Identification and characterisation of somatic regulatory mutations in the breast cancer genome

Luminal breast cancer remains a major clinical challenge with over 2 million cases diagnosed annually. While prognosis is favourable in these patients, roughly 40% will relapse over the course of the next 20 years. Understanding the evolution of disseminated tumour cells at distal sites is critical to effectively treating these patients. While metastatic driver mutations, such as those in the Oestrogen Receptor (ESR1) gene, can be identified in many cases for a significant proportion of patients, clear drivers remain elusive. A limitation of previous genomics studies in metastatic breast cancer is their focus on the coding genome. Advances in our understanding have revealed the critical role of regulatory elements such as enhancers and promoters in transcriptional regulation. This effect is mediated through the functional and hierarchical organisation of chromatin within the nucleus, the key unit of chromatin organisation is the Topologically Associating Domains (TADs). TAD organisation is, in part, mediated by the CCCTC-Binding Factor (CTCF) protein which physically binds to DNA mediating the formation of loops and domains. Together promoters, enhancers, and CTCF-bound regions provide potential as sites for non-coding mutations to occur, drastically impacting gene regulation and tumour evolution. In this work we interrogate the contribution of regulatory element mutations in the evolution of metastatic breast cancer. This is done through two projects. First, a proof of principle study functionally characterising a clinically relevant CTCF binding site mutation. Second, through the design of an informed panel of regulatory regions utilised in a longitudinal targeted sequencing study in patient samples and a CRISPRi perturbation study in cell lines. Through these studies we provide evidence that the mutation of TAD boundary associated CTCF binding sites is unlikely to contribute to tumour evolution. We also fail to identify recurrence of non-coding drivers, though more patient specific mutations may contribute to metastatic evolution. Results obtained from the CRISPRi screen illustrate the functionality of the regulatory regions in the panel, identifying regulatory elements that confer fitness or vulnerabilities when specifically repressed. This study identifies that repression of several members of the NF-κB signalling pathway provides MCF7 cells with an advantage in adapting to oestrogen deprivation. This data underlines the importance of regulatory regions in the evolution of luminal breast cancers and indicates that non-genetic mechanisms may play a key role.Open Acces

Polytraumatized patient lower extremity nonunion development: Raw data

In this article we report data collected to evaluate the pathomechanistic effect of acute anaerobic metabolism in the polytraumatized patient and its subsequent effect on fracture nonunion; see "Base Deficit ≥6 within 24 Hours of Injury is a Risk Factor for Fracture Nonunion in the Polytraumatized Patient" (Sardesai et al., 2021) [1]. Data was collected on patients age ≥16 with an Injury Severity Score (ISS) >16 that presented between 2013-2018 who sustained a fracture of the tibia or femur distal to the femoral neck. Patients presenting to our institution greater than 24 hours post-injury and those with less than three months follow-up were excluded. Medical charts were reviewed to collect patient demographic information and known nonunion risk-factors, including smoking, alcohol use, and diabetes. In addition, detailed injury characteristics to quantify injury magnitude including ISS, Glasgow Coma Scale (GCS) at admission, and ICU length of stay were recorded. ISS values were obtained from our institutional trauma database where they are entered by individuals trained in ISS calculations. Associated fracture-related features including fracture location, soft-tissue injury (open vs. closed fracture), vascular injury, and compartment syndrome were recorded. Finally, vital signs, base deficit (BD), and blood transfusions over 24 hours from admission were recorded. We routinely measure BD and less consistently measure serum lactate in trauma patients at the time of presentation or during resuscitation. BD values are automatically produced by our laboratory with any arterial blood gas order, and we recorded BD values from the medical record. Clinical notes and radiographs were reviewed to confirm fracture union versus nonunion and assess for deep infection at the fracture site. Patients were categorized as having a deep infection if they were treated operatively for the infection prior to fracture healing or classification as a nonunion. Nonunion was defined by failure of progressive healing on sequential radiographs and/or surgical treatment for nonunion repair at least six months post-injury

Erratum: “Searches for Gravitational Waves from Known Pulsars at Two Harmonics in 2015–2017 LIGO Data” (2019, ApJ, 879, 10)

Due to an error at the publisher, in the published article the number of pulsars presented in the paper is incorrect in multiple places throughout the text. Specifically, "222" pulsars should be "221." Additionally, the number of pulsars for which we have EM observations that fully overlap with O1 and O2 changes from "168" to "167." Elsewhere, in the machine-readable table of Table 1 and in Table 2, the row corresponding to pulsar J0952-0607 should be excised as well. Finally, in the caption for Table 2 the number of pulsars changes from "188" to "187.

Search for gravitational waves from Scorpius X-1 in the second Advanced LIGO observing run with an improved hidden Markov model

We present results from a semicoherent search for continuous gravitational waves from the low-mass x-ray binary Scorpius X-1, using a hidden Markov model (HMM) to track spin wandering. This search improves on previous HMM-based searches of LIGO data by using an improved frequency domain matched filter, the J-statistic, and by analyzing data from Advanced LIGO's second observing run. In the frequency range searched, from 60 to 650 Hz, we find no evidence of gravitational radiation. At 194.6 Hz, the most sensitive search frequency, we report an upper limit on gravitational wave strain (at 95% confidence) of h095%=3.47×10-25 when marginalizing over source inclination angle. This is the most sensitive search for Scorpius X-1, to date, that is specifically designed to be robust in the presence of spin wandering. © 2019 American Physical Society

Search for gravitational waves from Scorpius X-1 in the second Advanced LIGO observing run with an improved hidden Markov model

We present results from a semicoherent search for continuous gravitational waves from the low-mass x-ray binary Scorpius X-1, using a hidden Markov model (HMM) to track spin wandering. This search improves on previous HMM-based searches of LIGO data by using an improved frequency domain matched filter, the J-statistic, and by analyzing data from Advanced LIGO’s second observing run. In the frequency range searched, from 60 to 650 Hz, we find no evidence of gravitational radiation. At 194.6 Hz, the most sensitive search frequency, we report an upper limit on gravitational wave strain (at 95% confidence) of h95%0=3.47×10−25 when marginalizing over source inclination angle. This is the most sensitive search for Scorpius X-1, to date, that is specifically designed to be robust in the presence of spin wandering

Erratum: "A Gravitational-wave Measurement of the Hubble Constant Following the Second Observing Run of Advanced LIGO and Virgo" (2021, ApJ, 909, 218)

[no abstract available

GW190412: Observation of a Binary-Black-Hole Coalescence with Asymmetric Masses

We report the observation of gravitational waves from a binary-black-hole coalescence during the first two weeks of LIGO’s and Virgo’s third observing run. The signal was recorded on April 12, 2019 at 05∶30∶44 UTC with a network signal-to-noise ratio of 19. The binary is different from observations during the first two observing runs most notably due to its asymmetric masses: a ∼30 M_⊙ black hole merged with a ∼8 M_⊙ black hole companion. The more massive black hole rotated with a dimensionless spin magnitude between 0.22 and 0.60 (90% probability). Asymmetric systems are predicted to emit gravitational waves with stronger contributions from higher multipoles, and indeed we find strong evidence for gravitational radiation beyond the leading quadrupolar order in the observed signal. A suite of tests performed on GW190412 indicates consistency with Einstein’s general theory of relativity. While the mass ratio of this system differs from all previous detections, we show that it is consistent with the population model of stellar binary black holes inferred from the first two observing runs

Properties and Astrophysical Implications of the 150 M_⊙ Binary Black Hole Merger GW190521

The gravitational-wave signal GW190521 is consistent with a binary black hole (BBH) merger source at redshift 0.8 with unusually high component masses, 85⁺²¹₋₁₄ M_⊙ and 66⁺¹⁷₋₁₈ M_⊙, compared to previously reported events, and shows mild evidence for spin-induced orbital precession. The primary falls in the mass gap predicted by (pulsational) pair-instability supernova theory, in the approximate range 65–120 M_⊙. The probability that at least one of the black holes in GW190521 is in that range is 99.0%. The final mass of the merger 142⁺²⁸₋₁₆ M_⊙) classifies it as an intermediate-mass black hole. Under the assumption of a quasi-circular BBH coalescence, we detail the physical properties of GW190521's source binary and its post-merger remnant, including component masses and spin vectors. Three different waveform models, as well as direct comparison to numerical solutions of general relativity, yield consistent estimates of these properties. Tests of strong-field general relativity targeting the merger-ringdown stages of the coalescence indicate consistency of the observed signal with theoretical predictions. We estimate the merger rate of similar systems to be 0.13_(-0.11)^(+0.30) Gpc⁻³ yr⁻¹. We discuss the astrophysical implications of GW190521 for stellar collapse and for the possible formation of black holes in the pair-instability mass gap through various channels: via (multiple) stellar coalescences, or via hierarchical mergers of lower-mass black holes in star clusters or in active galactic nuclei. We find it to be unlikely that GW190521 is a strongly lensed signal of a lower-mass black hole binary merger. We also discuss more exotic possible sources for GW190521, including a highly eccentric black hole binary, or a primordial black hole binary

Searches for gravitational waves from known pulsars at two harmonics in 2015-2017 LIGO data

International audienceWe present a search for gravitational waves from 222 pulsars with rotation frequencies ≳10 Hz. We use advanced LIGO data from its first and second observing runs spanning 2015–2017, which provides the highest-sensitivity gravitational-wave data so far obtained. In this search we target emission from both the l = m = 2 mass quadrupole mode, with a frequency at twice that of the pulsar’s rotation, and the l = 2, m = 1 mode, with a frequency at the pulsar rotation frequency. The search finds no evidence for gravitational-wave emission from any pulsar at either frequency. For the l = m = 2 mode search, we provide updated upper limits on the gravitational-wave amplitude, mass quadrupole moment, and fiducial ellipticity for 167 pulsars, and the first such limits for a further 55. For 20 young pulsars these results give limits that are below those inferred from the pulsars’ spin-down. For the Crab and Vela pulsars our results constrain gravitational-wave emission to account for less than 0.017% and 0.18% of the spin-down luminosity, respectively. For the recycled millisecond pulsar J0711−6830 our limits are only a factor of 1.3 above the spin-down limit, assuming the canonical value of 1038 kg m2 for the star’s moment of inertia, and imply a gravitational-wave-derived upper limit on the star’s ellipticity of 1.2 × 10−8. We also place new limits on the emission amplitude at the rotation frequency of the pulsars