Remote observations of the solar photospheric light scattered by electrons (the K-corona) and dust (the F-corona or zodiacal light) have been made from the ground during eclipses
and from space at ...distances as small as 0.3 astronomical units
to the Sun. Previous observations
of dust scattering have not confirmed the existence of the theoretically predicted dust-free zone near the Sun
. The transient nature of the corona has been well characterized for large events, but questions still remain (for example, about the initiation of the corona
and the production of solar energetic particles
) and for small events even its structure is uncertain
. Here we report imaging of the solar corona
during the first two perihelion passes (0.16-0.25 astronomical units) of the Parker Solar Probe spacecraft
, each lasting ten days. The view from these distances is qualitatively similar to the historical views from ground and space, but there are some notable differences. At short elongations, we observe a decrease in the intensity of the F-coronal intensity, which is suggestive of the long-sought dust free zone
. We also resolve the fine-scale plasma structure of very small eruptions, which are frequently ejected from the Sun. These take two forms: the frequently observed magnetic flux ropes
and the predicted, but not yet observed, magnetic islands
arising from the tearing-mode instability in the current sheet. Our observations of the coronal streamer evolution confirm the large-scale topology of the solar corona, but also reveal that, as recently predicted
, streamers are composed of yet smaller substreamers channelling continual density fluctuations at all visible scales.
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.
Of the patients undergoing radical cystectomy, 20–80% experience relapse. Minimally invasive methods for early detection of metastatic relapse after cystectomy and for monitoring ongoing therapy are ...urgently needed to improve individualised follow-up and treatment. Therefore, we evaluated the use of circulating tumour DNA (ctDNA) in plasma and urine to detect metastatic relapse after cystectomy and measure treatment efficacy. We exome sequenced tumour and germline DNA from patients with muscle-invasive bladder cancer and monitored ctDNA in 370 liquid biopsies throughout the disease courses by 84 personalised digital droplet polymerase chain reaction assays targeting 61 genes. Patients were prospectively recruited between 2013 and 2017. Patients with metastatic relapse had significantly higher ctDNA levels compared with disease-free patients (p<0.001). The median positive lead time between ctDNA detection in plasma and diagnosis of relapse was 101 d after cystectomy (range 0–932 d). Early detection of metastatic relapse and treatment response using liquid biopsies represents a novel, highly sensitive tool for monitoring patients, supporting clinicians, and guiding treatment decisions.
Measurement of tumour-specific mutations in plasma and urine may be a powerful tool to monitor response during treatment and identify early signs of metastatic disease.
Liquid biopsy analysis of tumour-specific mutations is a highly sensitive method for monitoring early signs of metastatic disease in patients with bladder cancer. Furthermore, liquid biopsy monitoring methods may help inform clinicians on treatment efficacy.
Exosomes are small secreted vesicles that can transfer their content to recipient cells. In cancer, exosome secretion has been implicated in tumor growth and metastatic spread. In this study, we ...explored the possibility that exosomal pathways might discard tumor-suppressor miRNA that restricts metastatic progression. Secreted miRNA characterized from isogenic bladder carcinoma cell lines with differing metastatic potential were uncoupled from binding to target transcripts or the AGO2-miRISC complex. In metastatic cells, we observed a relative increase in secretion of miRNA with tumor-suppressor functions, including miR23b, miR224, and miR921. Ectopic expression of miR23b inhibited invasion, anoikis, angiogenesis, and pulmonary metastasis. Silencing of the exocytotic RAB family members RAB27A or RAB27B halted miR23b and miR921 secretion and reduced cellular invasion. Clinically, elevated levels of RAB27B expression were linked to poor prognosis in two independent cohorts of patients with bladder cancer. Moreover, highly exocytosed miRNA from metastatic cells, such as miR23b, were reduced in lymph node metastases compared with patient-matched primary tumors and were correlated with increments in miRNA-targeted RNA. Taken together, our results suggested that exosome-mediated secretion of tumor-suppressor miRNA is selected during tumor progression as a mechanism to coordinate activation of a metastatic cascade.
microRNAs (miRNA) are short, endogenous transcripts that negatively regulate the expression of specific mRNA targets. miRNAs are found both in tissues and body fluids such as plasma. A major ...perspective for the use of miRNAs in the clinical setting is as diagnostic plasma markers for neoplasia. While miRNAs are abundant in tissues, they are often scarce in plasma. For quantification of miRNA in plasma it is therefore of importance to use a platform with high sensitivity and linear performance in the low concentration range. This motivated us to evaluate the performance of three commonly used commercial miRNA quantification platforms: GeneChip miRNA 2.0 Array, miRCURY Ready-to-Use PCR, Human panel I+II V1.M, and TaqMan Human MicroRNA Array v3.0.
Using synthetic miRNA samples and plasma RNA samples spiked with different ratios of 174 synthetic miRNAs we assessed the performance characteristics reproducibility, recovery, specificity, sensitivity and linearity. It was found that while the qRT-PCR based platforms were sufficiently sensitive to reproducibly detect miRNAs at the abundance levels found in human plasma, the array based platform was not. At high miRNA levels both qRT-PCR based platforms performed well in terms of specificity, reproducibility and recovery. At low miRNA levels, as in plasma, the miRCURY platform showed better sensitivity and linearity than the TaqMan platform.
For profiling clinical samples with low miRNA abundance, such as plasma samples, the miRCURY platform with its better sensitivity and linearity would probably be superior.
Landslides have been identified on several solar system bodies, and different mechanisms have been proposed to explain their runout length. We analyze images from the Rosetta mission and report the ...global characterization of such features on comet 67P/Churyumov‐Gerasimenko's surface. By assuming the height to runout length as an approximation for the friction coefficient of landslide material, we find that on comet 67P, this ratio falls between 0.50 and 0.97. Such unexpected high values reveal a rocky‐type mechanical behavior that is much more akin to Earth dry landslides than to icy satellites' mass movements. This behavior indicates that 67P and likely comets in general are characterized by consolidated materials possibly rejecting the idea that they are fluffy aggregates. The variability of the runout length among 67P landslides can be attributed to the different volatile content located in the top few meters of the cometary crust, which can drive the mass movement.
Plain Language Summary
Comet 67P Churyumov‐Gerasimenko has been imaged with unprecedented spatial detail thanks to the high‐resolution OSIRIS camera (Optical, Spectroscopic and Infrared Remote Imaging System) on board the Rosetta spacecraft. 67P is characterized by an extremely diverse morphology comprising different surface features such as rough consolidated terrains, smooth plains, unconsolidated mantles, pits, fractures, cliffs, cuestas, ubiquitous boulders, and layers. The peculiarity of 67P is also reflected by the widespread presence of landslides. By using high‐resolution images, we analyze the shape and aspect ratio of the landslides located on comet 67P finding a mechanical behavior of the cometary material that is more akin to Earth dry landslides than to icy satellites' mass movements. These results make 67P a very peculiar object, mainly composed by ices and refractory materials but characterized by rocky‐type properties rather than icy‐type characteristics. In addition, the considerable variability among the different landslides of 67P suggests that different volatile contents located in the top few meters of the cometary crust play a fundamental role on mass movement, hence being a general indicator for the subsurface cometary heterogeneities.
Key Points
The height to runout length (H/L) of comet 67P/Churyumov‐Gerasimenko landslides ranges between 0.50 and 0.97
67P landslide reveal a rocky‐type mechanical behavior indicating that comets are made by consolidated materials
The H/L variability is an indicator of the different volatile content located in the top few meters of the cometary crust
Diagnostic and prognostic tools for prostate cancer (PC) are suboptimal, causing overtreatment of indolent PC and risk of delayed treatment of aggressive PC. Here, we identify six novel candidate DNA ...methylation markers for PC with promising diagnostic and prognostic potential.
Microarray-based screening and bisulfite sequencing of 20 nonmalignant and 29 PC tissue specimens were used to identify new candidate DNA hypermethylation markers for PC. Diagnostic and prognostic potential was evaluated in 35 nonmalignant prostate tissue samples, 293 radical prostatectomy (RP) samples (cohort 1, training), and 114 malignant RP samples (cohort 2, validation) collected in Denmark, Switzerland, Germany, and Finland. Sensitivity and specificity for PC were evaluated by receiver operating characteristic analyses. Correlations between DNA methylation levels and biochemical recurrence were assessed using log-rank tests and univariate and multivariate Cox regression analyses.
Hypermethylation of AOX1, C1orf114, GAS6, HAPLN3, KLF8, and MOB3B was highly cancer specific (area under the curve, 0.89 to 0.98). Furthermore, high C1orf114 methylation was significantly (P < .05) associated with biochemical recurrence in multivariate analysis in cohort 1 (hazard ratio HR, 3.10; 95% CI, 1.89 to 5.09) and was successfully validated in cohort 2 (HR, 3.27; 95% CI, 1.17 to 9.12). Moreover, a significant (P < .05) three-gene prognostic methylation signature (AOX1/C1orf114/HAPLN3), classifying patients into low- and high-methylation subgroups, was trained in cohort 1 (HR, 1.91; 95% CI, 1.26 to 2.90) and validated in cohort 2 (HR, 2.33; 95% CI, 1.31 to 4.13).
We identified six novel candidate DNA methylation markers for PC. C1orf114 hypermethylation and a three-gene methylation signature were independent predictors of time to biochemical recurrence after RP in two PC patient cohorts.
In our study, whole‐genome methylation arrays were applied to identify novel genes with tumor specific DNA methylation of promoter CpG islands in pre‐malignant and malignant colorectal lesions. Using ...a combination of Illumina HumanMethylation27 beadchips, Methylation‐Sensitive High Resolution Melting (MS‐HRM) analysis, and Exon arrays (Affymetrix) the DNA methylation pattern of ∼14,000 genes and their transcript levels were investigated in six normal mucosas, six adenomas and 30 MSI and MSS carcinomas. Sixty eight genes with tumor‐specific hypermethylation were identified (p < 0.005). Identified hypermethylated sites were validated in an independent sample set of eight normal mucosas, 12 adenomas, 40 MSS and nine MSI cancer samples. The methylation patterns of 15 selected genes, hypermethylated in adenomas and carcinomas (FLI1, ST6GALNAC5, TWIST1, ADHFE1, JAM2, IRF4, CNRIP1, NRG1 and EYA4), in carcinomas only (ABHD9, AOX1 and RERG), or in MSI but not MSS carcinomas (RAMP2, DSC3 and MLH1) were validated using MS‐HRM. Four of these genes (MLH1, AOX1, EYA4 and TWIST1) had previously been reported to be hypermethylated in CRC. Eleven genes, not previously known to be affected by CRC specific hypermethylation, were identified and validated. Inverse correlation to gene expression was observed for six of the 15 genes with Spearman correlation coefficients ranging from −0.39 to −0.60. For six of these genes the altered methylation patterns had a profound transcriptional association, indicating that methylation of these genes may play a direct regulatory role. The hypermethylation changes often occurred already in adenomas, indicating that they may be used as biomarkers for early detection of CRC.
Colorectal cancer (CRC) is characterized by major inter-tumor diversity that complicates the prediction of disease and treatment outcomes. Recent efforts help resolve this by sub-classification of ...CRC into natural molecular subtypes; however, this strategy is not yet able to provide clinicians with improved tools for decision making. We here present an extended framework for CRC stratification that specifically aims to improve patient prognostication. Using transcriptional profiles from 1,100 CRCs, including >300 previously unpublished samples, we identify cancer cell and tumor archetypes and suggest the tumor microenvironment as a major prognostic determinant that can be influenced by the microbiome. Notably, our subtyping strategy allowed identification of archetype-specific prognostic biomarkers that provided information beyond and independent of UICC-TNM staging, MSI status, and consensus molecular subtyping. The results illustrate that our extended subtyping framework, combining subtyping and subtype-specific biomarkers, could contribute to improved patient prognostication and may form a strong basis for future studies.
Display omitted
•Improved CRC prognostication by molecular subtyping and subtype-specific biomarkers•A model of CRC encompassing three cancer cell archetypes and five tumor archetypes•A CRC subtype, dARE, likely reflecting the host microbiota
Colorectal cancer (CRC) is characterized by major inter-tumor diversity that complicates the prediction of disease outcomes. Bramsen et al. find that an extended framework for CRC stratification that combines molecular subtyping and subtype-specific biomarkers can provide prognostic information beyond and independent of UICC-TNM staging, MSI status, and consensus molecular subtyping.
PDF
