Cyclic AMP Phosphodiesterase in Leydig Cell Preparations of the Rat Testis

Enzymatic digestion of the interstitial tissue of early juvenile and adult rat testes resulted in an enrichment of the Leydig cell population. The cells of the intertubular preparation from adult testes were separated by centrifugal elutriation, according to differences in sedimentation velocity, a counter-flow centrifugation technique leading to 70% Leydig cell purity. Using this approach, it was possible to demonstrate that Leydig cells from adult testes contain only low affinity isoenzymes of cyclic AMP phosphodiesterase (PDE; E.C.: 3.1.4.17), an intracellular regulator of cAMP. Starch gel electrophoresis showed that the isozyme of cAMP PDE of Leydig cells is masked in crude testis homogenates due to the relatively low level of these cells in the total population. In Leydig cells, there are two different electrophoretic forms expressed which resemble two of eleven different molecular forms of cAMP PDE demonstrated for comparison in 21 different organs of the adult rat.
An interstitial cell preparation from early juvenile testes, with a Leydig cell content of up to 20%, was also investigated electrophoretically with regard to molecular forms of cAMP PDE, the properties of which were characterized by kinetic analysis of cAMP hydrolysis. The results presented are discussed in relation to the onset of testosterone synthesis in Leydig cells of prepubertal rats leading to the initiation of male puberty.     

Carfilzomib,lenalidomide, dexamethasone,and cyclophosphamide (KRdc) as induction therapy for transplant-eligible,newly diagnosed multiple myeloma patients (Myeloma XI+): Interim analysis of an open-label randomised controlled trial

BackgroundCarfilzomib is a second-generation irreversible proteasome inhibitor that is efficacious in the treatment of myeloma and carries less risk of peripheral neuropathy than first-generation proteasome inhibitors, making it more amenable to combination therapy.Methods and findingsThe Myeloma XI+ trial recruited patients from 88 sites across the UK between 5 December 2013 and 20 April 2016. Patients with newly diagnosed multiple myeloma eligible for transplantation were randomly assigned to receive the combination carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide (KRdc) or a triplet of lenalidomide, dexamethasone, and cyclophosphamide (Rdc) or thalidomide, dexamethasone, and cyclophosphamide (Tdc). All patients were planned to receive an autologous stem cell transplantation (ASCT) prior to a randomisation between lenalidomide maintenance and observation. Eligible patients were aged over 18 years and had symptomatic myeloma. The co-primary endpoints for the study were progression-free survival (PFS) and overall survival (OS) for KRdc versus the Tdc/Rdc control group by intention to treat. PFS, response, and safety outcomes are reported following a planned interim analysis. The trial is registered (ISRCTN49407852) and has completed recruitment. In total, 1,056 patients (median age 61 years, range 33 to 75, 39.1% female) underwent induction randomisation to KRdc (n = 526) or control (Tdc/Rdc, n = 530). After a median follow-up of 34.5 months, KRdc was associated with a significantly longer PFS than the triplet control group (hazard ratio 0.63, 95% CI 0.51–0.76). The median PFS for patients receiving KRdc is not yet estimable, versus 36.2 months for the triplet control group (p < 0.001). Improved PFS was consistent across subgroups of patients including those with genetically high-risk disease. At the end of induction, the percentage of patients achieving at least a very good partial response was 82.3% in the KRdc group versus 58.9% in the control group (odds ratio 4.35, 95% CI 3.19–5.94, p < 0.001). Minimal residual disease negativity (cutoff 4 × 10⁻⁵ bone marrow leucocytes) was achieved in 55% of patients tested in the KRdc group at the end of induction, increasing to 75% of those tested after ASCT. The most common adverse events were haematological, with a low incidence of cardiac events. The trial continues to follow up patients to the co-primary endpoint of OS and for planned long-term follow-up analysis. Limitations of the study include a lack of blinding to treatment regimen and that the triplet control regimen did not include a proteasome inhibitor for all patients, which would be considered a current standard of care in many parts of the world.ConclusionsThe KRdc combination was well tolerated and was associated with both an increased percentage of patients achieving at least a very good partial response and a significant PFS benefit compared to immunomodulatory-agent-based triplet therapy.Trial registrationClinicalTrials.gov ISRCTN49407852.

Graham Jackson and co-workers study a combination induction treatment including carfilzomib for patients with transplant-eligible myeloma.