Osteopontin plasma levels and accelerated atherosclerosis in patients with CAD undergoing PCI: a prospective clinical study.

OBJECTIVES: Growing evidence supports the role played by inflammation in atherosclerosis. Identifying sensitive biomarkers is useful in predicting accelerated atherosclerosis. We investigated prospectively the relationship between plasma levels of inflammatory biomarkers [osteopontin, C-reactive protein (CRP), interleukin-6 (IL-6)] and instent restenosis, and rapid coronary plaque progression in patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI). METHODS: We studied 77 patients with CAD: 45 affected by unstable angina/non-ST elevation myocardial infarction [acute coronary syndrome (ACS)], and 32 by chronic coronary syndrome (CCS). Plasma osteopontin, IL-6, and CRP levels were measured before intervention in all patients; measurements were carried out on the basis of the following time course at 1,15, 30, 90, and 180 days follow-up in a subgroup of 39 consenting patients. Clinical and biohumoral data were correlated with baseline and 6-month PCI follow-up angiography. RESULTS: Osteopontin, IL-6, and CRP were higher in patients with ACS than in those with CCS (analysis of variance: P<0.001, 0.05, and 0.05, respectively). Baseline osteopontin levels proved to be associated with rapid coronary plaque progression (P=0.005) and instent restenosis (P=0.05). The highest osteopontin levels were found in patients with CAD with both rapid plaque progression and instent restenosis (P=0.003). PCI increased inflammatory markers acutely, and osteopontin remained elevated in patients with ACS. Patients with ACS showed a higher percentage (74%) of rapid plaque progression than those with CCS (26%) (P<0.05). CONCLUSION: The study prospectively shows the link between inflammatory status and accelerated atherosclerosis in patients with CAD undergoing PCI. The baseline and persistent rise of osteopontin is an expression of its contribution to the accelerated plaque progression, and therefore osteopontin may be a useful prognostic biomarker

Search for intermediate mass black hole binaries in the first and second observing runs of the Advanced LIGO and Virgo network

Gravitational-wave astronomy has been firmly established with the detection of gravitational waves from the merger of ten stellar-mass binary black holes and a neutron star binary. This paper reports on the all-sky search for gravitational waves from intermediate mass black hole binaries in the first and second observing runs of the Advanced LIGO and Virgo network. The search uses three independent algorithms: two based on matched filtering of the data with waveform templates of gravitational-wave signals from compact binaries, and a third, model-independent algorithm that employs no signal model for the incoming signal. No intermediate mass black hole binary event is detected in this search. Consequently, we place upper limits on the merger rate density for a family of intermediate mass black hole binaries. In particular, we choose sources with total masses M=m1+m2ϵ[120,800] M and mass ratios q=m2/m1ϵ[0.1,1.0]. For the first time, this calculation is done using numerical relativity waveforms (which include higher modes) as models of the real emitted signal. We place a most stringent upper limit of 0.20 Gpc-3 yr-1 (in comoving units at the 90% confidence level) for equal-mass binaries with individual masses m1,2=100 M and dimensionless spins χ1,2=0.8 aligned with the orbital angular momentum of the binary. This improves by a factor of ∼5 that reported after Advanced LIGO's first observing run

p53 Interacts with RNA Polymerase II through Its Core Domain and Impairs Pol II Processivity In Vivo

The tumor suppressor p53 principally functions as a gene-specific transcription factor. p53 triggers a variety of anti-proliferative programs by activating or repressing the transcription of effector genes in response to genotoxic stress. To date, much effort has been placed on understanding p53's ability to affect transcription in the context of its DNA-binding activity. How p53 regulates transcriptional output independent of DNA binding is less well understood. Here we provide evidence that human p53 can physically interact with the large subunit of RNA polymerase II (Pol II) both in in vitro interaction assays and in whole cell extracts, and that this interaction is mediated (at least in part) through p53's core DNA-binding domain and the Ser5-phosphorylated CTD of Pol II. Ectopic expression of p53, combined with mutations in transcription elongation factors or exposure to drugs that inhibit Pol II elongation, elicit sickness or lethality in yeast cells. These phenotypes are suppressed by oncogenic point mutations within p53's core domain. The growth phenotypes raise the possibility that p53 impairs Pol II elongation. Consistent with this, a p53-dependent increase in Pol II density is seen at constitutively expressed genes without a concomitant increase in transcript accumulation. Additionally, p53-expressing yeast strains exhibit reduced transcriptional processivity at an episomal reporter gene; this inhibitory activity is abolished by a core domain point mutation. Our results suggest a novel mechanism by which p53 can regulate gene transcription, and a new biological function for its core domain that is susceptible to inactivation by oncogenic point mutations

Suppression of FOXM1 Sensitizes Human Cancer Cells to Cell Death Induced by DNA-Damage

Irradiation and DNA-damaging chemotherapeutic agents are commonly used in anticancer treatments. Following DNA damage FOXM1 protein levels are often elevated. In this study, we sought to investigate the potential role of FOXM1 in programmed cell death induced by DNA-damage. Human cancer cells after FOXM1 suppression were subjected to doxorubicin or γ-irradiation treatment. Our findings indicate that FOXM1 downregulation by stable or transient knockdown using RNAi or by treatment with proteasome inhibitors that target FOXM1 strongly sensitized human cancer cells of different origin to DNA-damage-induced apoptosis. We showed that FOXM1 suppresses the activation of pro-apoptotic JNK and positively regulates anti-apoptotic Bcl-2, suggesting that JNK activation and Bcl-2 down-regulation could mediate sensitivity to DNA-damaging agent-induced apoptosis after targeting FOXM1. Since FOXM1 is widely expressed in human cancers, our data further support the fact that it is a valid target for combinatorial anticancer therapy

Mechanism of Cancer Cell Death Induced by Depletion of an Essential Replication Regulator

Background: Depletion of replication factors often causes cell death in cancer cells. Depletion of Cdc7, a kinase essential for initiation of DNA replication, induces cancer cell death regardless of its p53 status, but the precise pathways of cell death induction have not been characterized. Methodology/Principal Findings: We have used the recently-developed cell cycle indicator, Fucci, to precisely characterize the cell death process induced by Cdc7 depletion. We have also generated and utilized similar fluorescent cell cycle indicators using fusion with other cell cycle regulators to analyze modes of cell death in live cells in both p53-positive and-negative backgrounds. We show that distinct cell-cycle responses are induced in p53-positive and-negative cells by Cdc7 depletion. p53-negative cells predominantly arrest temporally in G2-phase, accumulating CyclinB1 and other mitotic regulators. Prolonged arrest at G2-phase and abrupt entry into aberrant M-phase in the presence of accumulated CyclinB1 are followed by cell death at the post-mitotic state. Abrogation of cytoplasmic CyclinB1 accumulation partially decreases cell death. The ATR-MK2 pathway is responsible for sequestration of CyclinB1 with 14-3-3s protein. In contrast, p53-positive cancer cells do not accumulate CyclinB1, but appear to die mostly through entry into aberrant S-phase after Cdc7 depletion. The combination of Cdc7 inhibition with known anti-cancer agents significantly stimulates cell death effects in cancer cells in a genotype-dependent manner, providing a strategic basis for future combination therapies

GWTC-3: Compact Binary Coalescences Observed by LIGO and Virgo during the Second Part of the Third Observing Run

The third Gravitational-Wave Transient Catalog (GWTC-3) describes signals detected with Advanced LIGO and Advanced Virgo up to the end of their third observing run. Updating the previous GWTC-2.1, we present candidate gravitational waves from compact binary coalescences during the second half of the third observing run (O3b) between 1 November 2019, 15∶00 Coordinated Universal Time (UTC) and 27 March 2020, 17∶00 UTC. There are 35 compact binary coalescence candidates identified by at least one of our search algorithms with a probability of astrophysical origin pastro>0.5. Of these, 18 were previously reported as low-latency public alerts, and 17 are reported here for the first time. Based upon estimates for the component masses, our O3b candidates with pastro>0.5 are consistent with gravitational-wave signals from binary black holes or neutron-star-black-hole binaries, and we identify none from binary neutron stars. However, from the gravitational-wave data alone, we are not able to measure matter effects that distinguish whether the binary components are neutron stars or black holes. The range of inferred component masses is similar to that found with previous catalogs, but the O3b candidates include the first confident observations of neutron-star-black-hole binaries. Including the 35 candidates from O3b in addition to those from GWTC-2.1, GWTC-3 contains 90 candidates found by our analysis with pastro>0.5 across the first three observing runs. These observations of compact binary coalescences present an unprecedented view of the properties of black holes and neutron stars

Search for Gravitational Waves Associated with Fast Radio Bursts Detected by CHIME/FRB during the LIGO-Virgo Observing Run O3a

We search for gravitational-wave (GW) transients associated with fast radio bursts (FRBs) detected by the Canadian Hydrogen Intensity Mapping Experiment Fast Radio Burst Project, during the first part of the third observing run of Advanced LIGO and Advanced Virgo (2019 April 1 15:00 UTC-2019 October 1 15:00 UTC). Triggers from 22 FRBs were analyzed with a search that targets both binary neutron star (BNS) and neutron star-black hole (NSBH) mergers. A targeted search for generic GW transients was conducted on 40 FRBs. We find no significant evidence for a GW association in either search. Given the large uncertainties in the distances of our FRB sample, we are unable to exclude the possibility of a GW association. Assessing the volumetric event rates of both FRB and binary mergers, an association is limited to 15% of the FRB population for BNS mergers or 1% for NSBH mergers. We report 90% confidence lower bounds on the distance to each FRB for a range of GW progenitor models and set upper limits on the energy emitted through GWs for a range of emission scenarios. We find values of order 1051-1057 erg for models with central GW frequencies in the range 70-3560 Hz. At the sensitivity of this search, we find these limits to be above the predicted GW emissions for the models considered. We also find no significant coincident detection of GWs with the repeater, FRB 20200120E, which is the closest known extragalactic FRB

Constraints on the Cosmic Expansion History from GWTC-3

We use 47 gravitational wave sources from the Third LIGO-Virgo-Kamioka Gravitational Wave Detector Gravitational Wave Transient Catalog (GWTC-3) to estimate the Hubble parameter H(z), including its current value, the Hubble constant H0. Each gravitational wave (GW) signal provides the luminosity distance to the source, and we estimate the corresponding redshift using two methods: the redshifted masses and a galaxy catalog. Using the binary black hole (BBH) redshifted masses, we simultaneously infer the source mass distribution and H(z). The source mass distribution displays a peak around 34Me, followed by a drop-off. Assuming this mass scale does not evolve with the redshift results in a H(z) measurement, yielding H0 = 68+12-8 km s-1 Mpc-1 (68% credible interval) when combined with the H0 measurement from GW170817 and its electromagnetic counterpart. This represents an improvement of 17% with respect to the H0 estimate from GWTC-1. The second method associates each GW event with its probable host galaxy in the catalog GLADE+, statistically marginalizing over the redshifts of each event's potential hosts. Assuming a fixed BBH population, we estimate a value of H0 = 68+8-6 km s-1 Mpc-1 with the galaxy catalog method, an improvement of 42% with respect to our GWTC-1 result and 20% with respect to recent H0 studies using GWTC-2 events. However, we show that this result is strongly impacted by assumptions about the BBH source mass distribution; the only event which is not strongly impacted by such assumptions (and is thus informative about H0) is the well-localized event GW190814

Clinical spectrum time course in non-Asian patients positive for anti-MDA5 antibodies

Objectives: To define the clinical spectrum time-course and prognosis of non-Asian patients positive for anti-MDA5 antibodies. Methods: We conducted a multicentre, international, retrospective cohort study. Results: 149 anti-MDA5 positive patients (median onset age 53 years, median disease duration 18 months), mainly females (100, 67%), were included. Dermatomyositis (64, 43%) and amyopathic dermatomyositis (47, 31%), were the main diagnosis; 15 patients (10%) were classified as interstitial pneumonia with autoimmune features (IPAF) and 7 (5%) as rheumatoid arthritis. The main clinical findings observed were myositis (84, 56%), interstitial lung disease (ILD) (108, 78%), skin lesions (111, 74%), and arthritis (76, 51%). The onset of these manifestations was not concomitant in 74 cases (50%). Of note, 32 (21.5%) patients were admitted to the intensive care unit for rapidly progressive-ILD, which occurred in median 2 months from lung involvement detection, in the majority of cases (28, 19%) despite previous immunosuppressive treatment. One-third of patients (47, 32% each) was ANA and anti-ENA antibodies negative and a similar percentage was anti-Ro52 kDa antibodies positive. Non-specific interstitial pneumonia (65, 60%), organising pneumonia (23, 21%), and usual interstitial pneumonia-like pattern (14, 13%) were the main ILD patterns observed. Twenty-six patients died (17%), 19 (13%) had a rapidly progressive-ILD. Conclusions: The clinical spectrum of the anti-MDA5 antibodies-related disease is heterogeneous. Rapidly-progressive ILD deeply impacts the prognosis also in non-Asian patients, occurring early during the disease course. Anti-MDA5 antibody positivity should be considered even when baseline autoimmune screening is negative, anti-Ro52 kDa antibodies are positive, and radiology findings show a NSIP pattern