging in vivo. This review offers a look into the basis of the technique, donor/acceptor pairs, experimental applications and prospects.