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Supplementary Table 1 from Genomic Profiling of MicroRNAs in Bladder Cancer: miR-129 Is Associated with Poor Outcome and Promotes Cell Death In vitro

Supplementary materials&methods and figure legends for supplementary figures and tables.

Supplementary Table 3 from Genomic Profiling of MicroRNAs in Bladder Cancer: miR-129 Is Associated with Poor Outcome and Promotes Cell Death In vitro

Analysis of RAB27A and RAB27B expression and genomic alterations in clinical samples. Effect of Rab27b knockdown on cell morphology and long-term growth kinetics.

Supplementary Table 6 from Genomic Profiling of MicroRNAs in Bladder Cancer: miR-129 Is Associated with Poor Outcome and Promotes Cell Death In vitro

Effect of RAB27A, RAB27B, and NSMASE2 inhibition on cellular migration and invasion. Bioinformatic analysis of mRNA target sites, AGO2 immunoprecipitation. Analysis of genomic alterations in the miR23b locus and correlation between expression and methylation of selected miRNAs (TCGA dataset).

Lists of i) top30 exocytosed miRNAs and ii) cellular-retained miRNAs.

microRNAs (miRNA) are involved in cancer development and progression, acting as tumor suppressors or oncogenes. Here, we profiled the expression of 290 unique human miRNAs in 11 normal and 106 bladder tumor samples using spotted locked nucleic acid–based oligonucleotide microarrays. We identified several differentially expressed miRNAs between normal urothelium and cancer and between the different disease stages. miR-145 was found to be the most down-regulated in cancer compared with normal, and miR-21 was the most up-regulated in cancer. Furthermore, we identified miRNAs that significantly correlated to the presence of concomitant carcinoma in situ. We identified several miRNAs with prognostic potential for predicting disease progression (e.g., miR-129, miR-133b, and miR-518c*). We localized the expression of miR-145, miR-21, and miR-129 to urothelium by in situ hybridization. We then focused on miR-129 that exerted significant growth inhibition and induced cell death upon transfection with a miR-129 precursor in bladder carcinoma cell lines T24 and SW780 cells. Microarray analysis of T24 cells after transfection showed significant miR-129 target down-regulation (P = 0.0002) and pathway analysis indicated that targets were involved in cell death processes. By analyzing gene expression data from clinical tumor samples, we identified significant expression changes of target mRNA molecules related to the miRNA expression. Using luciferase assays, we documented a direct link between miR-129 and the two putative targets GALNT1 and SOX4. The findings reported here indicate that several miRNAs are differentially regulated in bladder cancer and may form a basis for clinical development of new biomarkers for bladder cancer. [Cancer Res 2009;69(11):4851–60]

Supplementary Figure 1 from Genomic Profiling of MicroRNAs in Bladder Cancer: miR-129 Is Associated with Poor Outcome and Promotes Cell Death In vitro

Characterization of cells upon miRNA overexpression and knockdown.

Lists of A)Quantitative mass spectrometry results of RNA-binding proteins in exosomes, B) Selected miRNAs for further analysis, and C) Downregulated mRNA transcripts (selected) upon RAB27B knockdown.

miRNA profiling in exosomes and cells.

Supplementary Table 2 from Genomic Profiling of MicroRNAs in Bladder Cancer: miR-129 Is Associated with Poor Outcome and Promotes Cell Death In vitro

Supplementary Table 4 from Genomic Profiling of MicroRNAs in Bladder Cancer: miR-129 Is Associated with Poor Outcome and Promotes Cell Death In vitro

BACKGROUND: An improved risk assessment of patients with bladder cancer (BC) is important to optimize clinical management. OBJECTIVE: To identify whether immune cell subpopulations and cancer cell-intrinsic features are associated with outcome and response to first-line chemotherapy in BC. DESIGN, SETTING, AND PARTICIPANTS: Primary tumor tissue from 785 patients with BC (stage Ta-T4b) were stained using multiplex immunofluorescence (CD3, CD8, FOXP3, CD20, CD68, CD163, and MHC-I) and immunohistochemistry (pancytokeratin, CK5/6, GATA3, programmed death 1 [PD-1], and programmed death ligand 1 [PD-L1]). A digital image analysis quantified staining results within the carcinoma cell and stromal part of the tumor. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Primary endpoints were progression-free survival, recurrence-free survival, and response to first-line chemotherapy. Optimal cutoff values for investigated markers were estimated using maximally selected rank statistics and receiver operating characteristic for each primary endpoint. Time-to-event analyses were performed using Cox regression analyses. RESULTS AND LIMITATIONS: Several immune subpopulations were independently associated with clinical outcomes. Especially, high PD-1 and PD-L1 expression was independently associated with an increased risk of recurrence and progression in non-muscle-invasive tumors, but with a lower risk of recurrence in muscle-invasive tumors. Furthermore, we observed a lower likelihood of response to first-line chemotherapy in patients with basal differentiation features. Finally, a model combining clinical risk factors with our most evident prognosticator improved prediction accuracy compared with clinical risk factors alone for progression in non-muscle-invasive BC and recurrence in muscle-invasive BC. The use of tissue microarrays and a long inclusion period are limitations to this study. CONCLUSIONS: Immune cell subpopulations and cancer cell-intrinsic features are associated with different clinical outcomes in BC. PATIENT SUMMARY: Immune cells play an important role in cancer development and treatment outcomes. Infiltration with specific immune cells and the presence of markers associated with immune evasion in the tumor predict clinical outcomes in bladder cancer.

Bladder field cancerization may be associated with disease outcome in patients with bladder cancer. To investigate this, we analyzed biopsies from bladder urothelium and urine samples by genomics and proteomics analyses. Samples were procured from multiple timepoints from 134 patients with early stage bladder cancer and detailed long term follow-up. We measured the field cancerization in normal-appearing bladder biopsies and found that high levels were associated with high tumor mutational burden, high neoantigen load, and high tumor-associated CD8 T-cell exhaustion. Non-synonymous mutations in known bladder cancer driver genes such asKDM6AandTP53were identified as early disease drivers in normal urothelium. High field cancerization was associated with worse outcome but not with response to BCG. The level of urinary tumor DNA (utDNA) reflected the bladder tumor burden and originated from both tumors and field cancerization. High utDNA levels after BCG were associated with worse clinical outcomes for the patients. Our results indicate that the level of field cancerization may affect clinical outcome, tumor development and immune responses. utDNA measurements have significant prognostic value and reflect the disease status of the bladder.

Contains fulltext : 293880.pdf (Publisher’s version ) (Closed access) BACKGROUND: Genomic regions identified by genome-wide association studies (GWAS) for bladder cancer risk provide new insights into etiology. OBJECTIVE: To identify new susceptibility variants for bladder cancer in a meta-analysis of new and existing genome-wide genotype data. DESIGN, SETTING, AND PARTICIPANTS: Data from 32 studies that includes 13,790 bladder cancer cases and 343,502 controls of European ancestry were used for meta-analysis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSES: Log-additive associations of genetic variants were assessed using logistic regression models. A fixed-effects model was used for meta-analysis of the results. Stratified analyses were conducted to evaluate effect modification by sex and smoking status. A polygenic risk score (PRS) was generated on the basis of known and novel susceptibility variants and tested for interaction with smoking. RESULTS AND LIMITATIONS: Multiple novel bladder cancer susceptibility loci (6p.22.3, 7q36.3, 8q21.13, 9p21.3, 10q22.1, 19q13.33) as well as improved signals in three known regions (4p16.3, 5p15.33, 11p15.5) were identified, bringing the number of independent markers at genome-wide significance (p

Take Home Message Four promising biomarkers were found to be predictive for intravesical mitomycin C in non–muscle-invasive bladder cancer patients. Prospective validation is needed., Background Currently, no biomarkers of response to mitomycin C have been identified in non–muscle-invasive bladder cancer patients. Predictive biomarkers could improve the treatment outcome and eliminate adverse events from unnecessary treatment. Objective To identify and validate predictive biomarkers of chemoresection with mitomycin C. Design, setting, and participants The intervention group of a randomised controlled trial was identified for analyses. The study was conducted between January 2018 and June 2019 in two major urological departments in Denmark. Patients had a history of Ta low-grade/high-grade disease and were included upon recurrence. The intervention group (58 patients) received chemoresection with mitomycin C. Tumour and reference germline DNA from prior tumours were analysed by whole exome sequencing. Predictive biomarkers were validated in the context of Ta low-grade tumours from the UROMOL study. Outcome measurements and statistical analysis Response to chemotherapy (intervention group from the randomised controlled trial) and recurrence-free survival (UROMOL cohort) were measured. Groups were compared using Fisher’s exact test and Wilcoxon rank sum test. Results and limitations Chemoresponse was associated with the mutation status of SPTAN1, APC, and FGFR3, and the level of APOBEC signature contribution (p = 0.035, p = 0.034, p = 0.055, and p = 0.035, respectively). The main limitations include no biopsy for biomarker discovery immediately prior to chemoresection and the unmatched validation cohort. Conclusions Mutation status of APC, SPTAN1, and FGFR3 and the level of mutational contribution from APOBEC-related signatures were identified as potential predictive biomarkers for chemoresection with mitomycin C in non–muscle-invasive bladder cancer patients. A prospective validation study is however needed. Patient summary We investigated DNA from noninvasive bladder tumours in order to predict treatment response to chemotherapy. Four biomarkers showed promising results, which should be tested in future studies.

SummaryCurrent transcriptomic classification systems for bladder cancer do not consider the level of intra-tumor subtype heterogeneity. Here we present an investigation of the extent and possible clinical impact of intra-tumor heterogeneity across early and more advanced disease stages of bladder cancer. We performed single nucleus RNA-sequencing of 48 bladder tumors and four of these tumors were additionally analyzed using spatial transcriptomics. Total bulk RNA-sequencing and spatial proteomics data were available from the same tumors for comparison, along with detailed clinical follow-up of the patients. We demonstrate that tumors display varying levels of intra-tumor subtype heterogeneity and show that a higher class 2a weight estimated from bulk RNA-sequencing data is associated with worse outcome in patients with molecular high-risk class 2a tumors. Our results indicate that discrete subtype assignments from bulk RNA-sequencing data may lack biological granularity and continuous class scores could improve clinical risk stratification of patients.HighlightsSingle nucleus RNA-sequencing of tumors from 48 bladder cancer patients.Tumors display varying levels of intra-tumor subtype heterogeneity at single nucleus and bulk tumor level.The level of subtype heterogeneity could be estimated from both single nucleus and bulk RNA-sequencing data with a high concordance between the two.High class 2a weight estimated from bulk RNA-sequencing data is associated with worse outcome in patients with molecular high-risk class 2a tumors.

PurposeInvestigate and compare the use of plasma- and urine DNA mutation analysis for predicting neoadjuvant chemotherapy (NAC) response and long-term oncological outcome in patients with muscle invasive bladder cancer.Experimental DesignWhole exome sequencing of tumor and germline DNA was performed for 92 patients treated with NAC followed by radical cystectomy (RC). A custom NGS panel capturing approx. 50 mutations per patient was designed and utilized to track tumor-derived DNA (tdDNA) in liquid biopsies. A total of 447 plasma samples, 281 urine supernatants and 123 urine pellets collected before, during and after treatment were analyzed. Patients were enrolled from 2013-2019 with a median follow-up time of 41.3 months after RC.ResultsWe identified tdDNA before initiation of NAC in 89% of urine supernatants, 85% of urine pellets and 43% of plasma samples. tdDNA levels were higher in urine supernatants and urine pellets compared to plasma samples (pp=0.006,p=0.002). A combined measure from plasma and urine supernatant tdDNA dynamics stratified patients by outcome (p=0.003).ConclusionsAnalysis of tdDNA in plasma and urine samples both separately and combined has potential to predict treatment response and outcome.

In this work we performed a polarimetric study of a fast and wide coronal mass ejection (CME) observed on 12 July 2012 by the COR1 and COR2 instruments onboard the Solar TErrestrial RElations Observatory (STEREO) mission. The CME source region was an X1.4 flare located at approximately S15W01 on the solar disk, as observed from the Earth's perspective. The position of the CME as derived from the 3D Graduated Cylindrical Shell (GCS) reconstruction method was at around S18W00 at 2.5 solar radii and S07W00 at 5.7 solar radii, meaning that the CME was deflected towards the Equator while propagating outward in the corona. The projected speed of the leading edge of the CME also evolved from around 200 km s−1 in the lower corona to around 1000 km s−1 in the COR2 field of view. The degree of polarisation of the CME is around 65% but it can go as high as 80% in some CME regions. The CME showed deviation of the polarisation angle from the tangential in the range of 10 - 15∘ (or more). Our analysis showed that this is mostly due to the fact that the sequence of three polarised images from where the polarised parameters are derived is not taken simultaneously, but at a difference of a few seconds in time. In this interval of time, the CME moves by at least two pixels in the FOV of the instruments and this displacement results in uncertainties in the polarisation parameters (degree of polarisation, polarisation angle, etc.). We propose some steps forward to improve the derivation of the polarisation. This study is important for analysing the future data from instruments with polarisation capabilities.

APOBEC3A (A3A) and APOBEC3B (A3B) enzymes drive APOBEC-mediated mutagenesis. Identification of factors affecting the activity of these enzymes could help modulate mutagenesis and associated clinical outcomes. Here, we show that canonical and alternatively spliced A3A and A3B isoforms produce corresponding mutagenic and non-mutagenic enzymes. Increased expression of the mutagenic A3B isoform predicted shorter progression-free survival in bladder cancer. We demonstrate that the production of mutagenic vs. non-mutagenic A3B protein isoforms was considerably affected by inclusion/skipping of exon 5 in A3B. Furthermore, exon 5 skipping, resulting in lower levels of mutagenic A3B enzyme, could be increased in vitro. Specifically, we showed the effects of treatment with an SF3B1 inhibitor affecting spliceosome interaction with a branch point site in intron 4, or with splice-switching oligonucleotides targeting exon 5 of A3B. Our results underscore the clinical role of A3B and implicate alternative splicing of A3B as a mechanism that could be targeted to restrict APOBEC-mediated mutagenesis., A. Rouf Banday et al. report targeting alternative splicing of APOBEC3B as a strategy to modulate APOBEC-mediated mutagenesis in cancers. Higher expression of the mutagenic APOBEC3B isoform predicted shorter progression-free survival in bladder cancer patients. Expression of this mutagenic isoform could be decreased by inducing skipping of APOBEC3B exon 5 in cells treated with SF3B1 inhibitor or splice-switching oligos.

Background: Standard treatment of localized muscle invasive bladder cancer (MIBC) is neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC); however, only 40-50% respond to NAC and approx. 50% experience relapse. Evaluation of treatment efficacy and early detection of relapse are therefore major clinical challenges. Methods: We present a clinical update of a previously described cohort of 68 patients who received NAC prior to RC (NAC cohort; Christensen et al. JCO 2019; median follow-up (FU) of 58 months) together with evaluation of a retrospectively collected cohort of 120 patients who did not receive NAC (no-NAC cohort; median FU of 71 months). Circulating tumor DNA (ctDNA) was analyzed before NAC (NAC cohort, n=63), prior to RC (NAC cohort, n=67; no-NAC cohort, n=115) and after RC (NAC cohort, n=66; no-NAC cohort, n=37) using Signatera™. RNA-seq was performed on 176 tumors. Results: Updated clinical FU for the NAC cohort showed that ctDNA-positive patients had significantly worse recurrence-free survival (RFS) compared to ctDNA-negative patients (before NAC: HR=16, 95%CI=3.6-70.5, p=0.0002; during surveillance after RC: HR=27.6, 95%CI=7.9-96.9, p Conclusion: Presence of ctDNA was associated with worse prognosis for both NAC and no-NAC treated patients. Transcriptomic analysis of primary tumors showed that anti-tumor immune responses may be associated with a particularly good outcome whereas EMT may be promoting more aggressive disease. Citation Format: Sia Viborg Lindskrog, George Laliotis, Karin Birkenkamp-Demtröder, Iver Nordentoft, Philippe Lamy, Elshaddai Z. White, Natalia Pajak, Tine G. Andreasen, Punashi Dutta, Meenakshi Malhotra, Shruti Sharma, Mark Calhoun, Adam ElNaggar, Minetta C. Liu, Mads Agerbæk, Jørgen B. Jensen, Lars Dyrskjøt. Utility of circulating tumor DNA and transcriptomic profiling in predicting outcome in muscle invasive bladder cancer patients. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5600.

Background: The genomic landscape of cancer is complex and includes mutations and copy number alterations (CNAs) that affect several cancer related pathways and drive tumor evolution. Non-muscle-invasive bladder cancers (NMIBC) are largely orphan for integrative genomic studies. Large studies are needed to delineate the genomic complexity and heterogeneity of NMIBC. Methods: A total of 438 patients with NMIBC were analyzed, 296 of which were part of the UROMOL cohort (PMID: 27321955). The median follow-up was 5 years. The progression rate was 13% (n= 56). Whole exome sequencing (WES) was performed on DNA from tumor (~150x) and matched germline samples to call somatic mutations. Additionally, shallow whole genome sequencing (sWGS; ~2x) was performed on DNA from 362 of the tumors to quantify CNAs. RNA-sequencing was available for 414 of the samples, and tumors were classified according to the UROMOL2021 transcriptomic classes. We identified significantly mutated genes by mutsigCV and significantly amplified or deleted regions by GISTIC2. Results: The median tumor mutation burden (TMB) was 3.7/Mb. TMB was not associated with progression (p=0.28). A total of 61 genes were significantly mutated in the cohort, the most frequent being FGFR3 (61%), KDM6A (44%) and KMT2D (38%). Mutations in EP300 and RHOB were significantly associated with an increased risk of progression after adjusting for grade and stage (p=0.040 and 0.044, respectively). Several mutations showed a strong transcriptomic class dependent occurrence: mutations in RB1, TP53, ERCC2 and ERBB2 were enriched in the aggressive class 2a, FGFR3 and STAG2 in class 1 and class 3, and KMT2C and KMT2D in class 3. Genome doubling was identified in 15% of the tumors. These tumors were enriched in the aggressive classes 2a and 2b and were associated with increased risk of progression (p=0.0049). In addition, we observed several significantly altered genomic regions, the most significant being deletions in 9p21.3 (CDKN2A & CDKN2B, 64%), 2q37.1 (GIGYF2 & EIF4E2, 28%) and amplification in 11q13.3 (CCND1, 9%). Class 2a tumors were enriched for genomic alterations in most of the significant regions. 9p21.3 was the only region with frequent homozygous losses (22%). High-level gains were prognostic of progression, independently of ploidy, stage and grade, for several regions, including 4p16.3 (FGFR3, p=0.00013), 17q23.2(TBX2, p=0.0004) and 8p11.23(ZNF703, p=0.011). In addition, we observed an enrichment of uniparental disomy in 4p16.3 (FGFR3, 8%). Conclusion: Here we investigated the landscape of DNA alterations in NMIBC in a large patient cohort of NMIBC samples with paired transcriptomic data and detailed clinical follow-up. We identified several novel genomic alterations; specifically, we showed that 15% of the tumors had genome doublings, and we identified a complex underlying copy number landscape of the region containing FGFR3. Citation Format: Frederik Prip, Philippe Lamy, Iver Nordentoft, Sia Viborg Lindskrog, Trine Strandgaard, Karin Birkenkamp-Demtröder, Gregers G. Hermann, Astrid C. Petersen, Veronika Bahlinger, Marc-Oliver Grimm, Marcus Horstmann, Karin Mogensen, Roman Nawroth, Ulrika Segersten, Danijel Sikic, Kim E. M van Kessel, Tobias Maurer, Tatjana Simic, Arndt Hartmann, Ellen C. C. Zwarthoff, Per-Uno Malmström, Torben Steiniche, Jørgen Bjerggaard Jensen, Núria Malats, Francisco X. Real, Lars Dyrskjøt. Comprehensive genomic characterization of early-stage bladder cancer from 438 patients by whole genome- and exome sequencing. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6075.

International audience; Eclipse observations of the W-L corona show linear rays above active regions at times of solar maximum. We show that these linear rays are also observed in the field-of-view of the C2-LASCO coronagraph, in perfect correspondence with the eclipse results. A selected prominent case taken from the 2001 eclipse observation in Angola is analysed with several different methods, including the use of a synoptic map constructed using SoHO/LASCO C2 images. A clear signature of time variations near the eclipse observation is detected, suggesting that at least some parts of the beam are collimated. These observations strongly suggest high speed streams that apparently ignore the potential large scale coronal magnetic field rooted rather low in the corona. A possible origin is the neutral magnetic points located above the active region. Several mechanisms exist to explain how the plasma is accelerated in these regions to large quasi-relativistic velocities, possibly related to the occurrence of type III radio bursts. We point out a curious analogy with phenomena occurring inside coronal holes.

BackgroundThe functional status of immune cells within the tumor microenvironment and tumor characteristics may explain Bacillus Calmette-Guérin (BCG)-failure in high-risk non-muscle invasive bladder cancer (NMIBC).ObjectiveTo characterize molecular correlates of BCG-failure using a multiomics approach.Design, Setting, and ParticipantsBCG-treated NMIBC patients (n=156) were included. Metachronous tumors were analyzed using RNA-sequencing (n=170) and whole exome sequencing (n=198). Urine samples were analyzed for immune-oncology related proteins (n=190), and tumor-derived DNA (tdDNA; n=192).Outcome Measurement and Statistical AnalysisPrimary endpoint was BCG-failure. Cox regression, Wilcoxon Rank Sum test, t-test or Fisher’s exact test were used.Results and LimitationsBCG caused activation of the immune system regardless of clinical response; however, immune-inhibitory proteins were observed in the urine of BCG-unresponsive patients post-treatment (CD70, PD1, CD5). BCG-failure was associated with post-BCG T-cell exhaustion (p=0.0021). Pre-BCG tumors from patients with post-BCG T-cell exhaustion were characterized by high expression of cell division and immune-related genes. A high post-BCG exhaustion prediction score in pre-BCG tumors was associated with worse post-BCG high-grade recurrence free survival (HGRFS), reflecting BCG-failure (p=0.0084). Pre-BCG tumors of class 2a and 2b were likewise associated with worse post-BCG HGRFS(p=0.0023). Post-BCG exhaustion was observed in patients with high pre-BCG neoantigen load (p=0.023) and mutations in MUC4 (p=0.0007). Finally, absence of post-BCG tdDNA clearance identified patients at high risk of recurrence (p=0.028). The retrospective design, lack of maintenance BCG, and partial overlap in analyses are limitations to the study.ConclusionsBCG failure may be caused by T-cell exhaustion. Tumor subtype and Pre-BCG tumor characteristics may identify patients at high risk of BCG-failure prior to treatment. Urinary measurements have the potential to be used as a real-time assessment of treatment response.Patient SummaryA dysfunctional immune response to BCG therapy may explain lack of response to the treatment.

Overtreatment with cisplatin-based chemotherapy is a major issue in the management of muscle-invasive bladder cancer (MIBC), and currently none of the reported biomarkers for predicting response have been implemented in the clinic. Here we perform a comprehensive multi-omics analysis (genomics, transcriptomics, epigenomics and proteomics) of 300 MIBC patients treated with chemotherapy (neoadjuvant or first-line) to identify molecular changes associated with treatment response. DNA-based associations with response converge on genomic instability driven by a high number of chromosomal alterations, indels, signature 5 mutations and/or BRCA2 mutations. Expression data identifies the basal/squamous gene expression subtype to be associated with poor response. Immune cell infiltration and high PD-1 protein expression are associated with treatment response. Through integration of genomic and transcriptomic data, we demonstrate patient stratification to groups of low and high likelihood of cisplatin-based response. This could pave the way for future patient selection following validation in prospective clinical trials., There are currently only a few biomarkers to predict the response of muscle invasive bladder cancer to therapy. Here, the authors analyse 300 tumors using exome and RNA sequencing and find that tumors with a high degree of genomic instability and a non-basal/squamous gene expression subtype are most likely to respond to treatment.

The solar wind measured in situ by Parker Solar Probe in the very inner heliosphere is studied in combination with the remote-sensing observation of the coronal source region provided by the METIS coronagraph aboard Solar Orbiter. The coronal outflows observed near the ecliptic by Metis on 2021 January 17 at 16:30 UT, between 3.5 and 6.3 R ⊙ above the eastern solar limb, can be associated with the streams sampled by PSP at 0.11 and 0.26 au from the Sun, in two time intervals almost 5 days apart. The two plasma flows come from two distinct source regions, characterized by different magnetic field polarity and intensity at the coronal base. It follows that both the global and local properties of the two streams are different. Specifically, the solar wind emanating from the stronger magnetic field region has a lower bulk flux density, as expected, and is in a state of well-developed Alfvénic turbulence, with low intermittency. This is interpreted in terms of slab turbulence in the context of nearly incompressible magnetohydrodynamics. Conversely, the highly intermittent and poorly developed turbulent behavior of the solar wind from the weaker magnetic field region is presumably due to large magnetic deflections most likely attributed to the presence of switchbacks of interchange reconnection origin.

Background: Non-muscle-invasive bladder cancer (NMIBC) is characterized by frequent recurrences and a risk of progression in stage and grade. Increased knowledge of underlying biological mechanisms is needed.Objective: To identify single nucleotide polymorphisms (SNPs) associated with recurrence-free (RFS) and progression-free (PFS) survival in NMIBC.Design, setting, and participants: We analyzed outcome data from 3400 newly diagnosed NMIBC patients from the Netherlands, the UK, Canada, and Spain. We generated genome-wide germline SNP data using Illumina OmniExpress and Infinium Global Screening Array in combination with genotype imputation.Outcome measurements and statistical analysis: Cohort-specific genome-wide association studies (GWASs) for RFS and PFS were performed using a Cox proportional hazard model. Results were combined in a fixed-effect inverse-variance weighted meta-analysis. Candidate genes for the identified SNP associations were prioritized using functional annotation, gene-based analysis, expression quantitative trait locus analysis, and transcription factor binding site databases. Tumor expression levels of prioritized genes were tested for association with RFS and PFS in an independent NMIBC cohort.Results and limitations: This meta-analysis revealed a genome-wide significant locus for RFS on chromosome 14 (lead SNP rs12885353, hazard ratio [HR] C vs T allele 1.55, 95% confidence interval [CI] 1.33-1.82, p = 4.0 x 10(-8)), containing genes G2E3 and SCFD1. Higher expression of SCFD1 was associated with increased RFS (HR 0.70, 95% CI 0.59-0.84, p(FDR) = 0.003). Twelve other loci were suggestively associated with RFS (p < 10(-5)), pointing toward 18 additional candidate genes. For PFS, ten loci showed suggestive evidence of association, indicating 36 candidate genes. Expression levels of ten of these genes were statistically significantly associated with PFS, of which four (IFT140, UBE2I, FAHD1, and NME3) showed directional consistency with our meta-analysis results and published literature.Conclusions: In this first prognostic GWAS in NMIBC, we identified several novel candidate loci and five genes that showed convincing associations with recurrence or progression.Patient summary: In this study, we searched for inherited DNA changes that affect the outcome of non-muscle-invasive bladder cancer (NMIBC). We identified several genes that are associated with disease recurrence and progression. The roles and mechanisms of these genes in NMIBC prognosis should be investigated in future studies. (C) 2021 The Authors. Published by Elsevier B.V. on behalf of European Association of Urology.

563 Background: Muscle-invasive bladder cancer (MIBC) accounts for ~25–30% of all bladder cancer diagnoses. With neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) as standard-of-care, the 5-year survival rate ranges from 40%–60%. Bladder-sparing protocols (BSP) have emerged as a feasible alternative to RC for MIBC treatment, however better tools are needed. In this study, we evaluated the prognostic value of circulating tumor DNA (ctDNA) in predicting recurrence in patients who achieved pathological complete response (pCR). Methods: We analyzed a previously described cohort of 68 patients (656 plasma samples; Christensen et al., JCO 2019) with MIBC who received NAC prior to cystectomy. Patients had an updated median follow-up of 58.94 months (range: 7.19-81.77) post-cystectomy. ctDNA was analyzed at baseline (before NAC; N=64), and prior to cystectomy (N=65) using a commercially available assay (Signatera, Natera, Inc.). Additionally, exploratory RNA-Seq was performed on tumors from 59 patients (samples with >5M total counts were utilized). Pathway analysis was used to compare ctDNA-positive and ctDNA-negative patients who failed to achieve pCR. Results: Of the 64 patients with ctDNA results available at baseline, 59.4% (38/64) tested ctDNA-negative, and of these 84.2% (32/38) achieved pCR. Furthermore, 40.6% (26/64) tested ctDNA-positive, and only 34.6% (9/26) achieved pCR. Likewise, prior to cystectomy, 83.9% (52/62) of patients were ctDNA-negative, and 80.7% (42/52) achieved pCR, while none of the ctDNA-positive patients achieved pCR (positive predictive value 100%; negative predictive value 80.8%). Based on both ctDNA timepoints, the probability of ctDNA-negative patients to achieve pCR was significantly higher than ctDNA-positive patients ( p

Vernazza, P., et al., Until recently, the 3D shape, and therefore density (when combining the volume estimate with available mass estimates), and surface topography of the vast majority of the largest (D ≥ 100 km) main-belt asteroids have remained poorly constrained. The improved capabilities of the SPHERE/ZIMPOL instrument have opened new doors into ground-based asteroid exploration. Aims. To constrain the formation and evolution of a representative sample of large asteroids, we conducted a high-angular-resolution imaging survey of 42 large main-belt asteroids with VLT/SPHERE/ZIMPOL. Our asteroid sample comprises 39 bodies with D ≥ 100 km and in particular most D ≥ 200 km main-belt asteroids (20/23). Furthermore, it nicely reflects the compositional diversity present in the main belt as the sampled bodies belong to the following taxonomic classes: A, B, C, Ch/Cgh, E/M/X, K, P/T, S, and V. Methods. The SPHERE/ZIMPOL images were first used to reconstruct the 3D shape of all targets with both the ADAM and MPCD reconstruction methods.We subsequently performed a detailed shape analysis and constrained the density of each target using available mass estimates including our own mass estimates in the case of multiple systems. Results. The analysis of the reconstructed shapes allowed us to identify two families of objects as a function of their diameters, namely spherical and elongated bodies. A difference in rotation period appears to be the main origin of this bimodality. In addition, all but one object (216 Kleopatra) are located along the Maclaurin sequence with large volatile-rich bodies being the closest to the latter. Our results further reveal that the primaries of most multiple systems possess a rotation period of shorter than 6 h and an elongated shape (c=a ≤ 0.65). Densities in our sample range from ∼1.3 g cm-3 (87 Sylvia) to ∼4.3 g cm-3 (22 Kalliope). Furthermore, the density distribution appears to be strongly bimodal with volatile-poor (P ≥ 2.7 g cm-3) and volatile-rich (P ≤ 2.2 g cm-3) bodies. Finally, our survey along with previous observations provides evidence in support of the possibility that some C-complex bodies could be intrinsically related to IDP-like P- and D-type asteroids, representing different layers of a same body (C: core; P/D: outer shell). We therefore propose that P/ D-types and some C-types may have the same origin in the primordial trans-Neptunian disk., We warmly thank the ESO staff at Paranal and in particular Henri Boffin for providing us precious support and advice throughout the entire observing programme. P.V., A.D., M.F., L.J. and B.C. were supported by CNRS/INSU/PNP. The work of T.S-R. was carried out through grant APOSTD/2019/046 by Generalitat Valenciana (Spain). This work was supported by the MINECO (Spanish Ministry of Economy) through grant RTI2018-095076-B-C21 (MINECO/FEDER, UE). TRAPPIST project is funded by the Belgian Fund for Scientic Research (Fond National de la Recherche Scientique, FNRS) under the grant PDR T.0120.21. E.J. is a FNRS Senior Research Associate. F.M. is supported by the National Science Foundation under Grant No. 1743015.

[Aims] To interpret adaptive-optics observations of (216) Kleopatra, we need to describe an evolution of multiple moons orbiting an extremely irregular body and include their mutual interactions. Such orbits are generally non-Keplerian and orbital elements are not constants. [Methods] Consequently, we used a modified N-body integrator, which was significantly extended to include the multipole expansion of the gravitational field up to the order ℓ = 10. Its convergence was verified against the 'brute-force' algorithm. We computed the coefficients Cℓ m, Sℓ m for Kleopatra's shape, assuming a constant bulk density. For Solar System applications, it was also necessary to implement a variable distance and geometry of observations. Our χ2 metric then accounts for the absolute astrometry, the relative astrometry (second moon with respect to the first), angular velocities, and silhouettes, constraining the pole orientation. This allowed us to derive the orbital elements of Kleopatra's two moons. [Results] Using both archival astrometric data and new VLT/SPHERE observations (ESO LP 199.C-0074), we were able to identify the true periods of the moons, P1 = (1.822359 ± 0.004156) d, P2 = (2.745820 ± 0.004820) d. They orbit very close to the 3:2 mean-motion resonance, but their osculating eccentricities are too small compared to other perturbations (multipole, mutual), meaning that regular librations of the critical argument are not present. The resulting mass of Kleopatra, m1 = (1.49 ± 0.16) × 10-12 M· or 2.97 × 1018 kg, is significantly lower than previously thought. An implication explained in the accompanying paper is that (216) Kleopatra is a critically rotating body., Broz, M. et al., This work has been supported by the Czech Science Foundation through grant 21-11058S (M. Brož, D. Vokrouhlický), 20-08218S (J. Hanuš, J. Ďurech), and by the Charles University Research program No. UNCE/SCI/023. This material is partially based upon work supported by the National Science Foundation under Grant No. 1743015. P.V., A.D., M.F. and B.C. were supported by CNRS/INSU/PNP. M.M. was supported by the National Aeronautics and Space Administration under grant No. 80NSSC18K0849 issued through the Planetary Astronomy Program. The work of TSR was carried out through grant APOSTD/2019/046 by Generalitat Valenciana (Spain). This work was supported by the MINECO (Spanish Ministry of Economy) through grant RTI2018-095076-B-C21 (MINECO/FEDER, UE). The research leading to these results has received funding from the ARC grant for Concerted Research Actions, financed by the Wallonia-Brussels Federation. TRAPPIST is a project funded by the Belgian Fonds (National) de la Recherche Scientifique (F.R.S.-FNRS) under grant FRFC 2.5.594.09.F. TRAPPIST-North is a project funded by the University of Liège, and performed in collaboration with Cadi Ayyad University of Marrakesh. E. Jehin is a FNRS Senior Research Associate.

Bilobate comets—small icy bodies with two distinct lobes—are a common configuration among comets, but the factors shaping these bodies are largely unknown. Cometary nuclei, the solid centres of comets, erode by ice sublimation when they are sufficiently close to the Sun, but the importance of a comet’s internal structure on its erosion is unclear. Here we present three-dimensional analyses of images from the Rosetta mission to illuminate the process that shaped the Jupiter-family bilobate comet 67P/Churyumov–Gerasimenko over billions of years. We show that the comet’s surface and interior exhibit shear-fracture and fault networks, on spatial scales of tens to hundreds of metres. Fractures propagate up to 500 m below the surface through a mechanically homogeneous material. Through fracture network analysis and stress modelling, we show that shear deformation generates fracture networks that control mechanical surface erosion, particularly in the strongly marked neck trough of 67P/Churyumov–Gerasimenko, exposing its interior. We conclude that shear deformation shapes and structures the surface and interior of bilobate comets, particularly in the outer Solar System where water ice sublimation is negligible. The shape and internal structure of bilobate comet 67P is controlled by shear deformation inducing mechanically driven erosion along shear fracture networks, according to a 3D analysis of images from the Rosetta mission.

Introduction: Gold standard treatment in patients with high-risk non-muscle invasive bladder cancer (NMIBC) includes Bacillus Calmette-Guérin (BCG), which activates the immune cells to kill remaining cancerous cells after surgical removal of the tumors. However, 40% of patients do not have a clinical benefit of BCG. The presence of immune cells, their functional state, as well as genomic alterations in the tumor and the normal appearing urothelial tissue, defined as field effect, may have significant impact on therapeutic outcome. Materials and methods: To investigate this, we analyzed samples from 156 patients diagnosed with NMIBC, including 237 tumors, 569 urine samples, and 305 biopsies of adjacent normal appearing urothelium. Patients had a median follow-up time of 8 years. 70 patients (45%) progressed to muscle-invasive bladder cancer or experienced early high grade recurrence within two years after ended BCG treatment, defined as BCG failure. Urinary levels of 92 immune-oncology related proteins were measured in pre- and post-treatment samples using the Olink proteomics platform. Total RNA- and whole exome sequencing (WES) data was generated from tumors before and after BCG. Clonal patient-specific mutations were selected for deep-targeted sequencing of the adjacent normal appearing biopsies. The level of field effect was defined as the mean of the variant allele frequency for mutations observed in normal biopsies. Results: We found that treatment with BCG activated the immune system regardless of clinical outcome. However, patients differed in urinary protein profile after BCG depending on their clinical response. Transcriptomic analysis of tumors showed that UROMOL2021 subtypes were significantly associated with outcome and clinical response (p=0.018). Paired tumors showed a shift in subtype to an immune infiltrated subtype (class 2b) after treatment in 36% of cases. Patients with BCG failure showed signs of immune exhaustion after treatment indicated by higher expression of the T cell exhaustion marker genes CTLA4 (p=0.0067), LAG3 (p=0.00012), TIM-3 (p=0.022), KLRG1 (p=0.028), and PD-1 (p=0.047), and higher immune cell infiltration (p=0.011). Genomic features such as mutational signatures and mutational load were not predictive of clinical response. Interestingly, BCG-responsive patients had a high level of field effect before BCG (p=0.0026), suggesting that field effect could lead to increased BCG efficacy. Conclusion: BCG treatment was associated with immune system activation reflected in both urine and tissue samples. In patients with BCG failure, we observed an immune exhausted phenotype after treatment, and we observed a high level of field effect before treatment in responsive patients. Collectively, this could indicate that increased immunogenicity and prolonged immune activation are key factors in BCG treatment responsiveness. Citation Format: Trine Strandgaard, Iver Nordentoft, Emil Christensen, Sia Lindskrog, Philippe Lamy, Karin Birkenkamp-Demtröder, Torben Steiniche, Jørgen Bjerggaard Jensen, Lars Dyrskjøt. Elevated T cell exhaustion and immune cell infiltration is associated with BCG failure in patients with non-muscle invasive bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1282.

Introduction: Single cell technologies now make it possible to study tumor ecosystems at single cell resolution and may improve our biological understanding of disease aggressiveness and tumor heterogeneity. Whereas single-cell RNA-sequencing of clinical tumor biopsies requires immediate processing after tissue acquisition, single-nucleus RNA-sequencing (snRNA-seq) allows profiling of single nuclei isolated from frozen tumor tissue from patients with long-term follow-up and known clinical outcomes. Methods: We performed snRNA-seq of frozen tumors from 48 bladder cancer (BC) patients (10 Ta, 13 T1, 25 T2-4) using an optimized DroNc-seq protocol. Nuclei were isolated from frozen biopsies using IgePal lysis buffer and droplets were created using the Dolomite Bio platform followed by library generation and sequencing on an Illumina NovaSeq 6000. All epithelial nuclei were classified according to the UROMOL classes of non-muscle-invasive BC or the consensus classes of muscle-invasive BC. Bulk total RNA-sequencing (RNA-seq) was available for 44 of the tumors for comparison. Three tumors were additionally analyzed using 10x Chromium for validation and four tumors were analyzed using 10x Visium Spatial Transcriptomics. Results: After pre-processing the raw sequencing data, we obtained data from 117,653 nuclei in total and 59,201 nuclei remained after quality control filtering (1,233 nuclei per tumor and 529 expressed genes per nuclei on average). We focused our analysis on the epithelial compartment, as it constituted the bulk of the tumors (99% of all nuclei). UMAP visualization and clustering of all tumors were mainly driven by patient origin indicating a high level of inter-tumor heterogeneity. To explore intra-tumor heterogeneity and the association to disease aggressiveness, we characterized the tumors individually using hallmark BC gene signatures. Finally, we explored the composition of transcriptomic classes for each tumor and found that 52% of tumors displayed profound intra-tumor class heterogeneity with less than 70% of all nuclei belonging to a single class. The dominating transcriptomic class of single nuclei was only consistent in 44% of the tumors when compared to the overall transcriptomic class from bulk RNA-seq. This may be explained by several levels of heterogeneity and method differences, including the technical challenges of applying a bulk classifier to single nuclei data. We are currently investigating whether specific epithelial subpopulations are associated to outcome and whether signatures derived from snRNA-seq data can be recovered in bulk RNA-seq data and used as prognostic predictors. Conclusion: Our results highlight the biological complexity of bladder tumors and underline the importance of considering the extent of intra-tumor heterogeneity in the clinical management of BC patients. Citation Format: Sia V. Lindskrog, Sofie S. Schmøkel, Iver Nordentoft, Philippe Lamy, Michael Knudsen, Jørgen B. Jensen, Lars Dyrskjøt. Single-nucleus RNA-sequencing of human bladder tumors delineates intra-tumor cellular and subtype heterogeneity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3483.

Background Standard treatment in patients with localized muscle-invasive bladder cancer (MIBC) is neoadjuvant chemotherapy (NAC) followed by radical cystectomy (CX). Importantly, there is currently no clinically validated way to estimate response to NAC before CX, where a pathological assessment of tumor down-staging is used as a proxy for response. Identification and tracking of circulating tumor DNA (ctDNA) has been shown to reflect prognosis and treatment response in several cancers, including bladder cancer. Here, we aim to investigate the capability of a combined plasma, urine supernatant and urine pellet mutation analysis by deep targeted sequencing for detecting residual tumor and treatment response before CX. Methods In total, 92 patients with localized MIBC treated with NAC followed by CX were included in the study. DNA extracted from primary tumors and leukocytes were subjected to whole exome sequencing for identification of approx. 50 mutations per patient that were used to design a custom NGS panel. Urine supernatants (n=281), urine pellets (n=114) and plasma samples (n=167), collected before CX, were subjected to deep targeted sequencing employing unique molecular identifiers (UMI). Mutations were assessed using the Shearwater algorithm and samples were further assessed using Fisher’s Method and bootstrapping of random mutations. In-silico analyses identified the limit of detection to be approx. 0.1%. For 56 patients, plasma mutation data (n=288 samples) were obtained from a previously published study by our group. Results Tumor derived DNA levels in paired urine supernatants and pellets were correlated (rho=0.8), however with higher levels in pellets when adjusting for the extracted amount of DNA (p Conclusions Tumor derived DNA was more frequently observed in urine samples and at higher levels compared to plasma samples. Interestingly, we show that tumor derived DNA dynamics in urine supernatants might better reflect the local tumor environment and plasma-based tumor derived DNA better reflects outcome following surgery, i.e. disease dissemination. Citation Format: Emil Christensen, Iver Nordentoft, Sara K. Elbæk, Karin Birkenkamp-Demtröder, Ann Taber, Michael Knudsen, Philippe Lamy, Mads Agerbæk, Jørgen B. Jensen, Lars Dyrskjøt. Treatment response and outcome prediction guided by deep targeted sequencing of urine and plasma samples in patients with muscle-invasive bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1275.

Background: Prostate cancer (PC) is the fifth most lethal male malignancy worldwide, as advanced metastatic castration resistant PC (mCRPC) remains incurable. Genomic biomarkers that can predict treatment response are urgently needed to facilitate personalized mCRPC treatment. Such biomarkers can be identified by whole genome sequencing (WGS) of tumor biopsies. Blood plasma can serve as a non-invasive liquid tumor biopsy as it contains cell free DNA (cfDNA), a subset of which in cancer patients is tumor-derived (circulating tumor DNA; ctDNA). The biomarker discovery potential of WGS of cfDNA in mCRPC remains largely undescribed, as most WGS studies to date have focused on tissue biopsies. Thus, we here aimed to characterize the genomic tumor landscape of mCRPC using WGS of cfDNA. Methods: We previously performed low-pass WGS (mean coverage: 0.5X) of cfDNA sampled prior to initiation of first-line mCRPC treatment from 143 mCRPC patients (mean ctDNA fraction: 0.15). From these, 10 patients with high (>0.35) ctDNA fractions who received enzalutamide as first-line mCRPC treatment were selected for deeper WGS here. Matched germline DNA from buffy coat (peripheral blood mononuclear cells) was also sequenced. Single-nucleotide variants (SNVs) were called with Mutect2 and CaVEMan, indels with Mutect2 and Pindel, copy-number variants (CNVs) with ASCAT, and structural variants (SVs) with BRASS. For the final analysis, we considered only SNVs and indels called by both tools. Results: We sequenced germline samples to a mean coverage of 25X (range: 19-28X) and cfDNA samples to a mean coverage of 32X (range: 23-43X). We identified a median of 5,241 SNVs/indels (range: 3,422-48,314) per patient and the mean tumor mutation burden was 1.7 mutations/Mb. One sample had >9 times more SNVs/indels than the median, suggesting microsatellite instability. Among the most recurrently mutated genes were LRP1B (7/10 patients), ARSB (5/10 patients), and TP53 (4/10 patients). COSMIC mutational signature analysis revealed that the clock-like signatures 1, 5, and 40 were most frequent. In contrast, the hypermutated sample was driven primarily by the defective DNA mismatch repair signatures 15, 26, and 44. CNVs affected a mean of 40.9% of the genome. Common PC CNVs were observed, including gains at chromosome 8 (MYC) in 8/10 patients and losses at chromosome 10 (PTEN) in 5/10 patients. Recurrent focal amplifications (defined as >8 copies in regions Conclusion: This study highlights that WGS of cfDNA contributes to the identification of genomic aberrations that may serve as potential biomarkers to guide personalized treatment of mCRPC in the future. Citation Format: Simone Weiss, Philippe Lamy, Maibritt Nørgaard, Michael Knudsen, Jørgen B. Jensen, Jakob S. Pedersen, Michael Borre, Karina D. Sørensen. Whole genome sequencing of liquid tumor biopsies (ctDNA) from men with metastatic castration resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3409.

For more than two decades the SOHO/SWAN instrument has been monitoring the full-sky hydrogen backscattered Lyman-α emission, and the derived three-dimensional solar wind proton flux. We present a comparison of the time series of the latitude-integrated hydrogen ionization rates (β) derived from the inversion of the SWAN full-sky maps with the integrated coronal electron density derived from the inversion of SOHO/LASCO-C2 white light images. The analysis shows a variable time lag of the SWAN β of a few Carrington rotations, correlated with the solar cycle phase (larger delay during solar maxima compared to minima). This is a direct consequence of the variation of the size of the hydrogen ionization cavity and the time it takes for hydrogen atoms to propagate in the inner heliosphere. This effect should be taken into account in studies of the interstellar neutral populations in interplanetary space.

The molecular landscape in non-muscle-invasive bladder cancer (NMIBC) is characterized by large biological heterogeneity with variable clinical outcomes. Here, we perform an integrative multi-omics analysis of patients diagnosed with NMIBC (n = 834). Transcriptomic analysis identifies four classes (1, 2a, 2b and 3) reflecting tumor biology and disease aggressiveness. Both transcriptome-based subtyping and the level of chromosomal instability provide independent prognostic value beyond established prognostic clinicopathological parameters. High chromosomal instability, p53-pathway disruption and APOBEC-related mutations are significantly associated with transcriptomic class 2a and poor outcome. RNA-derived immune cell infiltration is associated with chromosomally unstable tumors and enriched in class 2b. Spatial proteomics analysis confirms the higher infiltration of class 2b tumors and demonstrates an association between higher immune cell infiltration and lower recurrence rates. Finally, the independent prognostic value of the transcriptomic classes is documented in 1228 validation samples using a single sample classification tool. The classifier provides a framework for biomarker discovery and for optimizing treatment and surveillance in next-generation clinical trials., Multiple molecular profiling methods are required to study urothelial non-muscle-invasive bladder cancer (NMIBC) due to its heterogeneity. Here the authors integrate multi-omics data of 834 NMIBC patients, identifying a molecular subgroup associated with multiple alterations and worse outcomes.

International audience; We present the polarimetric analysis of the white-light images of the corona obtained with the Large-Angle Spectrometric COronagraph LASCO-C3 onboard the Solar and Heliospheric Observatory (SOHO) from 1996 to 2019, leading to the separation of the K- and F-components and the derivation of the electron-density distribution. The analysis makes use of polarized sequences composed of three images obtained through three polarizers oriented at +60°, 0°, and -60°, complemented by a neighboring unpolarized image. However, the degradation of the 0° polarizer noticed in 1999 compelled us to reconstruct the corresponding images from those obtained with the two other polarizers and the unpolarized ones thereafter. The analysis closely follows the method developed for LASCO-C2 (Lamy et al. in Solar Phys. 295, 89, 2020) and implements the formalism of Mueller, albeit with additional difficulties notably the presence of a non-axially symmetric component of stray light. Critical corrections were derived from a SOHO roll sequence and from consistency criteria (e.g. the “tangential” direction of polarization). The quasi-uninterrupted photopolarimetric analysis of the outer corona over two complete Solar Cycles 23 and 24 was successfully achieved and our final results encompass the characterization of its polarization, of its polarized radiance, of the two-dimensional electron density, and of the K-corona. Comparison between the C3 and C2 results in the region where their fields of view overlap shows an overall agreement. The C3 results are further in agreement with those of eclipses and radio-ranging measurements to an elongation of ≈10 R⊙ but tend to diverge further out. Although the coronal polarization out to 20 R⊙ is still highly correlated with the temporal variation of the total magnetic field, this divergence probably results from the increasing polarization of the F-corona with increasing solar elongation.

The last thirty years of cosmochemistry and planetary science have shown that one major Solar System reservoir is vastly undersampled in the available suite of extra-terrestrial materials, namely small bodies that formed in the outer Solar System (>10 AU). Because various dynamical evolutionary processes have modified their initial orbits (e.g., giant planet migration, resonances), these objects can be found today across the entire Solar System as P/D near-Earth and main-belt asteroids, Jupiter and Neptune Trojans, comets, Centaurs, and small (diameter < 200 km) trans-Neptunian objects. This reservoir is of tremendous interest, as it is recognized as the least processed since the dawn of the Solar System and thus the closest to the starting materials from which the Solar System formed. Some of the next major breakthroughs in planetary science will come from studying outer Solar System samples (volatiles and refractory constituents) in the laboratory. Yet, this can only be achieved by an L-class mission that directly collects and returns to Earth materials from this reservoir. It is thus not surprising that two White Papers advocating a sample return mission of a primitive Solar System small body (ideally a comet) were submitted to ESA in response to its Voyage 2050 call for ideas for future L-class missions in the 2035-2050 time frame. One of these two White Papers is presented in this article., Experimental Astronomy, 54 (2-3), ISSN:0922-6435, ISSN:1572-9508

In this work, we present an investigation of the wind in the solar corona that has been initiated by observations of the resonantly scattered ultraviolet emission of the coronal plasma obtained with UVCS-SOHO, designed to measure the wind outflow speed by applying Doppler dimming diagnostics. Metis on Solar Orbiter complements the UVCS spectroscopic observations that were performed during solar activity cycle 23 by simultaneously imaging the polarized visible light and the H I Lyman-α corona in order to obtain high spatial and temporal resolution maps of the outward velocity of the continuously expanding solar atmosphere. The Metis observations, taken on May 15, 2020, provide the first H I Lyman-α images of the extended corona and the first instantaneous map of the speed of the coronal plasma outflows during the minimum of solar activity and allow us to identify the layer where the slow wind flow is observed. The polarized visible light (580–640 nm) and the ultraviolet H I Lyα (121.6 nm) coronal emissions, obtained with the two Metis channels, were combined in order to measure the dimming of the UV emission relative to a static corona. This effect is caused by the outward motion of the coronal plasma along the direction of incidence of the chromospheric photons on the coronal neutral hydrogen. The plasma outflow velocity was then derived as a function of the measured Doppler dimming. The static corona UV emission was simulated on the basis of the plasma electron density inferred from the polarized visible light. This study leads to the identification, in the velocity maps of the solar corona, of the high-density layer about ±10° wide, centered on the extension of a quiet equatorial streamer present at the east limb – the coronal origin of the heliospheric current sheet – where the slowest wind flows at about 160 ± 18 km s−1 from 4 R⊙ to 6 R⊙. Beyond the boundaries of the high-density layer, the wind velocity rapidly increases, marking the transition between slow and fast wind in the corona.

Carri, B., et al., [Context] Dynamical models of Solar System evolution have suggested that the so-called P- and D-type volatile-rich asteroids formed in the outer Solar System beyond Neptune's orbit and may be genetically related to the Jupiter Trojans, comets, and small Kuiper belt objects (KBOs). Indeed, the spectral properties of P- and D-type asteroids resemble that of anhydrous cometary dust. Aims. We aim to gain insights into the above classes of bodies by characterizing the internal structure of a large P- and D-type asteroid. [Methods] We report high-angular-resolution imaging observations of the P-type asteroid (87) Sylvia with the Very Large Telescope Spectro-Polarimetric High-contrast Exoplanet REsearch (SPHERE) instrument. These images were used to reconstruct the 3D shape of Sylvia. Our images together with those obtained in the past with large ground-based telescopes were used to study the dynamics of its two satellites. We also modeled Sylvia's thermal evolution. [Results] The shape of Sylvia appears flattened and elongated (a/b 1.45; a/c 1.84). We derive a volume-equivalent diameter of 271 ± 5 km and a low density of 1378 ± 45 kg m-3. The two satellites orbit Sylvia on circular, equatorial orbits. The oblateness of Sylvia should imply a detectable nodal precession which contrasts with the fully-Keplerian dynamics of its two satellites. This reveals an inhomogeneous internal structure, suggesting that Sylvia is differentiated. [Conclusions] Sylvia's low density and differentiated interior can be explained by partial melting and mass redistribution through water percolation. The outer shell should be composed of material similar to interplanetary dust particles (IDPs) and the core should be similar to aqueously altered IDPs or carbonaceous chondrite meteorites such as the Tagish Lake meteorite. Numerical simulations of the thermal evolution of Sylvia show that for a body of such a size, partial melting was unavoidable due to the decay of long-lived radionuclides. In addition, we show that bodies as small as 130-150 km in diameter should have followed a similar thermal evolution, while smaller objects, such as comets and the KBO Arrokoth, must have remained pristine, which is in agreement with in situ observations of these bodies. NASA Lucy mission target (617) Patroclus (diameter ≈140 km) may, however, be differentiated., This work has been supported by the Czech Science Foundation through grants 20-08218S (J. Hanuš, J. Ďurech) and by the Charles University Research program No. UNCE/SCI/023. The work of TSR was carried out through grant APOSTD/2019/046 by Generalitat Valenciana (Spain). This work was supported by the MINECO (Spanish Ministry of Economy) through grant RTI2018-095076-B-C21 (MINECO/FEDER, UE). This material is partially based upon work supported by the National Science Foundation under Grant No. 1743015.

We present a photometrically accurate restitution of the K and F coronae from white-light images obtained over 24 Years [1996--2019] by the Large-Angle Spectrometric COronagraph "LASCO-C2" onboard the Solar and Heliospheric Observatory (SOHO). The procedure starts with the data set coming from the polarimetric separation of images of 512 x 512 pixels in which the F-corona and the instrumental stray light are entangled. Disentangling these components proceeds in three stages, each composed of several steps. Stage 1 establishes the distinct variations of the radiance of these components with the Sun--SOHO distance and generate a new data set of median images calculated for each Carrington rotation. Stage 2 achieves the restitution of a set of 36 stray light images reflecting its temporal variation and the periodic rolls of SOHO which started in 2003. Stage 3 achieves the restitution of the F-corona and a time series of daily images is generated. These results allowed us processing the whole set of routine LASCO-C2 images of 1024 x 1024 pixels (approximately 626000 images) and producing calibrated, high resolution images of the K-corona. We extend our past conclusions that the temporal variation of the integrated radiance of the K-corona tracks the solar activity over two solar cycles 23 and 24 and that it is highly correlated with the temporal variation of the total magnetic field. The behaviours of the integrated radiance during the last few years of the declining phases of solar cycles 23 and 24 are remarkably similar, reaching the same floor level and leading to a duration of 11.0 year for the latter cycle, in agreement with the sunspot determination., 1. Added two new Sections 3.5 and 4.2 discussing uncertainties, with new Figures (21 and 23); results unchanged. 2. Added a comparison with the results of Hayes et al. (2001) in Fig. 24

Chromosomal instability in cancer consists of dynamic changes to the number and structure of chromosomes(1,2). The resulting diversity in somatic copy number alterations (SCNAs) may provide the variation necessary for tumour evolution(1,3,4). Here we use multi-sample phasing and SCNA analysis of 1,421 samples from 394 tumours across 22 tumour types to show that continuous chromosomal instability results in pervasive SCNA heterogeneity. Parallel evolutionary events, which cause disruption in the same genes (such asBCL9, MCL1,ARNT(also known asHIF1B),TERTandMYC) within separate subclones, were present in 37% of tumours. Most recurrent losses probably occurred before whole-genome doubling, that was found as a clonal event in 49% of tumours. However, loss of heterozygosity at the human leukocyte antigen (HLA) locus and loss of chromosome 8p to a single haploid copy recurred at substantial subclonal frequencies, even in tumours with whole-genome doubling, indicating ongoing karyotype remodelling. Focal amplifications that affected chromosomes 1q21 (which encompassesBCL9, MCL1andARNT), 5p15.33 (TERT), 11q13.3 (CCND1), 19q12 (CCNE1) and 8q24.1 (MYC) were frequently subclonal yet appeared to be clonal within single samples. Analysis of an independent series of 1,024 metastatic samples revealed that 13 focal SCNAs were enriched in metastatic samples, including gains in chromosome 8q24.1 (encompassingMYC) in clear cell renal cell carcinoma and chromosome 11q13.3 (encompassingCCND1) in HER2(+)breast cancer. Chromosomal instability may enable the continuous selection of SCNAs, which are established as ordered events that often occur in parallel, throughout tumour evolution.Chromosomal instability enables the continuous selection of somatic copy number alterations, which are established as ordered events that often occur in parallel, throughout tumour evolution and metastasis.