MMP Inhibition in Prostate Cancer

Matrix metalloproteinases (MMPs) play a significant role during the development and metastasis of prostate cancer (CaP). CaP cells secrete high levels of MMPs and low levels of endogenous MMP inhibitors (TIMPs), thus creating an excess balance of MMPs. Established CaP cell lines that express high levels of MMPs frequently metastasize to the bone and the lungs. Drugs such as Taxol and alendronate that reduce cell motility and calcium metabolism reduce bony metastasis of xenografted CaP tumors. We tested several synthetic, nontoxic inhibitors of MMPs that can be administered orally, including doxycycline (DC) and chemically modified tetracyclines (CMTs) on CaP cells in vitro and on a rat CaP model in vivo. Among several anti‐MMP agents tested, CMT‐3 (6‐deoxy, 6‐demethyl,4‐de‐dimethylamino tetracycline) showed highest activity against CaP cell invasion and cell proliferation. Micromolar concentration of CMT‐3 and DC inhibited both the secretion and activity of MMPs by CaP cells. When tested for in vivo efficacy in the Dunning rat CaP model by daily oral gavage, CMT‐3 and DC both reduced the lung metastases (> 50%). CMT‐3, but not DC, inhibited tumor incidence (55 ± 9%) and also reduced the tumor growth rate (27 ± 9.3%). More significantly, the drugs showed minimum systemic toxicity. Ongoing studies indicate that CMT‐3 may inhibit the skeletal metastases of CaP cells and delay the onset of paraplegia due to lumbar metastases. These preclinical studies provide the basis for clinical trials of CMT‐3 for the treatment of metastatic disease

Search for gravitational-lensing signatures in the full third observing run of the LIGO-Virgo network

International audienceGravitational lensing by massive objects along the line of sight to the source causes distortions of gravitational wave-signals; such distortions may reveal information about fundamental physics, cosmology and astrophysics. In this work, we have extended the search for lensing signatures to all binary black hole events from the third observing run of the LIGO--Virgo network. We search for repeated signals from strong lensing by 1) performing targeted searches for subthreshold signals, 2) calculating the degree of overlap amongst the intrinsic parameters and sky location of pairs of signals, 3) comparing the similarities of the spectrograms amongst pairs of signals, and 4) performing dual-signal Bayesian analysis that takes into account selection effects and astrophysical knowledge. We also search for distortions to the gravitational waveform caused by 1) frequency-independent phase shifts in strongly lensed images, and 2) frequency-dependent modulation of the amplitude and phase due to point masses. None of these searches yields significant evidence for lensing. Finally, we use the non-detection of gravitational-wave lensing to constrain the lensing rate based on the latest merger-rate estimates and the fraction of dark matter composed of compact objects

Search for gravitational-lensing signatures in the full third observing run of the LIGO-Virgo network

International audienceGravitational lensing by massive objects along the line of sight to the source causes distortions of gravitational wave-signals; such distortions may reveal information about fundamental physics, cosmology and astrophysics. In this work, we have extended the search for lensing signatures to all binary black hole events from the third observing run of the LIGO--Virgo network. We search for repeated signals from strong lensing by 1) performing targeted searches for subthreshold signals, 2) calculating the degree of overlap amongst the intrinsic parameters and sky location of pairs of signals, 3) comparing the similarities of the spectrograms amongst pairs of signals, and 4) performing dual-signal Bayesian analysis that takes into account selection effects and astrophysical knowledge. We also search for distortions to the gravitational waveform caused by 1) frequency-independent phase shifts in strongly lensed images, and 2) frequency-dependent modulation of the amplitude and phase due to point masses. None of these searches yields significant evidence for lensing. Finally, we use the non-detection of gravitational-wave lensing to constrain the lensing rate based on the latest merger-rate estimates and the fraction of dark matter composed of compact objects