DSS1 is an evolutionarily conserved acidic protein that binds to BRCA2. However, study of the function of DSS1 in mammalian cells has been hampered because endogenous DSS1 has not been detectable by Western blotting. Here, we developed a modified Western blotting protocol that detects endogenous DSS1 protein, and used it to study the function of DSS1 and its interaction with BRCA2 in mammalian cells. We found that essentially all BRCA2 in human cell lines is associated with DSS1. Importantly, we found that RNAi knockdown of DSS1 in human cell lines led to dramatic loss of BRCA2 protein, mainly due to its increased degradation. Furthermore, the stability of BRCA2 mutant devoid of the DSS1-binding domain is unaffected by the depletion of DSS1. Most notably, like BRCA2 depletion, DSS1 depletion also led to hypersensitivity to DNA damage. These results demonstrated that the stability of BRCA2 protein in mammalian cells depends on the presence of DSS1. Deletion or mutation of DSS1 or suppression of its expression by other mechanisms are therefore potential causative mechanisms for human breast and ovarian cancer. Such mechanisms may be relevant to sporadic as well as familiar breast cancer where BRCA1 and BRCA2 mutations are not present.

We search for signatures of gravitational lensing in the gravitational-wave signals from compact binary coalescences detected by Advanced Laser Interferometer Gravitational-wave Observatory (LIGO) and Advanced Virgo during O3a, the first half of their third observing run. We study: (1) the expected rate of lensing at current detector sensitivity and the implications of a non-observation of strong lensing or a stochastic gravitational-wave background on the merger-rate density at high redshift; (2) how the interpretation of individual high-mass events would change if they were found to be lensed; (3) the possibility of multiple images due to strong lensing by galaxies or galaxy clusters; and (4) possible wave-optics effects due to point-mass microlenses. Several pairs of signals in the multiple-image analysis show similar parameters and, in this sense, are nominally consistent with the strong lensing hypothesis. However, taking into account population priors, selection effects, and the prior odds against lensing, these events do not provide sufficient evidence for lensing. Overall, we find no compelling evidence for lensing in the observed gravitational-wave signals from any of these analyses.

We present a search for quasi-monochromatic gravitational-wave signals from the young, energetic X-ray pulsar PSR J0537−6910 using data from the second and third observing runs of LIGO and Virgo. The search is enabled by a contemporaneous timing ephemeris obtained using Neutron star Interior Composition Explorer (NICER) data. The NICER ephemeris has also been extended through 2020 October and includes three new glitches. PSR J0537 −6910 has the largest spin-down luminosity of any pulsar and exhibits fRequent and strong glitches. Analyses of its long-term and interglitch braking indices provide intriguing evidence that its spin-down energy budget may include gravitational-wave emission from a time-varying mass quadrupole moment. Its 62 Hz rotation frequency also puts its possible gravitational-wave emission in the most sensitive band of the LIGO/Virgo detectors. Motivated by these considerations, we search for gravitational-wave emission at both once and twice the rotation frequency from PSR J0537−6910. We find no signal, however, and report upper limits. Assuming a rigidly rotating triaxial star, our constraints reach below the gravitational-wave spin-down limit for this star for the first time by more than a factor of 2 and limit gravitational waves from the l = m = 2 mode to account for less than 14% of the spin-down energy budget. The fiducial equatorial ellipticity is constrained to less than about 3 ×10 −5 , which is the third best constraint for any young pulsar.

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3580 Background: AZD4877 is a potent, specific inhibitor of Eg5 (kinesin spindle protein). The only known function of Eg5 is to separate the centromeres during mitosis. Eg5 inhibition is thus specific for dividing cells, resulting in monoastral mitotic spindles (monoasters) and apoptotic cell death. Preclinically, hematologic tumor cell lines were generally more sensitive to AZD4877 than those derived from solid tumors. Methods: AZD4877 was administered IV daily x 3 as induction for up to 2 cycles, followed by consolidation (daily x 2) for up to 4 cycles. Eligibility criteria were standard. Results: Cohorts of 3–6 patients (pts) were treated at doses of 2, 4, 7, 10, 13, 16, and 18 mg/day. To date, 24 evaluable pts have received 33 induction and 3 consolidation cycles of treatment. Monoasters were detected at all dose levels evaluated (2, 7, 10, 13, and 18 mg/day). The T1/2 of AZD4877 ranged from 26 to 42 hr; PK were linear and drug levels non-cumulative. Myelosuppression, the dose limiting toxicity (DLT) in solid tumor studies, was not considered a DLT in this trial. Mucositis was the DLT at 18 mg/day; with 1 pt developing Gr 3 palmar-plantar syndrome at this dose. Bone marrow biopsies were undertaken at screening and as clinically indicated. In pts with evaluable biopsies, marrow blasts decreased by 60–80% in 2 pts, and by 30–50% in 3 pts, with no response in 3 pts. Conclusions: Enrollment is ongoing at 16 mg, the likely Phase 2 dose. Preliminary results suggest possible clinical activity in AML. An expansion phase at the MTD is planned. [Table: see text]