Medulloblastoma has a global impact on health related quality of life: Findings from an international cohort

BACKGROUND: Understanding the global impact of medulloblastoma on health related quality of life (HRQL) is critical to characterizing the broad impact of this disease and realizing the benefits of modern treatments. We evaluated HRQL in an international cohort of pediatric medulloblastoma patients. METHODS: Seventy-six patients were selected from 10 sites across North America, Europe, and Asia, who participated in the Medulloblastoma Advanced Genomics International Consortium (MAGIC). The Health Utilities Index (HUI) was administered to patients and/or parents at each site. Responses were used to determine overall HRQL and attributes (ie specific subdomains). The impact of various demographic and medical variables on HRQL was considered-including molecular subgroup. RESULTS: The majority of patients reported having moderate or severe overall burden of morbidity for both the HUI2 and HUI3 (HUI2 = 60%; HUI3 = 72.1%) when proxy-assessed. Self-care in the HUI2 was rated as higher (ie better outcome) for patients from Western versus Eastern sites, P = .02. Patients with nonmetastatic status had higher values (ie better outcomes) for the HUI3 hearing, HUI3 pain, and HUI2 pain, all P \u3c .05. Patients treated with a gross total resection also had better outcomes for the HUI3 hearing (P = .04). However, those who underwent a gross total resection reported having worse outcomes on the HUI3 vision (P = .02). No differences in HRQL were evident as a function of subgroup. CONCLUSIONS: By examining an international sample of survivors, we characterized the worldwide impact of medulloblastoma. This is a critical first step in developing global standards for evaluating long-term outcomes

Pattern of relapse and treatment response in WNT-activated medulloblastoma

Over the past decade, wingless-activated (WNT) medulloblastoma has been identified as a candidate for therapy de-escalation based on excellent survival; however, a paucity of relapses has precluded additional analyses of markers of relapse. To address this gap in knowledge, an international cohort of 93 molecularly confirmed WNT MB was assembled, where 5-year progression-free survival is 0.84 (95%, 0.763-0.925) with 15 relapsed individuals identified. Maintenance chemotherapy is identified as a strong predictor of relapse, with individuals receiving high doses of cyclophosphamide or ifosphamide having only one very late molecularly confirmed relapse (p = 0.032). The anatomical location of recurrence is metastatic in 12 of 15 relapses, with 8 of 12 metastatic relapses in the lateral ventricles. Maintenance chemotherapy, specifically cumulative cyclophosphamide doses, is a significant predictor of relapse across WNT MB. Future efforts to de-escalate therapy need to carefully consider not only the radiation dose but also the chemotherapy regimen and the propensity for metastatic relapses

Single-cell multiomics identifies clinically relevant mesenchymal stem-like cells and key regulators for MPNST malignancy

Malignant peripheral nerve sheath tumor (MPNST), a highly aggressive Schwann cell (SC)-derived soft tissue sarcoma, arises from benign neurofibroma (NF); however, the identity, heterogeneity and origins of tumor populations remain elusive. Nesti

The Stokes Phenomenon and Quantum Tunneling for de Sitter Radiation in Nonstationary Coordinates

We study quantum tunneling for the de Sitter radiation in the planar coordinates and global coordinates, which are nonstationary coordinates and describe the expanding geometry. Using the phase-integral approximation for the Hamilton-Jacobi action in the complex plane of time, we obtain the particle-production rate in both coordinates and derive the additional sinusoidal factor depending on the dimensionality of spacetime and the quantum number for spherical harmonics in the global coordinates. This approach resolves the factor of two problem in the tunneling method.Comment: LaTex 10 pages, no figur

Amicable pairs and aliquot cycles for elliptic curves

An amicable pair for an elliptic curve E/Q is a pair of primes (p,q) of good reduction for E satisfying #E(F_p) = q and #E(F_q) = p. In this paper we study elliptic amicable pairs and analogously defined longer elliptic aliquot cycles. We show that there exist elliptic curves with arbitrarily long aliqout cycles, but that CM elliptic curves (with j not 0) have no aliqout cycles of length greater than two. We give conjectural formulas for the frequency of amicable pairs. For CM curves, the derivation of precise conjectural formulas involves a detailed analysis of the values of the Grossencharacter evaluated at a prime ideal P in End(E) having the property that #E(F_P) is prime. This is especially intricate for the family of curves with j = 0.Comment: 53 page

Reconstruction of the Dark Energy equation of state

One of the main challenges of modern cosmology is to investigate the nature of dark energy in our Universe. The properties of such a component are normally summarised as a perfect fluid with a (potentially) time-dependent equation-of-state parameter $w(z)$. We investigate the evolution of this parameter with redshift by performing a Bayesian analysis of current cosmological observations. We model the temporal evolution as piecewise linear in redshift between `nodes', whose $w$-values and redshifts are allowed to vary. The optimal number of nodes is chosen by the Bayesian evidence. In this way, we can both determine the complexity supported by current data and locate any features present in $w(z)$. We compare this node-based reconstruction with some previously well-studied parameterisations: the Chevallier-Polarski-Linder (CPL), the Jassal-Bagla-Padmanabhan (JBP) and the Felice-Nesseris-Tsujikawa (FNT). By comparing the Bayesian evidence for all of these models we find an indication towards possible time-dependence in the dark energy equation-of-state. It is also worth noting that the CPL and JBP models are strongly disfavoured, whilst the FNT is just significantly disfavoured, when compared to a simple cosmological constant $w=-1$. We find that our node-based reconstruction model is slightly disfavoured with respect to the $\Lambda$CDM model.Comment: 17 pages, 5 figures, minor correction

Sex differences in brain tumor glutamine metabolism reveal sex-specific vulnerabilities to treatment

BACKGROUND: Brain cancer incidence and mortality rates are greater in males. Understanding the molecular mechanisms that underlie those sex differences could improve treatment strategies. Although sex differences in normal metabolism are well described, it is currently unknown whether they persist in cancerous tissue. METHODS: Using positron emission tomography (PET) imaging and mass spectrometry, we assessed sex differences in glioma metabolism in samples from affected individuals. We assessed the role of glutamine metabolism in male and female murine transformed astrocytes using isotope labeling, metabolic rescue experiments, and pharmacological and genetic perturbations to modulate pathway activity. FINDINGS: We found that male glioblastoma surgical specimens are enriched for amino acid metabolites, including glutamine. Fluoroglutamine PET imaging analyses showed that gliomas in affected male individuals exhibit significantly higher glutamine uptake. These sex differences were well modeled in murine transformed astrocytes, in which male cells imported and metabolized more glutamine and were more sensitive to glutaminase 1 (GLS1) inhibition. The sensitivity to GLS1 inhibition in males was driven by their dependence on glutamine-derived glutamate for α-ketoglutarate synthesis and tricarboxylic acid (TCA) cycle replenishment. Females were resistant to GLS1 inhibition through greater pyruvate carboxylase (PC)-mediated TCA cycle replenishment, and knockdown of PC sensitized females to GLS1 inhibition. CONCLUSION: Our results show that clinically important sex differences exist in targetable elements of metabolism. Recognition of sex-biased metabolism may improve treatments through further laboratory and clinical research. FUNDING: This work was supported by NIH grants, Joshua\u27s Great Things, the Siteman Investment Program, and the Barnard Research Fund

A magnetic fabric study of the Aigoual–Saint Guiral–Liron granite pluton (French Massif Central) and relationships with its associated dikes.

International audienceIn the southeastern French Massif Central, the Aigoual–Saint Guiral–Liron pluton consists of porphyritic and microgranitic types. The latter is encountered within dikes forming the northern end of the pluton. Both types show prefull crystallization microstructures indicating weak subsolidus deformations. An anisotropy of magnetic susceptibility (AMS) study has been carried out to determine the granite fabric. Biotite, local hornblende, and small grains of magnetite are the main carriers of AMS in both types. Porphyritic granite and dikes display different AMS patterns related to magma dynamics and regional deformation recorded during crystallization. In the porphyritic type, the AMS lineation is mainly consistent with the regional, NW-SE to E-W trending, extensional event coeval with emplacement and crystallization of the pluton indicating an influence of regional tectonics on the linear fabric development. The dome shaped foliation pattern of the Saint Guiral massif likely corresponds to internal deformation-related processes within the pluton. In the microgranite dike swarm, the NNE-SSW trending lineations with shallow plunges record magmatic flow processes within dikes, i.e., magma injection and filling of dikes from a probable source located southwestward. Regional tectonics played a significant role in the pluton geometry and fabric development. For example, the NE-SW trend of the dikes suggests that extensional fractures took place in the same extensional strain field as elsewhere in the pluton. Different fabric development modes were therefore responsible for the contrasted fabric patterns between the microgranite and the porphyritic granite