We explored the impact of mutations in the NOTCH1, FBW7 and PTEN genes on prognosis and downstream signaling in a well-defined cohort of 47 patients with pediatric T-cell acute lymphoblastic leukemia ...(T-ALL). In T-ALL lymphoblasts, we identified high-frequency mutations in NOTCH1 (n=16), FBW7 (n=5) and PTEN (n=26). NOTCH1 mutations resulted in 1.3- to 3.3-fold increased transactivation of an HES1 reporter construct over wild-type NOTCH1; mutant FBW7 resulted in further augmentation of reporter gene activity. NOTCH1 and FBW7 mutations were accompanied by increased median transcripts for NOTCH1 target genes (HES1, DELTEX1 and cMYC). However, none of these mutations were associated with treatment outcome. Elevated HES1, DELTEX1 and cMYC transcripts were associated with significant increases in transcript levels of several chemotherapy relevant genes, including MDR1, ABCC5, reduced folate carrier, asparagine synthetase, thiopurine methyltransferase, BCL2 and dihydrofolate reductase. PTEN transcripts positively correlated with HES1 and cMYC transcript levels. Our results suggest that (1) multiple factors should be considered with attempting to identify molecular-based prognostic factors for pediatric T-ALL, and (2) depending on the NOTCH1 signaling status, modifications in the types or dosing of standard chemotherapy drugs for T-ALL, or combinations of agents capable of targeting NOTCH1, AKT and/or mTOR with standard chemotherapy agents may be warranted.
This report shows that an immortalized endothelial cell line (EA.hy 926) is able to substitute for secondary cultures of human umbilical vein endothelial cells (HUVEC) in the leucocyte:endothelial ...adherence assay. Enriched preparations of blood polymorphonuclear leucocytes, monocytes and resting and activated lymphocytes exhibited similar adherence characteristics to HUVEC and the EA.hy 926 cells. Cytokines such as tumour necrosis factor (TNF) act on endothelial cells to increase their adhesiveness for leucocytes and in this study there was no difference between TNF-treated HUVEC and EA.hy 926 cells in supporting the enhanced binding of leucocytes. The adherence promoting effect of TNF-treated EA.hy 926 cells appears to be dependent upon their endothelial properties since TNF treatment of A549 cells, the permanent human cell line used to generate the hybrid EA.hy 926 cells did not augment lymphocyte attachment. Monoclonal antibodies against CD11a and CD18 inhibited the binding of lymphocytes to untreated and TNF-treated HUVEC and EA.hy 926 cells and ICAM-1 expression was increased on both monolayers following treatment with TNF. The availability of a hybrid endothelial cell line whose adhesive properties are similar to those of recently isolated endothelial cells should benefit the study of factors that govern leucocyte-endothelial cell interactions and be advantageous to the longitudinal investigation of leucocyte adherence under static conditions.
We hypothesized that the rising levels of inflammatory markers with aging is explained by cardiovascular risk factors and morbidity becoming progressively more prevalent in older persons. Information ...on inflammatory markers, cardiovascular risk factors, and diseases was collected in 595 men and 748 women sampled from the general population (age, 20-102 years). In both men and women, older age was associated with higher levels of interleukin-6 (IL-6), IL-1 receptor antagonist (IL-1ra), IL-18, C-reactive protein (CRP), and fibrinogen, while soluble IL-6 receptor (sIL-6r) increased significantly with age only in men. Adjusting for cardiovascular risk factors and morbidity, the age regression coefficients became substantially smaller in models predicting IL-6, IL-1ra, IL-18, and fibrinogen and larger in the model predicting sIL6r. Adjustment for cardiovascular morbidity substantially reduced the effect of age on CRP in men but not in women. Findings were confirmed in a subgroup of 51 men and 45 women with low risk profile and no cardiovascular morbidity. Part of the “proinflammatory state” in older persons is related to the high prevalence of cardiovascular risk factor and morbidity.
Although de novo mutations (DNMs) are known to increase an individual’s risk of congenital defects, DNMs have not been fully explored regarding orofacial clefts (OFCs), one of the most common human ...birth defects. Therefore, whole-genome sequencing of 756 child-parent trios of European, Colombian, and Taiwanese ancestry was performed to determine the contributions of coding DNMs to an individual’s OFC risk. Overall, we identified a significant excess of loss-of-function DNMs in genes highly expressed in craniofacial tissues, as well as genes associated with known autosomal dominant OFC syndromes. This analysis also revealed roles for zinc-finger homeobox domain and SOX2-interacting genes in OFC etiology.
Distributions of thalamic and cortical connections were investigated in four macaque monkeys with long-standing, accidental trauma to a forelimb, to determine whether the growth of new connections ...plays a role in the reorganization of somatosensory cortex that occurs after major alterations in peripheral somatosensory inputs. In each monkey, microelectrode recordings of cortical areas 3b and 1 demonstrated massive reorganizations of the cortex related to the affected limb. Injections of tracers in area 1 of these monkeys revealed normal patterns of thalamocortical connections, but markedly expanded lateral connections in areas 3b and 1. Thus, the growth of intracortical but not thalamocortical connections could account for much of the reorganization of the sensory maps in cortex.
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