Dendritic cells in bone marrow at diagnosis and after chemotherapy in adult patients with acute myeloid leukaemia.

Dendritic cells (DCs) develop in the bone marrow from haematopoietic progenitor cells. Two subsets, plasmacytoid DCs (pDCs) and myeloid DCs (mDCs), have been identified. Little is known regarding DC levels in bone marrow of patients with acute myeloid leukaemia (AML) before and after chemotherapy. We investigated relative pDC and mDC levels in bone marrow from 37 hospital controls and 60 patients with AML [at diagnosis, complete remission (CR) and follow-up] using four-colour flow cytometry. The pDC immunophenotype was characterized as lin-/HLA-DR+/CD123 +  and mDC as lin-/HLA-DR+/CD11c+. In 69% of patients with AML, no DCs were detected at diagnosis. At CR, mDC levels were the same in patients with AML and hospital controls while pDC levels were slightly lower. There was no association between minimal residual disease or survival rates and DC levels. Patients with low mDC levels at CR were more likely to suffer from complicated infections, although the difference was not statistically significant. Altogether, there was a profound decrease in DC levels in patients with AML at diagnosis. DC levels increased at CR and were higher than in hospital controls after post-remission therapy, suggesting that DCs recover after repeated chemotherapy. There may be an association between mDC levels and infectious complications.

Glucocorticoid-induced cell death is mediated through reduced glucose metabolism in lymphoid leukemia cells.

Malignant cells are known to have increased glucose uptake and accelerated glucose metabolism. Using liquid chromatography and mass spectrometry, we found that treatment of acute lymphoblastic leukemia (ALL) cells with the glucocorticoid (GC) dexamethasone (Dex) resulted in profound inhibition of glycolysis. We thus demonstrate that Dex reduced glucose consumption, glucose utilization and glucose uptake by leukemic cells. Furthermore, Dex treatment decreased the levels of the plasma membrane-associated glucose transporter GLUT1, thus revealing the mechanism for the inhibition of glucose uptake. Inhibition of glucose uptake correlated with induction of cell death in ALL cell lines and in leukemic blasts from ALL patients cultured ex vivo. Addition of di-methyl succinate could partially overcome cell death induced by Dex in RS4;11 cells, thereby further supporting the notion that inhibition of glycolysis contributes to the induction of apoptosis. Finally, Dex killed RS4;11 cells significantly more efficiently when cultured in lower glucose concentrations suggesting that modulation of glucose levels might influence the effectiveness of GC treatment in ALL. In summary, our data show that GC treatment blocks glucose uptake by leukemic cells leading to inhibition of glycolysis and that these effects play an important role in the induction of cell death by these drugs.

Cell death induced by dexamethasone in lymphoid leukemia is mediated through initiation of autophagy.

Glucocorticoids are fundamental drugs used in the treatment of lymphoid malignancies with apoptotic cell death as the hitherto proposed mechanism of action. Recent studies, however, showed that an alternative mode of cell death, autophagy, is involved in the response to anticancer drugs. The specific role of autophagy and its relationship to apoptosis remains, nevertheless, controversial: it can either lead to cell survival or can function in cell death. We show that dexamethasone induced autophagy upstream of apoptosis in acute lymphoblastic leukemia cells. Inhibition of autophagy by siRNA-mediated repression of Beclin 1 expression inhibited apoptosis showing an important role of autophagy in dexamethasone-induced cell death. Dexamethasone treatment caused an upregulation of promyelocytic leukemia protein, PML, its complex formation with protein kinase B or Akt and a PML-dependent Akt dephosphorylation. Initiation of autophagy and the onset of apoptosis were both dependent on these events. PML knockout thymocytes were resistant to dexamethasone-induced death and upregulation of PML correlated with the ability of dexamethasone to kill primary leukemic cells. Our data reveal key mechanisms of dexamethasone-induced cell death that may inform the development of improved treatment protocols for lymphoid malignancies.

Dendritic cell regeneration in the bone marrow of children treated for acute lymphoblastic leukaemia.

Dendritic cells (DC) play a pivotal role in coordinating functions of the immune system. Little is known about DC levels in the bone marrow (BM) of patients receiving cytostatic treatment. We investigated DC levels by flow cytometry in BM at diagnosis, during and post-treatment in 76 children with acute lymphoblastic leukaemia (ALL). The levels of both plasmacytoid DC (pDC) and myeloid DC (mDC) were profoundly reduced at diagnosis. However, the levels of pDC and mDC were significantly higher in T-precursor ALL patients when compared with B-precursor ALL patient group (P = 0.044 and 0.041 respectively). Both subsets normalized in both standard-risk (SR) and high-risk patients after the end of induction at day 50. Patients with minimal residual disease (MRD) at day 50 had significantly higher pDC levels than MRD-negative patients (P = 0.021). In B-precursor SR ALL patients, mDC levels but not pDC levels decreased during prolonged maintenance treatment, remaining reduced at the end of treatment (P = 0.032) and at 6 months post-treatment (P = 0.028). In conclusion, levels of DC in BM normalize quickly in children treated for ALL. Long-term treatment may more profoundly affect mDC subset, which shows reduced levels several months after treatment.

[Effect of nifedipine in chronic left ventricular insufficiency in patients with post-infarction heart aneurysm]. / Vliianie nifedipina pri khronicheskoi levozheludochkovoi nedostatochnosti u bol'nykh s postinfarktnoi anevrizmoi serdtsa.

A study was made of a vasodilating effect of nifedipine on the hemodynamics of 30 patients with chronic postinfarction left ventricular aneurysm, with chronic cardiovascular insufficiency of the II-III degree according to NYHA. A mean value of the acontractile segment on ventriculograms was 32.5 +/- 1.7%. The main parameters of systemic hemodynamics were studied by a method of integral body rheography 1 hour before and after sublingual intake of 20 mg of nifedipine (Corinfar, GDR) at rest, after exercise and during rehabilitation. An increase in the stroke and cardiac indices at rest by an average of 16% was revealed including a noticeable nifedipine effect in patients with elevated final diastolic pressure or arterial tension. During physical exercise a tendency toward an increase in the cardiac output was observed, mainly at the expense of a rise of the stroke volume after drug intake.

[Changes in the interrelation between oxygen consumption and blood circulation in patients with stage II hypertension]. / Izmeneniia vzaimosviazi kislorodnogo obmena i krovoobrashcheniia u bol'nykh gipertonicheskoi bolezn'iu II stadii.

It was discovered that patients suffering from essential hypertension (EH) of the hypokinetic circulatory type (the cardiac index less than 2.7 1/min/m2) manifest an elevated level of energy metabolism which is mediated by the increased arteriovenous difference according to oxygen, accompanied by an increase in oxygen utilization ratio. In patients, the total peripheral resistance was higher as compared to that in normal subjects (P less than 0.01). In patients with EH of the hyperkinetic circulatory type (the cardiac index over 3.4 1/min/m2), there was a considerable increment of the outward work of the heart left ventricle, reduction in the arteriovenous difference according to oxygen, and diminution of the oxygen utilization ratio as compared with normal subjects. At the same time the energy metabolism and total peripheral vascular resistance did not differ from those in the control group (P greater than 0.05).