Emergence of translocation t(9;11)-positive leukemia during treatment of childhood acute lymphoblastic leukemia

Therapy-related acute myeloid leukemia (t-AML) characterized by the t(9;11)(p22;q23) translocation is one of the most frequent secondary malignancies. The timing of the initiation of translocation and of development of the malignant t(9;11) clone during chemotherapy is presently unknown. In the present study, we backtracked bone marrow samples from three children during treatment for acute lymphoblastic leukemia (ALL). Two patients developed a t(9;11)-positive t-AML 19 and 30 months after therapy start, whereas the third patient, diagnosed with a rare t(9;11)-positive ALL, suffered from an ALL relapse 23 months after initial diagnosis. The genomic MLL-MLLT3 (MLL-AF9) fusion site was amplified by a multiplex, nested long-range PCR and used as a clonal marker for quantification of the MLL-MLLT3-positive cells during chemotherapy. The t(9;11)-positive clone was detectable 13 and 18 months after therapy start in both t-AML cases, which was 6-12 months before clinical diagnosis of the secondary malignancy. In the t(9;11)-positive ALL patient, the identical leukemic clone reoccurred during maintenance therapy after a short molecular remission, 8 months before clinically overt ALL relapse. The time course and characteristics of the genomic breakpoints in the present t-AML cases support the hypothesis of translocation formation as a result of defective breakage repair after topoisomerase II cleavage.     

Expression of T cell receptor delta chains in benign and malignant T lineage lymphoproliferations

Recent studies in both human and murine systems have demonstrated the existence of a second CD3-associated T cell receptor (the gamma delta-TCR) distinct from the alpha beta heterodimer associated with antigen recognition by classical T cells. Using a monoclonal antibody specific for the delta component of the human gamma delta-TCR, the expression of this antigen in both benign, reactive lymphoid tissues and T lineage lymphomas was studied with immunohistologic techniques. In the normal thymus, TCR-delta+ cells constituted less than 5% of the CD3+ thymocytes and were located primarily in the medulla or juxtamedullary cortex. Within the T zones of 16 histologically varied reactive peripheral lymphoid tissues, including four patients with marked predominantly paracortical hyperplasia, the authors identified from less than 1% to a maximum of 5% TCR-delta+ cells. While these results are consistent with the hypothesis that TCR-gamma delta+ cells comprise a small distinct subpopulation of peripheral T cells in humans, selective localization or recruitment of these cells could not be demonstrated in any of a number of tissues or reactive situations. Among 62 T lineage lymphomas, including 14 CD3+/TCR-beta- cases, only two TCR-delta+ neoplasms were identified, both lymphoblastic lymphomas displaying the CD3+/CD4-/CD8- phenotype known to be associated with normal TCR-gamma delta+ T cells. Because the majority of CD3+/TCR-beta- lymphomas did not display TCR-delta, these results argue against the hypothesis that the high incidence of CD3/TCR-beta discordance noted in T lineage lymphomas represents preferential transformation of the TCR-delta-expressing subset.     

Hitting moving objects: is target speed used in guiding the hand?

We investigated what information subjects use when trying to hit moving targets. In particular, whether only visual information about the target's position is used to guide the hand to the place of interception or also information about its speed. Subjects hit targets that moved at different constant speeds and disappeared from view after varying amounts of time. This prevented the subjects from updating position information during the time that the target was invisible. Subjects hit further ahead of the disappearing point when the target moved faster, but not as much as they should have on the basis of the target's speed. This could be because more time is needed to perceive and use the correct speed than was available before the target disappeared. It could also be due to a speed-related misperception of the target's final position. The results of a second experiment were more consistent with the latter hypothesis. In a third experiment we moved the background to manipulate the perceived speed. This did not affect the hitting positions. We conclude that subjects respond only to the changing target position. Target speed influences the direction in which the hand moves indirectly, possibly via a speed-related misperception of position.     

S100A2, a putative tumor suppressor gene, regulates in vitro squamous cell carcinoma migration

It has been previously shown that S100A2 is down-regulated in tumor cells and can be considered a tumor suppressor. We have recently shown that this down-regulation can be observed particularly in epithelial tissue, where S100A2 expression decreases remarkably in tumors as compared with normal specimens. In the present paper we investigate whether S100A2 could play a tumor-suppressor role in certain epithelial tissues by acting at the cell migration level. To this end, we made use of five in vitro human head and neck squamous cell carcinoma lines in which we characterized S100A2 expression at both RNA and protein level. To characterize the influence of S100A2 on cell kinetic and cell motility features, we used two complementary approaches involving specific antisense oligonucleotides and the addition of S100A2 to the culture media. The different expression analyses gave a coherent demonstration of the fact that the FADU and the RPMI-2650 cell lines exhibit high and low levels of S100A2 expression, respectively. Antisense oligonucleotides (in FADU) and extracellular treatments (in RPMI) showed that, for these two models, S100A2 had a clear inhibitory influence on cell motility while modifying the cell kinetic parameters only slightly. These effects seem to be related, at least in part, to a modification in the polymerization/depolymerization dynamics of the actin microfilamentary cytoskeleton. Furthermore, we found evidence of the presence of the receptor for advanced glycation end-products (RAGE) in RPMI cells, which may act as a receptor for extracellular S100A2. The present study therefore presents experimentally based evidence showing that S100A2 could play a tumor-suppressor role in certain epithelial tissues by restraining cell migration features, at least in the case of head and neck squamous cell carcinomas.     

Local intrarenal vasoconstrictor-vasodilator interactions in mild partial ureteral obstruction.

Micropuncture studies were performed in Munich-Wistar rats with surgically created chronic partial unilateral ureteral obstruction (UUO). Mean values for superficial single nephron (SN)GFR, total GFR, and initial glomerular plasma flow rate (QA) in obstructed kidneys were essentially identical to values in nonobstructed kidneys. Nevertheless, glomerular capillary hydraulic pressure (PGC) was significantly higher in obstructed than in nonobstructed kidneys. This increase in PGC served to offset the markedly reduced glomerular capillary ultrafiltration coefficient that was also confined to the kidneys ipsilateral to the ureteral obstruction. During infusion of indomethacin or meclofenamate, SNGFR and QA decreased significantly, in association with elevations in arteriolar resistances in obstructed kidneys, whereas such changes were not observed in nonobstructed kidneys. The results suggest that local intrarenal factors, rather than circulating or systemic factor(s), bring about functional adaptations to partial ureteral obstruction. In particular, an indomethacin- and meclofenamate-sensitive vasodilator (presumably prostaglandin) plays a role in antagonizing the effects of a simultaneously acting vasoconstrictor which, although not identified, displayed the functional properties of angiotensin II.     

Characterization of monocyte-derived dendritic cells in recent-onset diabetes mellitus type 1

Dendritic cells (DC) may play an important role in the immunopathogenesis of type 1 diabetes mellitus (DM-1). In this study, we have analyzed phenotypical changes during cytokine-driven maturation from CD14+ monocytes to mature DC and DC-dependent T-cell stimulation in recent-onset pediatric DM-1 patients and healthy controls. DC maturation was monitored by flow cytometric analyses for the expression of surface markers (HLA-DR, CD1a, CD40, CD80, CD86, CD83, CD14, CD32, mannose-receptor, and CD11c). Flow cytometric analysis of isolated peripheral blood monocytes did not reveal apparent differences between patients and controls. During DC maturation no obvious differences in the expression patterns of surface markers over time or evidence for maturation impairments in DM-1 patients could be appreciated. Solely, a marginal, but significant, transient down-regulation of CD1a on Day 3 (mean MDFI 3.82 vs 7.25; P = 0.021), which was accompanied by an increase of IL-6, could be observed. The comparison of mature DCs (Day 10) between patients and controls indicated no significant differences, except for CD83 (mean MDFI 1.7 vs 1.5; P = 0.042) and CD80 (mean MDFI 15.92 vs 12.73; P = 0.042). Moreover, no difference in T-cell stimulatory capacity was seen. In conclusion, our analysis of a cohort of recent-onset DM-1 patients and controls does not support a role for disease-related alterations in cytokine-driven maturation of monocyte-derived DC.