ATRX loss in glioma results in dysregulation of cell-cycle phase transition and ATM inhibitor radio-sensitization.

ATRX, a chromatin remodeler protein, is recurrently mutated in H3F3A-mutant pediatric glioblastoma (GBM) and isocitrate dehydrogenase (IDH)-mutant grade 2/3 adult glioma. Previous work has shown that ATRX-deficient GBM cells show enhanced sensitivity to irradiation, but the etiology remains unclear. We find that ATRX binds the regulatory elements of cell-cycle phase transition genes in GBM cells, and there is a marked reduction in Checkpoint Kinase 1 (CHEK1) expression with ATRX loss, leading to the early release of G2/M entry after irradiation. ATRX-deficient cells exhibit enhanced activation of master cell-cycle regulator ATM with irradiation. Addition of the ATM inhibitor AZD0156 doubles median survival in mice intracranially implanted with ATRX-deficient GBM cells, which is not seen in ATRX-wild-type controls. This study demonstrates that ATRX-deficient high-grade gliomas (HGGs) display Chk1-mediated dysregulation of cell-cycle phase transitions, which opens a window for therapies targeting this phenotype.

Sampling the Variational Posterior with Local Refinement.

Variational inference is an optimization-based method for approximating the posterior distribution of the parameters in Bayesian probabilistic models. A key challenge of variational inference is to approximate the posterior with a distribution that is computationally tractable yet sufficiently expressive. We propose a novel method for generating samples from a highly flexible variational approximation. The method starts with a coarse initial approximation and generates samples by refining it in selected, local regions. This allows the samples to capture dependencies and multi-modality in the posterior, even when these are absent from the initial approximation. We demonstrate theoretically that our method always improves the quality of the approximation (as measured by the evidence lower bound). In experiments, our method consistently outperforms recent variational inference methods in terms of log-likelihood and ELBO across three example tasks: the Eight-Schools example (an inference task in a hierarchical model), training a ResNet-20 (Bayesian inference in a large neural network), and the Mushroom task (posterior sampling in a contextual bandit problem).

Abdominal Aorta Bullet Embolism: Presentation and Management.

Penetrating cardiac injury (PCI) secondary to a gunshot wound presents with several complications and a mortality rate of 94% before reaching the hospital. Current literature search reveals that embolism of bullet fragments after gunshot wounds are exceptionally rare. Additionally, no reported case was found regarding bullet embolism following left atrium penetration at the time of this case report. This case describes a 34-year-old male who presented to a level I trauma center after sustaining a gunshot wound to the posterior torso. Imaging demonstrated several fragments in the mid-thoracic region in addition to the primary bullet fragment located within the aorta at the bifurcation of the iliac arteries likely due to left atrial penetration and subsequent embolization.

Loss of CDKN1C in a Recurrent Atypical Teratoid/Rhabdoid Tumor.

Atypical teratoid/rhabdoid tumor (AT/RT) is a malignant tumor that is commonly associated with biallelic alterations of SMARCB1. Recurrent or refractory AT/RT has not been molecularly characterized as well. We present the case of a child with recurrent AT/RT who underwent clinically integrated molecular profiling (germline DNA and tumor DNA/RNA sequencing). This demonstrated a somatic lesion in CDKN1C alongside hallmark loss of SMARCB1. This data allowed us to explore potential personalized therapies for this patient and expose a molecular driver that may be involved in similar cases.

Survival and Proliferation of Neural Progenitor-Derived Glioblastomas Under Hypoxic Stress is Controlled by a CXCL12/CXCR4 Autocrine-Positive Feedback Mechanism.

Purpose: One likely cause of treatment failure in glioblastoma is the persistence of glioma stem-like cells (GSLCs) which are highly resistant to therapies currently employed. We found that CXCL12 has highest expression in glioma cells derived from neural progenitor cells (NPC). The development and molecular signature of NPC-derived glioblastomas were analyzed and the therapeutic effect of blocking CXCL12 was tested.Experimental Design: Tumors were induced by injecting DNA into the lateral ventricle of neonatal mice, using the Sleeping Beauty transposase method. Histology and expression of GSLC markers were analyzed during disease progression. Survival upon treatment with pharmacologic (plerixafor) or genetic inhibition of CXCR4 was analyzed. Primary neurospheres were generated and analyzed for proliferation, apoptosis, and expression of proteins regulating survival and cell-cycle progression.Results: Tumors induced from NPCs display histologic features of human glioblastoma and express markers of GSLC. In vivo, inhibiting the CXCL12/CXCR4 signaling axis results in increased survival of tumor-bearing animals. In vitro, CXCR4 blockade induces apoptosis and inhibits cell-cycle progression, downregulates molecules regulating survival and proliferation, and also blocks the hypoxic induction of HIF-1α and CXCL12. Exogenous administration of CXCL12 rescues the drug-induced decrease in proliferation.Conclusions: This study demonstrates that the CXCL12/CXCR4 axis operates in glioblastoma cells under hypoxic stress via an autocrine-positive feedback mechanism, which promotes survival and cell-cycle progression. Our study brings new mechanistic insight and encourages further exploration of the use of drugs blocking CXCL12 as adjuvant agents to target hypoxia-induced glioblastoma progression, prevent resistance to treatment, and recurrence of the disease. Clin Cancer Res; 23(5); 1250-62. ©2016 AACR.

Characterizing and targeting PDGFRA alterations in pediatric high-grade glioma.

Pediatric high-grade glioma (HGG, WHO Grade III and IV) is a devastating brain tumor with a median survival of less than two years. PDGFRA is frequently mutated/ amplified in pediatric HGG, but the significance of this finding has not been fully characterized. We hypothesize that alterations of PDGFRA will promote distinct prognostic and treatment implications in pediatric HGG. In order to characterize the impact of PDGFR pathway alterations, we integrated genomic data from pediatric HGG patients (n=290) from multiple pediatric datasets and sequencing platforms. Integration of multiple human datasets showed that PDGFRA mutation, but not amplification, was associated with older age in pediatric HGG (P= <0.0001). In multivariate analysis, PDGFRA mutation was correlated with worse prognosis (P = 0.026), while PDGFRA amplification was not (P = 0.11). By Kaplan-Meier analysis, non-brainstem HGG with PDGFRA amplification carried a worse prognosis than non-brainstem HGG without PDGFRA amplification (P = 0.021). There were no pediatric patients with PDGFRA-amplified HGG that survived longer than two years. Additionally, we performed paired molecular profiling (germline / tumor / primary cell culture) and targeting of an infant thalamic HGG with amplification and outlier increased expression of PDGFRA. Dasatinib inhibited proliferation most effectively. In summary, integration of the largest genomic dataset of pediatric HGG to date, allowed us to highlight that PDGFRA mutation is found in older pediatric patients and that PDGFRA amplification is prognostic in non-brainstem HGG. Future precision-medicine based clinical trials for pediatric patients with PDGFRA-altered HGG should consider the optimized delivery of dasatinib.

Headache and insomnia: their relation reviewed.

OBJECTIVE: Headache and insomnia are both very common and burdensome complaints worldwide. Numerous articles have been written on the relation between them, but the number of scientific articles is limited. The purpose of this review is to summarize the current scientific literature and analyze it in light of the nature of the headache-insomnia relation. METHODS: An extensive literature search was conducted using the terms, headache, migraine, insomnia, sleep, sleep deprivation, and sleep loss, on the search engines PubMed, ScienceDirect, Medline, and Google Scholar. A total of twelve research articles were found, discussing the relation of insomnia to headache in general, tension-type headache, migraine, and chronic headache. The majority of the studies are cross-sectional but two are longitudinal. RESULTS: The studies suggest an association between headache and insomnia but an asymmetrical one, with headache being more associated with insomnia than the other way around. Therefore, in the association of headache and insomnia, other factors associated with headache or migraine probably play a role, as well. CONCLUSION: As insomnia appears to be a risk factor for headache or migraine onset, insomnia patients should probably be routinely evaluated for headache. As it also seems a risk factor for increased headache frequency, in particular in tension headache and migraine, patients with these conditions should probably be routinely treated for insomnia, if present, as part of their overall management.