G9a histone methyltransferase inhibitor BIX01294 promotes expansion of adult cardiac progenitor cells without changing their phenotype or differentiation potential.

OBJECTIVES: As a follow-up to our previous reports showing that the G9a histone methyltransferase-specific inhibitor BIX01294 enhances bone marrow cell cardiac potential, this drug was examined for its effects on cardiomyocytes and mouse cardiac progenitor cells (CPCs). MATERIALS AND METHODS: Cardiomyocytes and cardiac explants were cultured ± BIX01294, and examined for changes in cardiac function, protein and gene expression. Additionally, enriched populations of CPCs, contained in the 'phase bright cell' component of explants, were harvested from non-treated and BIX01294-treated cardiac tissue, and assayed for differences in cell phenotype and differentiation potential. Mouse CPCs were cultured with rat cardiomyocytes to allow differentiation of the progenitors to be assayed using species-specific PCR primers. RESULTS: While BIX01294 had no discernible effect on myocyte function and sarcomeric organization, treatment with this drug significantly increased CPC proliferation, as indicated by enhanced MTT metabolization and BrdUrd incorporation (4.1- and 2.0-fold, respectively, P < 0.001) after 48 h labelling, and increased Ki67 expression (4.8-fold, P < 0.001) after 7 days culture. Heart explants exposed to BIX01294 generated 3.6-fold (P < 0.005) greater yields of CPCs by 2 weeks culture. Importantly, CPCs obtained from non-treated and BIX01294-treated cultures did not differ in phenotype or differentiation potential. CONCLUSIONS: These data indicate that BIX01294 can expand CPCs without undermining their capacity as cardiac progenitors, and suggest that this drug may have utility for generating large numbers of CPCs for cardiac repair.

Angio-immunoblastic T-cell lymphoma in evolution: a case report.

Angio-immunoblastic T-cell lymphoma (AITL), a rare disease that constitutes 1% to 2% of non-Hodgkin's lymphomas, presents in middle-aged and elderly individuals. This report describes a patient with high-grade fever and lymphadenopathy. An extensive in-hospital work-up that included lymph node biopsy yielded negative results. The patient became asymptomatic for 4 wk, but then symptoms recurred with more pronounced lymphadenopathy. A computed tomography scan documented recurrent diffuse lymphadenopathy. Another lymph node biopsy revealed florid changes that strongly suggested AITL. Flow cytometry confirmed this diagnosis. The patient was treated with hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) and achieved complete remission after the first cycle. The patient developed sepsis during the second cycle and expired within 4 mo of diagnosis. The prognosis and natural course of AITL are poor when the classic chemotherapy protocol is administered. When infection has been ruled out, physicians should be wary of aggressive lymphomas that present with diffuse lymphadenopathy and fever.

Chromosomal analyses of 52 cases of follicular lymphoma with t(14;18), including blastic/blastoid variant.

We have identified 52 patients of follicular lymphoma (FL) with t(14;18)(q32;q21). Histologically, the lymphomas were placed into six groups according to their cellular composition and growth pattern. Chromosome analysis revealed that all cases but one had additional secondary chromosomal abnormalities. The most frequent numerical aberrations were gains of chromosomes 7 (38%), X (36%), 5 (15%), 12 (15%), 18/der(18)t(14;18) (25%), and 21 (15%). Structural abnormalities of chromosome 1 were seen in 19 tumors (36%) affecting both arms with breakpoints clustered at 1p36. Other structural abnormalities included partial deletions of 6q, 10q, and 13q. Breakpoint at 8q24 was seen in four cases. The chromosome aberrations were correlated with the morphological subtypes of follicular lymphoma. Gain of chromosome 7 appeared to be associated with follicular large cell lymphoma. The incidence of trisomy 5 and 12, and 13q- was higher in follicular lymphoma with aggressive histological features than in low-grade lymphoma. In addition, complexity of the karyotype and high degree of polyploidy increased with the grade. The most valuable cytogenetic markers in the t(14;18) lymphomas are those involving 8q24 which was found exclusively in the blastic/blastoid variant FL. Therefore, chromosome analysis in relation to histologic pattern of follicular lymphoma can provide additional information in predicting tumor evolution and transformation to a higher-grade malignancy.

From molecules to mind.

This paper describes the relation between genes at the molecular level and the brain at the organ level, and biological, social and environmental factors. The malleability of the brain and the effect of external factors and experience on influencing gene expression and brain structure and function are discussed.

From molecules to mind

This paper describes the relation between genes at the molecular level and the brain at the organ level, and biological, social and environmental factors. The malleability of the brain and the effect of external factors and experience on influencing gene expression and brain structure and function are discussed

WNT signaling modulates the diversification of hematopoietic cells.

WNT proteins compose a family of secreted signaling molecules that regulate cell fate and behavior. The possible influence of WNTs on hematopoietic cell fate was examined. Both hematopoietic progenitor cell (HPC)-enriched embryonic avian bone marrow cells and the quail mesodermal stem cell line QCE6 were used for these studies. Under optimized conditions, the bone marrow and QCE6 cells behaved identically and developed into red blood cells (RBCs), monocytes, macrophages, granulocytes, and thrombocytes. This broad range of blood cell phenotypes exhibited by QCE6 cells was dependent on their active expression of WNT11. However, when QCE6 cells were prevented from producing WNT11-by expression of a stably transfected WNT11 antisense transgene-the cultures were dominated by highly vacuolated macrophages. RBCs were absent from these cultures, and the presence of monocytes was greatly diminished. Exposure of these WNT11 antisense cells to soluble WNT11 or WNT5a restored the broad range of blood cell phenotypes exhibited by parental QCE6 cells. Overexpression of WNT protein in QCE6 cells further increased the prevalence of RBCs and monocytes and greatly diminished the appearance of macrophages. Accordingly, treatment of HPC-enriched bone marrow cultures with soluble WNT11 or WNT5a inhibited macrophage formation. Instead, monocytes and RBCs were the prevalent cells displayed by WNT-treated bone marrow cultures. Together, these data indicate that WNTs may play a major role in regulating hematopoietic cell fate.

Speech recognition with reduced spectral cues as a function of age.

Adult listeners are able to recognize speech even under conditions of severe spectral degradation. To assess the developmental time course of this robust pattern recognition, speech recognition was measured in two groups of children (5-7 and 10-12 years of age) as a function of the degree of spectral resolution. Results were compared to recognition performance of adults listening to the same materials and conditions. The spectral detail was systematically manipulated using a noise-band vocoder in which filtered noise bands were modulated by the amplitude envelope from the same spectral bands in speech. Performance scores between adults and older children did not differ statistically, whereas scores by younger children were significantly lower; they required more spectral resolution to perform at the same level as adults and older children. Part of the deficit in younger children was due to their inability to utilize fully the sensory information, and part was due to their incomplete linguistic/cognitive development. The fact that young children cannot recognize spectrally degraded speech as well as adults suggests that a long learning period is required for robust acoustic pattern recognition. These findings have implications for the application of auditory sensory devices for young children with early-onset hearing loss.

Treatment of iatrogenic femoral arterial pseudoaneurysms: comparison of US-guided thrombin injection with compression repair.

PURPOSE: To evaluate and compare the treatment of iatrogenic femoral arterial pseudoaneurysms by using ultrasonographically (US) guided direct thrombin injection with US-guided compression repair. MATERIALS AND METHODS: Twenty-six patients with iatrogenic femoral arterial pseudoaneurysms were treated with direct thrombin injection. With US guidance, a 22-gauge needle was placed into the pseudoaneurysm flow lumen and thrombin (mean volume, 0.35 mL; range, 0.10-0.60 mL) was injected with continuous color Doppler US guidance. Demographics, clinical variables, pseudoaneurysm characteristics, and results in these patients were compared with those in 281 consecutive patients who underwent US-guided compression repair. RESULTS: The success rate of thrombin injection was 96% (25 of 26 patients), which was significantly higher than that of compression, 74% (209 of 281 patients) (P =.013). Twenty of 26 (77%) patients required a single injection, and six (23%) required two injections. Mean thrombosis time for thrombin injection was 6 seconds, compared with 41.5 minutes for compression. For thrombin injection, there were no complications, foot pulses did not change and no patients required conscious sedation. Follow-up US at 24 hours showed no recurrent pseudoaneurysms. CONCLUSION: For the treatment of iatrogenic femoral arterial pseudoaneurysms, thrombin injection with US guidance appears to be superior to compression repair.