similar with respect to the preference rates for life-sustaining treatments compared with palliative care (46.9% vs 34.4% in the 60% survival group and 50.0% vs 40.6% in the 30% survival group; odds ratio [OR], 0.90; 95% CI, 0.31-2.63). A few patients were not able to formulate a preference (6 patients (18.8%) in the 60% survival group and 3 patients (9.4%) in the 30% survival group; OR, 0.423; 95% CI, 0.08-2.10). An analysis of the patients who formulated a preference showed that an attitude that mere survival is at least as important as quality of life was associated with a preference for life-sustaining treatments (OR, 10.28; 95% CI, 2.94-35.90). Increasing maternal age (OR, 0.77; 95% CI, 0.61-0.98) and childlessness (OR, 0.12; 95% CI 0.01-0.98) were associated with a preference for palliative care. Most patients would decide together with their partners (63 of 64 [98.4%]) and preferred to be empowered by their physicians in the decision-making process (48 of 64 [75%]). Discussion | In this study, it appeared that treatment preferences originated from individual characteristics and values rather than from reasoning about numerical outcome estimates. However, generalizability is limited and the results should be interpreted in light of the methods used. Patients made a one-time decision without personal feedback and patients actually affected might indicate different preferences. More studies are needed to help to improve our understanding of the information that parents facing extremely preterm birth want and need.
The identity and degree of heterogeneity of glial progenitors and their contributions to brain tumor malignancy remain elusive. By applying lineage-targeted single-cell transcriptomics, we uncover an unanticipated diversity of glial progenitor pools with unique molecular identities in developing brain. Our analysis identifies distinct transitional intermediate states and their divergent developmental trajectories in astroglial and oligodendroglial lineages. Moreover, intersectional analysis uncovers analogous intermediate progenitors during brain tumorigenesis, wherein oligodendrocyte-progenitor intermediates are abundant, hyper-proliferative, and progressively reprogrammed toward a stemlike state susceptible to further malignant transformation. Similar actively cycling intermediate progenitors are prominent components in human gliomas with distinct driver mutations. We further unveil lineage-driving networks underlying glial fate specification and identify Zfp36l1 as necessary for oligodendrocyte-astrocyte lineage transition and glioma growth. Together, our results resolve the dynamic repertoire of common and divergent glial progenitors during development and tumorigenesis and highlight Zfp36l1 as a molecular nexus for balancing glial cell-fate decision and controlling gliomagenesis. (A) Immunolabeling for GFAP and GS in the cortex of P5 hGFAP-GFP mice. (B) The percentage of indicated cells among hGFAP-GFP+ cells in P5 mouse cortices (n = 4 for GFAP; n = 3 for GS and PDGFRa). (C) Immunolabeling for GFAP, Olig2, and Slc1a3 from P5 hGFAP-GFP mice. (D) Zoom on boxed area in (C). (E) The percentage of Olig2+ and Olig2À cells among hGFAP-GFP+GFAP+ (left) or hGFAP-GFP+Slc1a3+ (right) cells in P5 mouse cortices (n = 3). (F) Immunolabeling of Blbp in the cortices from hGFAP-GFP mice at P3. (G) Expression of PDGFRa in the cortices of P5 hGFAP-GFP mice. (H) Immunolabeling for Ppp1r14b and Olig2 in the cortices of hGFAP-GFP mice at P3. (I) Immunolabeling for Olig2 and Ki67 from P5 hGFAP-GFP mice. (J) (Left) Enlarged images of (I) show cells co-labeled with Ki67 (arrows) and cells without Ki67 (arrowheads). (Right) Percentage of Olig2+ and Olig2À cells among Ki67+ hGFAP-GFP+ double-positive cells is shown (>300 cell counts from 3 cortices).
Medulloblastoma, the most common malignant childhood brain tumor, exhibits distinct molecular subtypes and cellular origins. Genetic alterations driving medulloblastoma initiation and progression remain poorly understood. Herein, we identify
GNAS
, encoding the G-protein Gsα, as a potent tumor suppressor gene that defines a subset of aggressive Sonic Hedgehog (Shh)-driven human medulloblastomas. Ablation of the single
Gnas
gene in anatomically-distinct progenitors is sufficient to induce Shh-associated medulloblastomas, which recapitulate their human counterparts. Gsα is highly enriched at the primary cilium of granule neuron precursors and suppresses Shh-signaling by regulating both the cAMP-dependent pathway and ciliary trafficking of Hedgehog pathway components. Elevation of a Gsα effector, cAMP, effectively inhibits tumor cell proliferation and progression in
Gnas
mutants. Thus, our gain- and loss-of-function studies identify a previously unrecognized tumor suppressor function for Gsα that acts as a molecular link across Shh-group medulloblastomas of disparate cellular and anatomical origins, illuminating G-protein modulation as a potential therapeutic avenue.
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