Additional file 2. Individual Patient Data for the UNC-CH/Vanderbilt/California Pacific Medical Research Institute. Abbreviations: F, female; M, male; MM, metastatic melanoma; f/u, follow-up; immunotx, immunotherapy; n/a, non applicable; n/a(CNA), copy number alteration not tested; †, ‡, § next generation sequencing of corresponding genes from the Foundation One CDx assay was not tested (Illumina 26-gene panel).
Abstract The Mars mission will result in an inevitable exposure to cosmic radiation that has been shown to cause cognitive impairments in rodent models, and possibly in astronauts engaged in deep space travel. Of particular concern is the potential for cosmic radiation exposure to compromise critical decision making during normal operations or under emergency conditions in deep space. Rodents exposed to cosmic radiation exhibit persistent hippocampal and cortical based performance decrements using six independent behavioral tasks administered between separate cohorts 12 and 24 weeks after irradiation. Radiation-induced impairments in spatial, episodic and recognition memory were temporally coincident with deficits in executive function and reduced rates of fear extinction and elevated anxiety. Irradiation caused significant reductions in dendritic complexity, spine density and altered spine morphology along medial prefrontal cortical neurons known to mediate neurotransmission interrogated by our behavioral tasks. Cosmic radiation also disrupted synaptic integrity and increased neuroinflammation that persisted more than 6 months after exposure. Behavioral deficits for individual animals correlated significantly with reduced spine density and increased synaptic puncta, providing quantitative measures of risk for developing cognitive impairment. Our data provide additional evidence that deep space travel poses a real and unique threat to the integrity of neural circuits in the brain.
Abstract Background Melanoma-intrinsic activated β-catenin pathway, the product of the catenin beta 1 ( CTNNB1) gene, has been associated with low/absent tumor-infiltrating lymphocytes, accelerated tumor growth, metastases development, and resistance to anti-PD-L1/anti-CTLA-4 agents in mouse melanoma models. Little is known about the association between the adenomatous polyposis coli (APC) and CTNNB1 gene mutations in stage IV melanoma with immunotherapy response and overall survival (OS). Methods We examined the prognostic significance of somatic APC / CTNNB1 mutations in the Cancer Genome Atlas Project for Skin Cutaneous Melanoma (TCGA-SKCM) database. We assessed APC / CTNNB1 mutations as predictors of response to immunotherapies in a clinicopathologically annotated metastatic patient cohort from three US melanoma centers. Results In the TCGA-SKCM patient cohort ( n = 434) presence of a somatic APC / CTNNB1 mutation was associated with a worse outcome only in stage IV melanoma ( n = 82, median OS of APC / CTNNB1 mutants vs. wild-type was 8.15 vs. 22.8 months; log-rank hazard ratio 4.20, p = 0.011). APC / CTNNB1 mutation did not significantly affect lymphocyte distribution and density. In the 3-melanoma institution cohort, tumor tissues underwent targeted panel sequencing using two standards of care assays. We identified 55 patients with stage IV melanoma and APC / CTNNB1 genetic aberrations (mut) and 169 patients without (wt). At a median follow-up of more than 25 months for both groups, mut compared with wt patients had slightly more frequent (44% vs. 39%) and earlier (66% vs. 45% within six months from original diagnosis of stage IV melanoma) development of brain metastases. Nevertheless, time-to-development of brain metastases was not significantly different between the two groups. Fortunately, mut patients had similar clinical benefits from PD-1 inhibitor-based treatments compared to wt patients (median OS 26.1 months vs. 29.9 months, respectively, log-rank p = 0.23). Less frequent mutations in the NF1 , RAC1 , and PTEN genes were seen in the mut compared with wt patients from the 3-melanoma institution cohort. Analysis of brain melanoma tumor tissues from a separate craniotomy patient cohort ( n = 55) showed that melanoma-specific, activated β-catenin (i.e., nuclear localization) was infrequent ( n = 3, 6%) and not prognostic in established brain metastases. Conclusions APC / CTNNB1 mutations are associated with a worse outcome in stage IV melanoma and early brain metastases independent of tumor-infiltrating lymphocyte density. However, PD1 inhibitor-based treatments provide comparable benefits to both mut and wt patients with stage IV melanoma.
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