Search

Selective inhibitors of cyclooxygenase-2 (COX-2) enzyme activity have shown chemopreventive activity in carcinogen-induced and transgenic rodent tumor models and clinically for colon cancer. However, the mechanism(s) by which COX-2 inhibitors reduce carcinogenesis remains controversial. We report herein that administration of the selective COX-2 inhibitor, celecoxib, significantly reduces the number of Gr1(+)CD11b(+) immature myeloid suppressor cells (IMSCs) during chemoprevention of 1,2-dimethylhydrazine diHCl-(1,2-DMH-) induction of large intestinal tumors in Swiss mice. Celecoxib administration also increased splenic lymphatic number and tumor infiltration by lymphocytes. The 1,2-DMH induction of large intestinal tumors was associated with a four-fold increase in IMSCs, and a decrease in splenic T cell number and function. Concordant with the changes in the IMSC frequency, messenger ribonucleic acid (mRNA) levels of inducible nitric oxide synthase (NOS-2) and arginase (Arg) were increased in the spleen of the tumor-bearing mice and normalized by celecoxib administration. In addition to delaying tumor induction, reducing tumor number, and increasing lymphocyte infiltration of tumors, celecoxib therapy reversed CD4(+) T cell loss, decreased IMSC numbers and increased mRNA levels of NOS-2 and Arg in the spleen. In summary, our results suggest that celecoxib chemoprevention of autochthonous intestinal tumors can regulate IMSCs and CD4(+) T cell numbers.

The focus of assessment and intervention is often aimed at increasing the lexical skills of young children with language impairment. Frequently, the use of nouns is the center of the lexical assessment. As a result, the production of verbs is not fully evaluated or integrated into treatment in a way that accounts for their semantic and syntactic complexity. This paper presents a probe for eliciting verbs from children, describes its effectiveness, and discusses the utility of and problems associated with developing such a probe.

Alternating verbs to indicate or to relinquish cause requires an understanding of semantic and syntactic knowledge. This study evaluated the ability of children with specific language impairment (SLI) to produce the causative alternation in comparison to age peers and to language peers. The children with SLI were proficient in lexically alternating verbs, yet provided fewer passive and periphrastic constructions and more different verbs and adjectival responses. Overgeneralization error data suggest that the semantic systems of some children with SLI were similar to their age comparisons. Individual differences within the SLI group suggested that some children were adept at providing syntactic responses and overgeneralizations, whereas some of the SLI group provided less mature responses of no alternations and no responses. These findings demonstrate a syntactic deficit in the causative alternation for some children with SLI.

NST provides graft-versus-leukemia (GVL) activity with reduced regimen related toxicity. We used a conditioning regimen consisting of Pentostatin 4 mg/m2 daily × 3 days and 200 cGy TBI 24 hrs prior to stem cell infusion in patients (pts) with high-risk/relapsed/refractory hematologic malignancies. The importance of the timing of stem cell infusion relative to Pentostatin administration was examined in a comparison of two sequential protocols. In cohort 1 (n=39) Pentostatin was given on days -21, -20, and -19. In cohort 2 (n=39) Pentostatin was given on days -10, -9, and -8. The median age of the day -21 cohort was 52 years (range 22–70) and the day -10 cohort was 59.5 years (range 36–70). The median number of prior therapies in the day -21 cohort was 4 (range 0–8), including prior autologous SCT in 22 pts, while in the day -10 cohort, the median number of prior therapies was 6 (range 0–18), including prior autologous SCT in 9 pts. Post-grafting immunosuppression was cyclosporine (CsA)/mycophenolate mofetil (MMF). In both protocols, CsA 2.0 mg/kg IV q12 hrs was administered on days -1, 0, and +1, and then converted to oral 5 mg/kg PO BID with a taper beginning on day +70. In the second protocol, pts with unrelated donor transplants tapered CsA starting at day +100. MMF at 15 mg/kg PO BID was administered on days 0–27 for related donor transplants in both protocols and in the second protocol this was extended until day +40 for the unrelated donor transplants. In the day -21 protocol, SCTs were obtained from matched related (n=14) or unrelated (n=25) donors. The cumulative incidence of all grades of acute GVHD at day 100 was 40% and was more common in unrelated donor (60%) vs. related donors (15%) transplants. In the day -10 protocol, SCT was performed with products from matched related (n=15) or unrelated (n=21) donors. The cumulative incidence of grade II–IV acute GVHD was approximately 35% (30% in related versus 40% in unrelated donors). In both protocols, the median chimerism values for CD3+ cells and white blood cells at day 28 were >80% and 90% donor cells, respectively. T, B and natural killer (NK) lymphocyte frequency and numbers were identical at protocol entry. One day following TBI conditioning, there was a 57% depression in CD3+ cells in the day -21 protocol that was retained on day 28 post transplant (55%). In the day -10 protocol, there was a significant depression (47%) in the frequency of CD3+ cells one day following TBI, which was depressed further (68%) on day 28 post transplant. The dendritic cells (DCs), both CD123+ and CD11c+, were not suppressed by the conditioning regimen. Separation of pts on day 28 into cohorts with an absolute number of CD3+ cells >0.25×106/ml revealed that those pts with a higher CD3+ cell count had a median OS time of 36.7 weeks, which was significantly longer than pts whose absolute number of CD3+ cells

NST is increasingly being used to introduce a graft-versus-malignancy (GVM) effect with reduced regimen related toxicity. The first NST protocol, which accrued patients (pts) between 9/01 and 7/04, 39 pts with high risk/relapsed/refractory hematopoietic malignancies who were not candidates for full intensity allogeneic SCT underwent NST using Pentostatin/TBI. Their median age was 52 years (range 22–70). The median number of prior therapies was 4 (range 0–8) including prior autologous SCT in 22 pts. Conditioning consisted of Pentostatin 4 mg/m2 daily on day -21, -20, and -19, followed by 200 cGy TBI on day -1. The second protocol, between 10/04 and 6/06, 24 pts received the same conditioning regime on days -10, -9, and -8, and TBI on day -1. The median age of these pts was 59.5 years (range 36–70) and the median number of prior therapies was 2 (range 0–6). Post-grafting immunosuppression was cyclosporine (CsA)/mycophenolate mofetil (MMF). In the both protocols CsA 2.0 mg/kg IV q12 hrs was administered on days -1, 0, and +1 and then converted to oral 5 mg/kg PO BID with a taper beginning on day +70. In the second protocol pts with unrelated donor transplants remain on CsA until day + 100. MMF at 15 mg/kg PO BID was administered on days 0–27 for related donor transplants in both protocols and in the second protocol this was extended until day +40 for the unrelated donor transplants. Results: In the day -21 protocol SCTs were from matched related (n=14) or unrelated (n=25) donors. The cumulative incidence of all grades of acute graft-versus-host disease (GVHD) at day 100 was 40% and was more common in unrelated donor transplants (60% vs. 15%). In the day -10 protocol, SCT was performed with products from matched related (n=8) or unrelated (n=16) donors. The cumulative incidence of grade II–IV acute GVHD was approximately XX% (XX% in related versus XX% in unrelated donors). In both protocols, the median chimerism values for CD3+ cells and WBC at day 28 were >80% and 90% donor cells, respectively and T, B and NK lymphocyte frequency and numbers were identical at protocol entry. One day following TBI conditioning there was a 32% depression in CD3+ cells in the day -21 protocol that was partially recovered on days 28 and 70 post transplant (27% and 16% respectively). In the day -10 protocol there was a 45% depression in the frequency of CD3+ cells (p Conclusions: There appears to be a trend for a lower incidence of acute GVHD in the day -10 protocol, which can be associated with a reduction in the frequency of circulating T cells. This significantly greater reduction in T cell frequency, observed one day following TBI and 28 days post transplant, is directly associated with the timing of transplant relative to pentostatin conditioning as the post-grafting immunosuppression was similar between the two protocols at these time points.