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The Galactic Center black hole Sagittarius A* (Sgr A*) is a prime observing target for the Event Horizon Telescope (EHT), which can resolve the 1.3 mm emission from this source on angular scales comparable to that of the general relativistic shadow. Previous EHT observations have used visibility amplitudes to infer the morphology of the millimeter-wavelength emission. Potentially much richer source information is contained in the phases. We report on 1.3 mm phase information on Sgr A* obtained with the EHT on a total of 13 observing nights over 4 years. Closure phases, the sum of visibility phases along a closed triangle of interferometer baselines, are used because they are robust against phase corruptions introduced by instrumentation and the rapidly variable atmosphere. The median closure phase on a triangle including telescopes in California, Hawaii, and Arizona is nonzero. This result conclusively demonstrates that the millimeter emission is asymmetric on scales of a few Schwarzschild radii and can be used to break 180-degree rotational ambiguities inherent from amplitude data alone. The stability of the sign of the closure phase over most observing nights indicates persistent asymmetry in the image of Sgr A* that is not obscured by refraction due to interstellar electrons along the line of sight.

We have constructed a five station 12 GHz atmospheric phase interferometer (API) for the Submillimeter Array (SMA) located near the summit of Mauna Kea, Hawaii. Operating at the base of unoccupied SMA antenna pads, each station employs a commercial low noise mixing block coupled to a 0.7 m off-axis satellite dish which receives a broadband, white noise-like signal from a geostationary satellite. The signals are processed by an analog correlator to produce the phase delays between all pairs of stations with projected baselines ranging from 33 to 261 m. Each baseline's amplitude and phase is measured continuously at a rate of 8 kHz, processed, averaged and output at 10 Hz. Further signal processing and data reduction is accomplished with a Linux computer, including the removal of the diurnal motion of the target satellite. The placement of the stations below ground level with an environmental shield combined with the use of low temperature coefficient, buried fiber optic cables provides excellent system stability. The sensitivity in terms of rms path length is 1.3 microns which corresponds to phase deviations of about 1 degree of phase at the highest operating frequency of the SMA. The two primary data products are: (1) standard deviations of observed phase over various time scales, and (2) phase structure functions. These real-time statistical data measured by the API in the direction of the satellite provide an estimate of the phase front distortion experienced by the concurrent SMA astronomical observations. The API data also play an important role, along with the local opacity measurements and weather predictions, in helping to plan the scheduling of science observations on the telescope.

We report on 230 GHz (1.3 mm) VLBI observations of M87 with the Event Horizon Telescope using antennas on Mauna Kea in Hawaii, Mt. Graham in Arizona and Cedar Flat in California. For the first time, we have acquired 230 GHz VLBI interferometric phase information on M87 through measurement of closure phase on the triangle of long baselines. Most of the measured closure phases are consistent with 0\\(^{\\circ}\\) as expected by physically-motivated models for 230 GHz structure such as jet models and accretion disk models. The brightness temperature of the event-horizon-scale structure is \\(\\sim 1 \\times 10^{10}\\) K derived from the compact flux density of \\(\\sim 1\\) Jy and the angular size of \\(\\sim 40 \\) \\(\\rm \\mu\\)as \\(\\sim\\) 5.5 \\(R_{{\\rm s}}\\), which is broadly consistent with the peak brightness of the radio cores at 1-86 GHz located within \\(\\sim 10^2\\) \\(R_{{\\rm s}}\\). Our observations occurred in the middle of an enhancement in very-high-energy (VHE) \\(\\rm \\gamma\\)-ray flux, presumably originating in the vicinity of the central black hole. Our measurements, combined with results of multi-wavelength observations, favor a scenario in which the VHE region has an extended size of \\(\\sim\\)20-60 \\(R_{{\\rm s}}\\).

A major aim of the vertebrate embryologist is to understand the mechanisms by which a group of cells controls the developmental fate of neighbouring cells. In this thesis, I have undertaken a study of the roles that growth factor signalling pathways play in the regulation of murine gastrulation and the formation and patterning of the embryonic mesoderm. A polymerase chain reaction screen was used to amplify tyrosine kinase mRNA expressed in in vitro-differentiated embryonic stem (ES) cells to initially define the growth factor receptor tyrosine kinases (RTKs) expressed during mammalian mesoderm formation. Fourteen different cytoplasmic or receptor tyrosine kinases were identified. Novel RTKs belonging to the Insulin, Ret, Kit/Pdgf, and FGF receptor families were isolated. Characterization centred around members of the FGFR and Kit/Pdgfr families of RTKs due to their demonstrated roles in a number of developmental systems. Both whole-mount and standard in situ hybridization analysis revealed that members of the Fgfr family were expressed early in development and suggested that they may play roles in controlling the development and segmentation of specific germ layers. The expression patterns of a Kit/Pdgfr-related RTK, now known as Flk1, and a novel RTK, designated Tek, correlate with the determination and differentiation, respectively, of the endothelial cell lineage. This work has identified the earliest known markers of endothelial cell precursors, blood vessels and the endocardium and has paved the way for a genetic and biochemical analysis of vasculogenesis. Functional characterization of Fgfr1 was carried out by gene targeting methodology. In the absence of Fgfr1 signalling, embryos displayed early growth defects, however they remained capable of gastrulating and generating mesoderm. The nascent mesoderm of Fgfr1 homozygous mutant embryos differentiated into diverse mesodermal subtypes, but mesodermal patterning was aberrant. Somites were never generated and axial mesoderm was greatly expanded at the expense of paraxial mesoderm. Embryos did not survive past embryonic day 9.5. These results suggest that FGFR1 transduces signals that specify mesodermal cell fates and regional patterning of the mesoderm during gastrulation and highlights the essential roles that growth signalling pathways play during embryogenesis.

Many primary-tumor subregions have low levels of molecular oxygen, termed hypoxia. Hypoxic tumors are at elevated risk for local failure and distant metastasis, but the molecular hallmarks of tumor hypoxia remain poorly defined. To fill this gap, we quantified hypoxia in 8,006 tumors across 19 tumor types. In ten tumor types, hypoxia was associated with elevated genomic instability. In all 19 tumor types, hypoxic tumors exhibited characteristic driver-mutation signatures. We observed widespread hypoxia-associated dysregulation of microRNAs (miRNAs) across cancers and functionally validated miR-133a-3p as a hypoxia-modulated miRNA. In localized prostate cancer, hypoxia was associated with elevated rates of chromothripsis, allelic loss of PTEN and shorter telomeres. These associations are particularly enriched in polyclonal tumors, representing a constellation of features resembling tumor nimbosus, an aggressive cellular phenotype. Overall, this work establishes that tumor hypoxia may drive aggressive molecular features across cancers and shape the clinical trajectory of individual tumors. Analysis of signatures of hypoxia in more than 8,000 tumors from 19 cancer types identifies hypoxia-driven mutation signatures and dysregulation of microRNAs.

Metastatic castration-resistant prostate cancer (mCRPC) has a highly complex genomic landscape. With the recent development of novel treatments, accurate stratification strategies are needed. Here we present the whole-genome sequencing (WGS) analysis of fresh-frozen metastatic biopsies from 197 mCRPC patients. Using unsupervised clustering based on genomic features, we define eight distinct genomic clusters. We observe potentially clinically relevant genotypes, including microsatellite instability (MSI), homologous recombination deficiency (HRD) enriched with genomic deletions and BRCA2 aberrations, a tandem duplication genotype associated with CDK12 −/− and a chromothripsis-enriched subgroup. Our data suggests that stratification on WGS characteristics may improve identification of MSI, CDK12 −/− and HRD patients. From WGS and ChIP-seq data, we show the potential relevance of recurrent alterations in non-coding regions identified with WGS and highlight the central role of AR signaling in tumor progression. These data underline the potential value of using WGS to accurately stratify mCRPC patients into clinically actionable subgroups. Detecting genomic abnormalities in metastatic castration-resistant prostate cancer (mCRPC) may impact clinical treatment. Here, the authors present whole-genome sequencing of metastatic biopsies from 197 mCRPC patients, highlighting the landscape of microsatellite stability, homologous repair deficiency, and other genomic subgroups.

Mathieu Lupien and colleagues analyze data from primary prostate tumors with and without TMPRSS2–ERG (T2E) rearrangements. They find that in T2E tumors, there is a distinct regulatory landscape resulting from the co-option of transcription factors by ERG which causes dependency on NOTCH signaling. TMPRSS2–ERG (T2E) structural rearrangements typify ∼50% of prostate tumors and result in overexpression of the ERG transcription factor. Using chromatin, genomic and expression data, we show distinct cis -regulatory landscapes between T2E-positive and non-T2E primary prostate tumors, which include clusters of regulatory elements (COREs). This difference is mediated by ERG co-option of HOXB13 and FOXA1, implementing a T2E-specific transcriptional profile. We also report a T2E-specific CORE on the structurally rearranged ERG locus arising from spreading of the TMPRSS2 locus pre-existing CORE, assisting in its overexpression. Finally, we show that the T2E-specific cis -regulatory landscape underlies a vulnerability against the NOTCH pathway. Indeed, NOTCH pathway inhibition antagonizes the growth and invasion of T2E-positive prostate cancer cells. Taken together, our work shows that overexpressed ERG co-opts master transcription factors to deploy a unique cis -regulatory landscape, inducing a druggable dependency on NOTCH signaling in T2E-positive prostate tumors.

Germline mutations in the BRCA2 tumour suppressor are associated with both an increased lifetime risk of developing prostate cancer (PCa) and increased risk of aggressive disease. To understand this aggression, here we profile the genomes and methylomes of localized PCa from 14 carriers of deleterious germline BRCA2 mutations ( BRCA2 -mutant PCa). We show that BRCA2 -mutant PCa harbour increased genomic instability and a mutational profile that more closely resembles metastastic than localized disease. BRCA2 -mutant PCa shows genomic and epigenomic dysregulation of the MED12L / MED12 axis, which is frequently dysregulated in metastatic castration-resistant prostate cancer (mCRPC). This dysregulation is enriched in BRCA2 -mutant PCa harbouring intraductal carcinoma (IDC). Microdissection and sequencing of IDC and juxtaposed adjacent non-IDC invasive carcinoma in 10 patients demonstrates a common ancestor to both histopathologies. Overall we show that localized castration-sensitive BRCA2 -mutant tumours are uniquely aggressive, due to de novo aberration in genes usually associated with metastatic disease, justifying aggressive initial treatment. Men that carrier BRCA2 germline mutations are at risk of developing prostate cancer. Here, the authors analyse the genomes of prostate cancer from these individuals and demonstrate increased genomic instability in comparison to sporadic prostate cancer.

Background Invasive cribriform and intraductal carcinoma (CR/IDC) is associated with adverse outcome of prostate cancer patients. The aim of this study was to determine the molecular aberrations associated with CR/IDC in primary prostate cancer, focusing on genomic instability and somatic copy number alterations (CNA). Methods Whole-slide images of The Cancer Genome Atlas Project (TCGA, N  = 260) and the Canadian Prostate Cancer Genome Network (CPC-GENE, N  = 199) radical prostatectomy datasets were reviewed for Gleason score (GS) and presence of CR/IDC. Genomic instability was assessed by calculating the percentage of genome altered (PGA). Somatic copy number alterations (CNA) were determined using Fisher-Boschloo tests and logistic regression. Primary analysis were performed on TCGA ( N  = 260) as discovery and CPC-GENE ( N  = 199) as validation set. Results CR/IDC growth was present in 80/260 (31%) TCGA and 76/199 (38%) CPC-GENE cases. Patients with CR/IDC and ≥ GS 7 had significantly higher PGA than men without this pattern in both TCGA (2.2 fold; p  = 0.0003) and CPC-GENE (1.7 fold; p  = 0.004) cohorts. CR/IDC growth was associated with deletions of 8p, 16q, 10q23, 13q22, 17p13, 21q22, and amplification of 8q24. CNAs comprised a total of 1299 gene deletions and 369 amplifications in the TCGA dataset, of which 474 and 328 events were independently validated, respectively. Several of the affected genes were known to be associated with aggressive prostate cancer such as loss of PTEN , CDH1 , BCAR1 and gain of MYC . Point mutations in TP53 , SPOP and FOXA1 were also associated with CR/IDC, but occurred less frequently than CNAs. Conclusions CR/IDC growth is associated with increased genomic instability clustering to genetic regions involved in aggressive prostate cancer. Therefore, CR/IDC is a pathologic substrate for progressive molecular tumour derangement.

Immune-mediated anti-tumoral responses, elicited by oncolytic viruses and augmented with checkpoint inhibition, may be an effective treatment approach for glioblastoma. Here in this multicenter phase 1/2 study we evaluated the combination of intratumoral delivery of oncolytic virus DNX-2401 followed by intravenous anti-PD-1 antibody pembrolizumab in recurrent glioblastoma, first in a dose-escalation and then in a dose-expansion phase, in 49 patients. The primary endpoints were overall safety and objective response rate. The primary safety endpoint was met, whereas the primary efficacy endpoint was not met. There were no dose-limiting toxicities, and full dose combined treatment was well tolerated. The objective response rate was 10.4% (90% confidence interval (CI) 4.2–20.7%), which was not statistically greater than the prespecified control rate of 5%. The secondary endpoint of overall survival at 12 months was 52.7% (95% CI 40.1–69.2%), which was statistically greater than the prespecified control rate of 20%. Median overall survival was 12.5 months (10.7–13.5 months). Objective responses led to longer survival (hazard ratio 0.20, 95% CI 0.05–0.87). A total of 56.2% (95% CI 41.1–70.5%) of patients had a clinical benefit defined as stable disease or better. Three patients completed treatment with durable responses and remain alive at 45, 48 and 60 months. Exploratory mutational, gene-expression and immunophenotypic analyses revealed that the balance between immune cell infiltration and expression of checkpoint inhibitors may potentially inform on response to treatment and mechanisms of resistance. Overall, the combination of intratumoral DNX-2401 followed by pembrolizumab was safe with notable survival benefit in select patients (ClinicalTrials.gov registration: NCT02798406). A safety and efficacy trial of a single intratumoral dose of the oncolytic adenovirus DNX-2401 followed by intravenous anti-PD-1 pembrolizumab in patients with recurrent glioblastoma shows an encouraging clinical benefit rate and 12 months overall survival.