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- Kotmayer, L, et al.
(författare)
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Landscape of BCL2 Resistance Mutations in a Real-World Cohort of Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia Treated with Venetoclax
- 2023
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Ingår i: International journal of molecular sciences. - : MDPI AG. - 1422-0067. ; 24:6
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Tidskriftsartikel (refereegranskat)abstract
- The oral, highly selective Bcl2 inhibitor venetoclax has substantially improved the therapeutic landscape of chronic lymphocytic leukemia (CLL). Despite the remarkable response rates in patients with relapsed/refractory (R/R) disease, acquired resistance is the leading cause of treatment failure, with somatic BCL2 mutations being the predominant genetic drivers underpinning venetoclax resistance. To assess the correlation between disease progression and the most common BCL2 mutations G101V and D103Y, sensitive (10−4) screening for the most common BCL2 mutations G101V and D103Y was performed in 67 R/R CLL patients during venetoclax single-agent or venetoclax–rituximab combination therapy. With a median follow-up time of 23 months, BCL2 G101V and D103Y were detected in 10.4% (7/67) and 11.9% (8/67) of the cases, respectively, with four patients harboring both resistance mutations. Ten out of eleven patients carrying BCL2 G101V and/or D103Y experienced relapse during the follow-up period, representing 43.5% of the cases (10/23) showing clinical signs of disease progression. All BCL2 G101V or D103Y variants were detected in patients receiving venetoclax as a continuous single-agent treatment while these mutations were not observed during or after fixed-duration venetoclax therapy. Targeted ultra-deep sequencing of BCL2 uncovered three additional variants in four patient samples obtained at relapse, suggesting convergent evolution and implying a cooperating role of BCL2 mutations in driving venetoclax resistance. This cohort is the largest R/R CLL patient population reported to date in which BCL2 resistance mutations were investigated. Our study demonstrates the feasibility and clinical value of sensitive screening for BCL2 resistance mutations in R/R CLL.
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| 2. |
- Elmegreen, B.G., et al.
(författare)
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Hubble Space Telescope Observations of the Interacting Galaxies NGC 2207 and IC 2163
- 2000
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Ingår i: Astronomical Journal. - : American Astronomical Society. - 1538-3881 .- 0004-6256. ; 120:2, s. 630-644
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Tidskriftsartikel (refereegranskat)abstract
- Hubble Space Telescope (HST) images of the galaxies NGC 2207 and IC 2163 show star formation and dust structures in a system that has experienced a recent grazing encounter. Tidal forces from NGC 2207 compressed and elongated the disk of IC 2163, forming an oval ridge of star formation along a caustic where the perturbed gas rebounded after its inward excursion. Gas flowing away from this ridge has a peculiar structure characterized by thin parallel dust filaments transverse to the direction of motion. The filaments become thicker and longer as the gas approaches the tidal arm. Star formation that occurs in the filaments consistently lags behind, as if the exponential disk pressure gradient pushes outward on the gas but not on the young stars. Numerical models suggest that the filaments come from flocculent spiral arms that were present before the interaction. The arms stretch out into parallel filaments as the tidal tail forms. A dust lane at the outer edge of the tidal tail is a shock front where the flow abruptly changes direction. Gas at small-to-intermediate radii along this edge flows back toward the galaxy, while elsewhere in the tidal arm, the gas flows outward.A spiral arm of NGC 2207 that is backlit by IC 2163 is seen with HST to contain several parallel, knotty filaments spanning the full width of the arm. These filaments are probably shock fronts in a density wave. The parallel structure suggests that the shocks occur in several places throughout the arm, or that the interarm gas is composed of spiral-like wisps that merge together in the arms. Blue clusters of star formation inside the clumps of these dust lanes show density-wave triggering in unprecedented detail. The star formation process seems to be one of local gravitational collapse, rather than cloud collisions. Spiral arms inside the oval of IC 2163 have a familiar geometry reminiscent of a bar, although there is no obvious stellar bar. The shape and orientation of these arms suggest they could be the result of inner Lindblad resonance–related orbits in the cos 2θ tidal potential that formed the oval. Their presence suggests that tidal forces alone may initiate a temporary nuclear gas flow and eventual starburst without first forming a stellar bar. Several emission structures resembling jets or conical flows that are 100–1000 pc long appear in these galaxies. In the western arm of NGC 2207, there is a dense dark cloud with a conical shape 400 pc long and a bright compact cluster at the tip, and there is a conical emission nebula of the same length that points away from the cluster in the other direction. This region also coincides with a nonthermal radio continuum source that is ~1000 times the luminosity of Cas A at λ = 20 cm. Surrounding clusters in arclike patterns may have been triggered by enormous explosions.
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