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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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| 4. |
- Pelaz, B, et al.
(författare)
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Diverse Applications of Nanomedicine
- 2017
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Ingår i: ACS nano. - : American Chemical Society (ACS). - 1936-086X .- 1936-0851. ; 11:3, s. 2313-2381
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Tidskriftsartikel (refereegranskat)
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| 5. |
- Ajzner, E, et al.
(författare)
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Anti-factor V auto-antibody in the plasma and platelets of a patient with repeated gastrointestinal bleeding
- 2003
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Ingår i: Journal of Thrombosis and Haemostasis. - : Elsevier BV. - 1538-7933 .- 1538-7836. ; 1:5, s. 943-949
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Tidskriftsartikel (refereegranskat)abstract
- Development of autoantibody against coagulation factor V (FV) is a rare clinical condition with hemorrhagic complications of varying severity. The aim of this study was to establish the pathomechanism of an acquired FV deficiency and characterize the FV inhibitor responsible for the clinical symptoms. A 78-year-old female was admitted to hospital with severe gastrointestinal bleeding. General clotting tests and determination of clotting factors were performed by standard methods. FV antigen and FV containing immune complexes were measured by ELISA. The FV molecule was investigated by Western blotting and by sequencing the f5 gene. The binding of patient's IgG to FV and activated FV (FVa) was demonstrated in an ELISA system and its effect on the procoagulant activity of FVa was tested in clotting tests and in a chromogenic prothrombinase assay. Localization of the epitope for the antibody was performed by blocking ELISA. FV activity was severely suppressed both in plasma and platelets. FV antigen levels were normal by ELISA using polyclonal anti-FV antibody or monoclonal antibody against the connecting region of FV, but depressed when HV1 monoclonal antibody against the C2 domain in the FV light-chain was used as capture antibody. The FV molecule was found intact. An IgG reacting with both FV and FVa was present in the patient's plasma and its binding to FV was inhibited by HV1 antibody. FV-containing immune complexes were detected in the patient's plasma and platelet lysate. The patient's IgG inhibited the procoagulant function of FVa. An anti-FV IgG was present in the patient's plasma and platelets. The autoantibody reacted with an epitope in the C2 domain of FV light chain and neutralized the procoagulant function of FVa.
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| 8. |
- Balogh, Johanna, et al.
(författare)
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Hearts from mice lacking desmin have a myopathy with impaired active force generation and unaltered wall compliance.
- 2002
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Ingår i: Cardiovascular Research. - 1755-3245. ; 53:2, s. 439-450
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Desmin intermediate filaments are key structures in the cytoskeleton of cardiac muscle. Since they are associated with Z-discs and intercalated discs, they may have a role in sarcomere alignment or force transmission. We have explored the mechanical function of the desmin filaments in the cardiac wall by comparing desmin-deficient (Des-/-) and wild-type (Des+/+) mice. METHODS: The Langendorff technique was used to examine the contractility of the whole heart. Rate of force generation, Ca(2+)-sensitivity and force per cross-sectional area were measured in skinned ventricle muscle preparations. RESULTS: Des-/- mice have a cardiomyopathy with increased heart weight. Diastolic pressure was increased at all filling volumes in the Des-/- group. Since passive wall stress (i.e. force per area) was unchanged, the alteration in diastolic pressure is a consequence of the thicker ventricle wall. Developed pressure, rate of pressure increase and developed wall stress were significantly reduced, suggesting that active force generation of the contractile apparatus is reduced in Des-/-. Concentrations of actin and myosin in the ventricle were unaltered. Measurements in skinned muscle preparations showed a lower active force development with unaltered Ca(2+)-sensitivity and rate of tension development. CONCLUSION: It is suggested that the intermediate filaments have a role in active force generation of cardiac muscle, possibly by supporting sarcomere alignment or force transmission. The desmin filaments do not contribute the passive elasticity of the ventricle wall. Des-/- mice provide a model for genetic cardiomyopathy where the main factor contributing to altered cardiac performance is a decrease in active force generation, possibly in combination with a loss of functional contractile units.
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| 10. |
- Balogh, Johanna, et al.
(författare)
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Lower active force generation and improved fatigue resistance in skeletal muscle from desmin deficient mice.
- 2003
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Ingår i: Journal of Muscle Research and Cell Motility. - 0142-4319. ; 24:7, s. 453-459
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Tidskriftsartikel (refereegranskat)abstract
- The mechanical effects of the intermediate filament protein desmin was examined in desmin deficient mice (Des-/-) and their wild type control (Des+/+). Active force generation was determined in intact soleus muscles and in skinned single fibres from soleus and psoas. A decreased force generation of skinned muscle fibres from Des-/- mice and a tendency towards decreased active force in intact soleus muscle were detected. Concentrations of the contractile protein actin and myosin were not altered in Des-/- muscles. Ca(2+)-sensitivity of skinned single fibres in Des-/- muscles was unchanged compared to Des+/+. Using a protocol with repeated short tetani an increased fatigue resistance was found in the intact soleus muscles from Des-/- mice. In conclusion, desmin intermediate filaments are required for optimal generation or transmission of active force in skeletal muscle. Although other studies have shown that the desmin intermediate filaments appear to influence Ca(2+)-handling, the Ca(2+)-sensitivity of the contractile filaments is not altered in skeletal muscle of Des-/- mice. Previous studies have reported a switch towards slower myosin isoforms in slow skeletal muscle of Des-/- mice. The increased fatigue resistance show that this change is reflected in the physiological function of the muscle.
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