We hypothesized that specific molecular mutations are important biomarkers for response to DNA methyltransferase inhibitors (DNMT inhibitors) and may have prognostic value in patients with myelodysplastic syndromes (MDS). Mutational analysis was performed in 92 patients with MDS and related disorders who received 5-azacytidine (n=55), decitabine (n=26) or both (n=11). Mutational status was correlated with overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) by univariate and multivariate analysis. Risk stratification models were created. TET2, DNMT3A, IDH1/IDH2, ASXL1, CBL, RAS and SF3B1 mutations were found in 18, 9, 8, 26, 3, 2 and 13% of patients, respectively. In multivariate analysis, TET2(MUT) and/or DNMT3A(MUT) (P=0.03), platelets > or = 100 × 10(9)/l (P=0.007) and WBC<3.0 × 10(9)/l (P=0.03) were independent predictors of better response. TET2(MUT) and/or DNMT3A(MUT) (P=0.04) status was also independently prognostic for improved PFS, as were good or intermediate cytogenetic risk (P<0.0001), age<60 (P=0.0001), treatment with both 5-azacytidine and decitabine (P=0.02) and hemoglobin > or = 10 g/dl (P=0.01). Better OS was associated with ASXL1(WT) (P=0.008) and SF3B1(MUT) (P=0.01), and, similar to PFS, cytogenetic risk (P=0.0002), age (P=0.02) and hemoglobin (P=0.04). These data support the role of molecular mutations as predictive biomarkers for response and survival in MDS patients treated with DNMT inhibitors.

We hypothesized that analysis of single nucleotide polymorphism arrays (SNP-A) and new molecular defects may provide new insight in the pathogenesis of systemic mastocytosis (SM). SNP-A karyotyping was applied to identify recurrent areas of loss of heterozygosity and bidirectional sequencing was performed to evaluate the mutational status of TET2, DNMT3A, ASXL1, EZH2, IDH1/IDH2 and the CBL gene family. Overall survival (OS) was analyzed using the Kaplan-Meier method. We studied a total of 26 patients with SM. In 67% of SM patients, SNP-A karyotyping showed new chromosomal abnormalities including uniparental disomy of 4q and 2p spanning TET2/KIT and DNMT3A. Mutations in TET2, DNMT3A, ASXL1 and CBL were found in 23%, 12%, 12%, and 4% of SM patients, respectively. No mutations were observed in EZH2 and IDH1/IDH2. Significant differences in OS were observed for SM mutated patients grouped based on the presence of combined TET2/DNMT3A/ASXL1 mutations independent of KIT (P = 0.04) and sole TET2 mutations (P<0.001). In conclusion, TET2, DNMT3A and ASXL1 mutations are also present in mastocytosis and these mutations may affect prognosis, as demonstrated by worse OS in mutated patients.

Our results reveal new functions and signaling pathways regulated by ARHGAP21, and indicate that it could contribute to prostate cancer progression.

Despite a clear role for leukocytes in modulating the pathophysiology of sickle cell disease (SCD), the mechanism by which leukocyte numbers are increased in this disorder remains unclear. Hypothesizing that the chronic inflammatory state, elicited by adhesive interactions involving various cell types, might underlie leukocytosis, we measured plasma levels of proinflammatory or myeloid cytokines that play a role in leukocytosis and examined their correlations with leukocyte numbers in patients with SCD. Our studies found that, although plasma levels of granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin 3, and macrophage colony-stimulating factor are elevated in steady-state patients with SCD, only plasma GM-CSF levels are positively correlated with the numbers of total leukocytes, neutrophils, monocytes, and eosinophils, regardless of whether they received hydroxyurea. GM-CSF levels were significantly decreased in patients on hydroxyurea therapy. These data suggest a role of GM-CSF in leukocytosis of SCD. In contrast, plasma levels of granulocyte colony-stimulating factor, a major cytokine that induces leukocytosis due to bacterial infection, were lower than those of control subjects. These results indicate that elevated GM-CSF levels may contribute, at least in part, to high leukocyte numbers in SCD. As plasma GM-CSF levels were decreased in patients on hydroxyurea therapy, hydroxyurea may decrease leukocyte numbers by reducing circulating GM-CSF levels.

Background: ARHGAP21 is an important Rho-GAP for Cdc42 involved in vesicle trafficking and focal adhesion kinase activity. Results: ARHGAP21 participates in cell-cell adhesion formation and cellular migration, interacts and modulates ␣-tubulin acetylation, and is essential for epithelial-mesenchymal transition. Conclusion: ARHGAP21 is a novel ␣-tubulin partner coordinating cell-cell adhesion, migration, and epithelial-mesenchymal transition. Significance: ARHGAP21 might be involved in cancer metastasis.

No abstract

Quercetin is one of the most abundant flavonoids, present in fruits and vegetables and has been shown to have multiple properties capable of reducing cell growth in cancer cells. Green tea is a widely consumed beverage, known for a potential source of free radical scavenging and anti-cancer activities. Herein, we investigate the in vivo antitumor efficacy of quercetin and green tea in human leukemia. Human tumors were xenografted into NOD/SCID mice. Quercetin and green tea reduced tumor growth in HL-60 xenografts accompanied by decreased expression of anti-apoptotic proteins, BCL-2, BCL-XL and MCL-1 and increased expression of BAX, a pro-apoptotic protein. Moreover, caspase-3 was activated to a greater extent after quercetin and green tea treatment. Quercetin and green tea also mediated G1 phase cell cycle arrest in HL-60 xenografts. Treatment with quercetin and green tea induced conversion of LC3-I to LC3-II as well as activation of autophagy proteins, suggesting that quercetin and green tea initiate the autophagic progression. We have provided evidence that quercetin and green tea induces signaling at the level of apoptosis, cell cycle and autophagy which converge to antigrowth effects in HL-60 xenograft mice suggesting that these compounds may be a compelling ally in cancer treatment.

The present study investigates the effects of xenotransplantation of Adipose Tissue Mesenchymal Stem Cells (AT-MSCs) in animals after ventral root avulsion. AT-MSC has similar characteristics to bone marrow mesenchymal stem cells (BM-MSCs), such as immunomodulatory properties and expression of neurotrophic factors. In this study, Lewis rats were submitted to surgery for unilateral avulsion of the lumbar ventral roots and received 5 × 105 AT-MSCs via the lateral funiculus. Two weeks after cell administration, the animals were sacrificed and the moto neurons, T lymphocytes and cell defense nervous system were analyzed. An increased neuronal survival and partial preservation of synaptophysin-positive nerve terminals, related to GDNF and BDNF expression of AT-MSCs, and reduction of pro-inflammatory reaction were observed. In conclusion, AT-MSCs prevent second phase neuronal injury, since they suppressed lymphocyte, astroglia and microglia effects, which finally contributed to rat motor-neuron survival and synaptic stability of the lesioned motor-neuron. Moreover, the survival of the injected AT- MSCs lasted for at least 14 days. These results indicate that neuronal survival after lesion, followed by mesenchymal stem cell (MSC) administration, might occur through cytokine release and immunomodulation, thus suggesting that AT-MSCs are promising cells for the therapy of neuronal lesions.