A Retrospective Genomic Landscape of 661 Young Adult Glioblastomas Diagnosed Using 2016 WHO Guidelines for Central Nervous System Tumors

The authors present a cohort of 661 young adult glioblastomas diagnosed using 2016 WHO World Health Organization Classification of Tumors of the Central Nervous System, utilizing comprehensive genomic profiling (CGP) to explore their genomic landscape and assess their relationship to currently defined disease entities. This analysis explored variants with evidence of pathogenic function, common copy number variants (CNVs), and several novel fusion events not described in literature. Tumor mutational burden (TMB) mutational signatures, anatomic location, and tumor recurrence are further explored. Using data collected from CGP, unsupervised machine-learning techniques were leveraged to identify 10 genomic classes in previously assigned young adult glioblastomas. The authors relate these molecular classes to current World Health Organization guidelines and reference current literature to give therapeutic and prognostic descriptions where possible

From Fire Comes Life: Why Courts Assessing Forest Fire Damages Should Recognize Ecological Benefits

Article reflects on recent federal decisions that awarded the federal government substantial recovery for damages from forest fires caused by the negligent conduct of a private party. In traditional forest fire cases, plaintiffs typically recovered damages for response and suppression costs, in addition to compensation for the value of damaged timber or restoration costs, but not for environmental impacts. By framing the effects of forest fires as “natural resource damages” and “intangible environmental damages,” the federal government has successfully recovered increasingly large amounts for the alleged harm to the environment and the value of lost ecosystem services. But a significant point of contention is whether there is any injury to the natural environment or loss of any ecological service following an unintentional forest fire that mimics a naturally occurring fire regime. Fire is an integral part of ecological landscapes and should be distinguished from traditional natural resource damage claims because of its role as a natural disturbance event and its beneficial effects. This Article proposes that forest fire damages be evaluated under a framework based on dynamic ecological principles that factors both beneficial and adverse impacts into recovery.https://digitalcommons.mainelaw.maine.edu/student-impact-summit/1002/thumbnail.jp

From Fire Comes Life: Why Courts Assessing Forest Fire Damages Should Recognize Ecological Benefits

Article reflects on recent federal decisions that awarded the federal government substantial recovery for damages from forest fires caused by the negligent conduct of a private party. In traditional forest fire cases, plaintiffs typically recovered damages for response and suppression costs, in addition to compensation for the value of damaged timber or restoration costs, but not for environmental impacts. By framing the effects of forest fires as “natural resource damages” and “intangible environmental damages,” the federal government has successfully recovered increasingly large amounts for the alleged harm to the environment and the value of lost ecosystem services. But a significant point of contention is whether there is any injury to the natural environment or loss of any ecological service following an unintentional forest fire that mimics a naturally occurring fire regime. Fire is an integral part of ecological landscapes and should be distinguished from traditional natural resource damage claims because of its role as a natural disturbance event and its beneficial effects. This Article proposes that forest fire damages be evaluated under a framework based on dynamic ecological principles that factors both beneficial and adverse impacts into recovery.https://digitalcommons.mainelaw.maine.edu/student-impact-summit/1002/thumbnail.jp

A Case Series of Metastatic Malignant Gastrointestinal Neuroectodermal Tumors and Comprehensive Genomic Profiling Analysis of 20 Cases

Malignant gastrointestinal neuroectodermal tumor (GNET) is an ultra-rare soft tissue sarcoma, therefore often misdiagnosed and has no available standard treatment. Here, we report 3 cases of metastatic GNET with variable clinical courses. Our small case series as well as extensive literature review, further support that GNET is a spectrum of diseases with variable inherent biology and prognosis. Surgical management in the setting of recurrent/metastatic disease may be appropriate for GNET with indolent nature. Response to systemic treatments including chemotherapy and targeted treatments is variable, likely related to heterogenous biology as well. Furthermore, we retrospectively identified 20 additional GNET cases from Foundation Medicine’s genomic database and expanded on their clinicopathological and genomic features. Comprehensive genomic profiling (CGP) with DNA and RNA sequencing of this cohort, in the course of clinical care, demonstrated recurrent EWSR1 chromosomal rearrangements and a sparsity of additional recurrent or driver genomic alterations. All cases had low tumor mutational burden (TMB) and were microsatellite stable.Medicine, Faculty ofNon UBCReviewedFacultyResearche

The core domain of chemokines binds CCR5 extracellular domains while their amino terminus interacts with the transmembrane helix bundle.

CCR5 is a functional receptor for various inflammatory CC-chemokines, including macrophage inflammatory protein (MIP)-1alpha and RANTES (regulated on activation normal T cell expressed and secreted), and is the main coreceptor of human immunodeficiency viruses. The second extracellular loop and amino-terminal domain of CCR5 are critical for chemokine binding, whereas the transmembrane helix bundle is involved in receptor activation. Chemokine domains and residues important for CCR5 binding and/or activation have also been identified. However, the precise way by which chemokines interact with and activate CCR5 is presently unknown. In this study, we have compared the binding and functional properties of chemokine variants onto wild-type CCR5 and CCR5 point mutants. Several mutations in CCR5 extracellular domains (E172A, R168A, K191A, and D276A) strongly affected MIP-1alpha binding but had little effect on RANTES binding. However, a MIP/RANTES chimera, containing the MIP-1alpha N terminus and the RANTES core, bound to these mutants with an affinity similar to that of RANTES. Several CCR5 mutants affecting transmembrane helices 2 and 3 (L104F, L104F/F109H/F112Y, F85L/L104F) reduced the potency of MIP-1alpha by 10-100 fold with little effect on activation by RANTES. However, the MIP/RANTES chimera activated these mutants with a potency similar to that of MIP-1alpha. In contrast, LD78beta, a natural MIP-1alpha variant, which, like RANTES, contains a proline at position 2, activated these mutants as well as RANTES. Altogether, these results suggest that the core domains of MIP-1alpha and RANTES bind distinct residues in CCR5 extracellular domains, whereas the N terminus of chemokines mediates receptor activation by interacting with the transmembrane helix bundle.Journal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe