This research examines whether visual and haptic map learning yield functionally equivalent spatial images in working memory, as evidenced by similar encoding bias and updating performance. In three experiments, participants learned four-point routes either by seeing or feeling the maps. At test, blindfolded participants made spatial judgments about the maps from imagined perspectives that were either aligned or misaligned with the maps as represented in working memory. Results from Experiments 1 and 2 revealed a highly similar pattern of latencies and errors between visual and haptic conditions. These findings extend the well known alignment biases for visual map learning to haptic map learning, provide further evidence of haptic updating, and most importantly, show that learning from the two modalities yields very similar performance across all conditions. Experiment 3 found the same encoding biases and updating performance with blind individuals, demonstrating that functional equivalence cannot be due to visual recoding and is consistent with an amodal hypothesis of spatial images.
Lenalidomide (3-(4-amino-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione)) is an agent approved for treatment of patients with del 5q myelodysplastic syndromes and previously treated multiple myeloma. Lenalidomide has been found in early clinical trials to have potential therapeutic activity in patients with relapsed chronic lymphocytic leukemia (CLL). The mechanism(s) whereby this drug is active in CLL is unknown. In particular, studies to date have not found lenalidomide to have any direct cytotoxic activity on CLL cells in vitro. This has stimulated speculation that this agent might adversely affect the positive influence of the microenvironment on leukemia-cell survival. We and others have observed that cells found in the leukemia microenvironment can support CLL-cell survival in vitro. One such type of cells are nurse-like cells (NLC), which can differentiate from the CD14-positive blood mononuclear cells of CLL patients into large, round adherent cells that can attract and support CLL cell survival in vitro for weeks, if not longer. We evaluated the effects of lenalidomide on primary leukemia-cell survival in vitro when the CLL cells from different patients (N=21) were cultured alone or together with NLC generated as previously described [Tsukada Blood 2002]. We assessed the in-vitro activity of lenalidomide on primary CLL cells from 21 patients, in duplicate in a series of 6 experiments. Lenalidomide at concentrations of 0.1μM-200μM did not significantly impact the survival of CLL cells that were cultured alone for up to 12 days. Analysis of cell surface markers revealed increased expression of CD38 at 36 hours in 5/5 lenalidomide treated CLL samples compared with untreated cells (MFIR 5.7 +/− .86 vs. 3.4 +/− .83 p=.003). We observed sustained upregualtion of CD40 and regulation of CXCR4 in the majority of cells treated with lenalidomide. When cultured with NLC, the survival of CLL cells was comparable to or significantly higher than that of CLL cells cultured alone 62.4% vs. 51% (+/−3% SEM n=21 p [<] 0.0005). The addition of lenalidomide at concentrations of 0.1μM and greater to co-cultures of NLC and CLL cells caused specific reductions in CLL cell survival to levels similar to or lower than that of CLL cells cultured without NLC. In the presence of NLC, lenalidomide at 1μM reduced CLL cell viability compared to control (41.5% vs. 56% +/−4% p [<] 0.0005 paired student t test n=13). For most patients the levels of CLL cell viability on days 4 through 8 in the co-cultures with lenalidomide was significantly lower than those of CLL cells co-cultured with NLC in the absence of lenalidomide. As such, this study reveals that physiologic concentrations of lenalidomide might abrogate the protective influence of NLC on CLL cell survival in vitro and potentially in vivo. Conceivably, those patients who have leukemia cells displaying a high dependency on NLC for survival in vitro also might be most likely to experience a favorable clinical response to treatment with lenalidomide. This hypothesis will be tested in a prospective manner with a planned clinical trial evaluating lenalidomide for treatment of CLL through the CLL Research Consortium.
Chronic lymphocytic leukemia (CLL) cells often undergo spontaneous apoptosis in vitro unless co-cultured with accessory cells, such as nurselike cells (NLC), which likely also function in the leukemia-cell microenvironment to promote CLL-cell survival in vivo. However, we observed the CLL cells of different patients varied in their relative dependency on NLC for survival, even when examined on NLC derived from the same donor. We hypothesized that the relative dependency on NLC was an intrinsic characteristic for each CLL cell population and that measurement of the relative degree of NLC-dependency might serve to segregate patients into subgroups with different biologic or clinical behavior. To test this hypothesis, we assessed the cyropreserved primary leukemia cells of 45 untreated CLL patients for their relative dependency on NLC for survival in vitro. NLC were generated as described through co-culture of CLL B cells with isolated CD14+ blood mononuclear cells of healthy donors. The viability of CLL cells cultured with or without NLC was determined after two days co-culture and compared with that of the initial CLL cell viability, which typically was greater than 85%. To assess the survival support provided by NLC to the leukemia cells we determined the relative viability of leukemia cells alone was divided by the viability of CLL cells co-cultured with NLC. CLL NLC dependency index NLC was defined as 1-relative viability. We multiplied this result by 100 and then subtracted the product from 1 to derive the NLCdependency index. The NLC-dependency index for the CLL cells from different patients (n =16) ranged from 0.5–63.7 with a median of 26.9. In contrast, we observed relatively little variation in the NLC-dependency index for any one sample when measured in different experiments (2–4 assays/sample). Furthermore, the NLC-dependency index for CLL cells collected at different times from any one patient also was relatively constant, resulting in an intrapatient variation of in NLC-dependency index of only 5.6%. Using recursive partitioning, we examined the relationship between the NLC-dependency index and time from diagnosis to first treatment for 45 patients. This allowed us to determine the optimal threshold for segregating patients into groups with high versus low NLCdependency. A NLC-dependency of 26 was found the optimal cut point to segregate the 45 patients into 2 groups that exhibited different median times from diagnosis to initial therapy. Using this threshold, the NLC dependency index could reliably segregate the patients into the two categories of high versus low NLC-dependency, even when assessed on CLL cells collected at different time points. There was a significant association between a high NLC dependency index and expression of CD38 (spearman’s rho = 0.4, p=0.008). CD38 is noted to be a receptor for CD31, which is found expressed on NLC. Moreover, when we segregated patients into groups of low versus high NLC-dependency based upon the index cut-off of 26, we found a significant association between high NLC-dependency and expression of CD38 [Fisher’s exact test, p=0.017]. Furthermore, we observed that patients with CLL cells that had a high NLC-dependency index experienced a significantly shorter median survival (4137 days) than did those patients with CLL cells that had a low NLC-dependency index (8276 days), using the log rank test (p=0.0037). (See Figure) The overall survival hazard ratio for NLC dependency was 11.5 (Cox proportional hazards regression, p=0.021). This intriguing inverse relationship between the relative dependency of CLL cells on NLC for in vitro survival and overall patient survival suggests that the microenvironment might play a significant role in the pathophysiology and/or progression of CLL and that agents targeting the leukemia-cell microenvironment might be effective in patients with relatively aggressive disease. Figure Figure
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