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Glioma-derived IL-33 orchestrates an inflammatory brain tumor microenvironment that accelerates glioma progression (2020)

De Boeck, Astrid ; Ahn, Bo Young ; D’Mello, Charlotte ; [et al.]

Springer Nature

In: Nature Communications. 2020; 11(1): 4997. Published 2020 Oct 05. doi: 10.1038/s41467-020-18569-4.

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Publication Date: 2020-10-05

Description: Despite a deeper molecular understanding, human glioblastoma remains one of the most treatment refractory and fatal cancers. It is known that the presence of macrophages and microglia impact glioblastoma tumorigenesis and prevent durable response. Herein we identify the dual function cytokine IL-33 as an orchestrator of the glioblastoma microenvironment that contributes to tumorigenesis. We find that IL-33 expression in a large subset of human glioma specimens and murine models correlates with increased tumor-associated macrophages/monocytes/microglia. In addition, nuclear and secreted functions of IL-33 regulate chemokines that collectively recruit and activate circulating and resident innate immune cells creating a pro-tumorigenic environment. Conversely, loss of nuclear IL-33 cripples recruitment, dramatically suppresses glioma growth, and increases survival. Our data supports the paradigm that recruitment and activation of immune cells, when instructed appropriately, offer a therapeutic strategy that switches the focus from the cancer cell alone to one that includes the normal host environment.

Electronic ISSN: 2041-1723

Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics

Published by Springer Nature

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The transcriptional landscape of Shh medulloblastoma (2021)

Skowron, Patryk ; Farooq, Hamza ; Cavalli, Florence M. G. ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 1749. Published 2021 Mar 19. doi: 10.1038/s41467-021-21883-0.

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Publication Date: 2021-03-19

Description: Sonic hedgehog medulloblastoma encompasses a clinically and molecularly diverse group of cancers of the developing central nervous system. Here, we use unbiased sequencing of the transcriptome across a large cohort of 250 tumors to reveal differences among molecular subtypes of the disease, and demonstrate the previously unappreciated importance of non-coding RNA transcripts. We identify alterations within the cAMP dependent pathway (GNAS, PRKAR1A) which converge on GLI2 activity and show that 18% of tumors have a genetic event that directly targets the abundance and/or stability of MYCN. Furthermore, we discover an extensive network of fusions in focally amplified regions encompassing GLI2, and several loss-of-function fusions in tumor suppressor genes PTCH1, SUFU and NCOR1. Molecular convergence on a subset of genes by nucleotide variants, copy number aberrations, and gene fusions highlight the key roles of specific pathways in the pathogenesis of Sonic hedgehog medulloblastoma and open up opportunities for therapeutic intervention.

Electronic ISSN: 2041-1723

Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics

Published by Springer Nature

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Biomechanical Consequences of Tibial Insert Thickness after Total Knee Arthroplasty: A Musculoskeletal Simulation Study (2021)

Tzanetis, Periklis ; Marra, Marco A. ; Fluit, René ; [et al.]

Molecular Diversity Preservation International

In: Applied Sciences. 2021; 11(5): 2423. Published 2021 Mar 09. doi: 10.3390/app11052423.

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Publication Date: 2021-03-09

Description: The thickness of the tibial polyethylene (PE) insert is a critical parameter to ensure optimal soft-tissue balancing in the intraoperative decision-making procedure of total knee arthroplasty (TKA). However, there is a paucity of information about the kinetic response to PE insert thickness variations in the tibiofemoral (TF) joint, and subsequently, the secondary effects on the patellofemoral (PF) biomechanics. Therefore, the purpose of this study was to investigate the influence of varying PE insert thickness on the ligament and TF compressive forces, as well as on the PF forces and kinematics, after a cruciate-retaining TKA. A previous patient-specific musculoskeletal model of TKA was adapted to simulate a chair-rising motion in which PE insert thickness was varied with 2 mm increments or decrements compared to the reference case (9 mm), from 5 mm up to 13 mm. Greater PE insert thickness resulted in higher ligament forces and concurrently increased the TF compressive force by 21% (13 mm), but slightly unloaded the PF joint with 7% (13 mm) while shifting the patella distally in the trochlear groove, compared to the reference case. Thinner PE inserts showed an opposite trend. Our findings suggest that the optimal PE insert thickness selection is a trade-off between the kinetic outcomes of the TF and PF joints.

Electronic ISSN: 2076-3417

Topics: Natural Sciences in General

Published by Molecular Diversity Preservation International

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Sex differences in oncogenic mutational processes (2020)

Li, Constance H. ; Prokopec, Stephenie D. ; Sun, Ren X. ; [et al.]

Springer Nature

In: Nature Communications. 2020; 11(1): 4330. Published 2020 Aug 28. doi: 10.1038/s41467-020-17359-2.

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Publication Date: 2020-08-28

Description: Sex differences have been observed in multiple facets of cancer epidemiology, treatment and biology, and in most cancers outside the sex organs. Efforts to link these clinical differences to specific molecular features have focused on somatic mutations within the coding regions of the genome. Here we report a pan-cancer analysis of sex differences in whole genomes of 1983 tumours of 28 subtypes as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We both confirm the results of exome studies, and also uncover previously undescribed sex differences. These include sex-biases in coding and non-coding cancer drivers, mutation prevalence and strikingly, in mutational signatures related to underlying mutational processes. These results underline the pervasiveness of molecular sex differences and strengthen the call for increased consideration of sex in molecular cancer research.

Electronic ISSN: 2041-1723

Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics

Published by Springer Nature

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Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples (2020)

Bailey, Matthew H. ; Meyerson, William U. ; Dursi, Lewis Jonathan ; [et al.]

Springer Nature

In: Nature Communications. 2020; 11(1): 4748. Published 2020 Sep 21. doi: 10.1038/s41467-020-18151-y.

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Publication Date: 2020-09-21

Description: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF

Electronic ISSN: 2041-1723

Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics

Published by Springer Nature

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