Protein kinase CK2 sustains acute myeloid leukemia cell growth, but its role in leukemia stem cells is largely unknown. Here, we discovered that the CK2 catalytic α and regulatory β subunits are ...consistently expressed in leukemia stem cells isolated from acute myeloid leukemia patients and cell lines. CK2 inactivation with the selective inhibitor CX-4945 or RNA interference induced an accumulation of leukemia stem cells in the late S-G2-M phases of the cell cycle and triggered late-onset apoptosis. As a result, leukemia stem cells displayed an increased sensitivity to the chemotherapeutic agent doxorubicin. From a molecular standpoint, CK2 blockade was associated with a downmodulation of the stem cell-regulating protein BMI-1 and a marked impairment of AKT, nuclear factor-κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) activation, whereas FOXO3a nuclear activity was induced. Notably, combined CK2 and either NF-κB or STAT3 inhibition resulted in a superior cytotoxic effect on leukemia stem cells. This study suggests that CK2 blockade could be a rational approach to minimize the persistence of residual leukemia cells.
Epstein-Barr virus (EBV)-associated malignancies, as well as lymphoblastoid cell lines (LCLs), obtained in vitro by EBV infection of B cells, express latent viral proteins and maintain their ability ...to grow indefinitely through inappropriate activation of telomere-specific reverse transcriptase (TERT), the catalytic component of telomerase. Our previous studies demonstrated that high levels of TERT expression in LCLs prevent the activation of EBV lytic cycle, which is instead triggered by TERT silencing. As lytic infection promotes the death of EBV-positive tumor cells, understanding the mechanism(s) by which TERT affects the latent/lytic status of EBV may be important for setting new therapeutic strategies. BATF, a transcription factor activated by NOTCH2, the major NOTCH family member in B cells, negatively affects the expression of BZLF1, the master regulator of viral lytic cycle. We therefore analyzed the interplay between TERT, NOTCH and BATF in LCLs and found that high levels of endogenous TERT are associated with high NOTCH2 and BATF expression levels. In addition, ectopic expression of TERT in LCLs with low levels of endogenous telomerase was associated with upregulation of NOTCH2 and BATF at both mRNA and protein levels. By contrast, infection of LCLs with retroviral vectors expressing functional NOTCH2 did not alter TERT transcript levels. Luciferase reporter assays, demonstrated that TERT significantly activated NOTCH2 promoter in a dose-dependent manner. We also found that NF-κB pathway is involved in TERT-induced NOTCH2 activation. Lastly, pharmacologic inhibition of NOTCH signaling triggers the EBV lytic cycle, leading to the death of EBV-infected cells. Overall, these results indicate that TERT contributes to preserve EBV latency in B cells mainly through the NOTCH2/BAFT pathway, and suggest that NOTCH2 inhibition may represent an appealing therapeutic strategy against EBV-associated malignancies.
Summary
The function of CD4+ T cells with regulatory activity (Tregs) is the down‐regulation of immune responses. This suppressive activity may limit the magnitude of effector responses, resulting in ...failure to control human immunodeficiency virus 1 (HIV‐1) infection, but may also suppress chronic immune activation, a characteristic feature of HIV‐1 disease. We evaluated the correlation between viral load, immune activation and Tregs in HIV‐1‐infected children. Eighty‐nine HIV‐1‐infected children (aged 6–14 years) were included in the study and analysed for HIV‐1 plasmaviraemia, HIV‐1 DNA load, CD4 and CD8 cell subsets. Treg cells CD4+ CD25highCD127lowforkhead box P3 (FoxP3high) and CD8‐activated T cells (CD8+CD38+) were determined by flow cytometry. Results showed that the number of activated CD8+CD38+ T cells increased in relation to HIV‐1 RNA plasmaviraemia (r = 0·403, P < 0·0001). The proportion of Tregs also correlated positively with HIV‐1 plasmaviraemia (r = 0·323, P = 0·002), but correlated inversely with CD4+ cells (r = −0·312, P = 0·004), thus suggesting a selective expansion along with increased viraemia and CD4+ depletion. Interestingly, a positive correlation was found between the levels of Tregs and CD8+CD38+ T cells (r = 0·305, P = 0·005), and the percentage of Tregs tended to correlate with HIV‐1 DNA load (r = 0·224, P = 0·062). Overall, these findings suggest that immune activation contributes to the expansion of Treg cells. In turn, the suppressive activity of Tregs may impair effector responses against HIV‐1, but appears to be ineffective in limiting immune activation.
Background. Epstein-Barr Virus (EBV) is involved in a wide range of malignancies, particularly in immuno-compromised subjects. In Africa, EBV primary infection occurs during early childhood, but ...little is known about the EBV load in Human Immunodeficiency Virus type 1 (HIV-1)-infected children. Methods. Blood samples from 213 HIV-1-infected children, 140 of whom were receiving antiretroviral therapy (ART), were collected at the Nsambya Hospital in Kampala, Uganda, and obtained for dried blood spot analysis. Nucleic acids were extracted and analyzed for quantification of EBV types 1 and 2; 16S ribosomal DNA (rDNA), a marker of microbial translocation; and HIV-1 RNA. Results. Ninety-two of 140 children (66%) receiving ART and 57 of 73 ART-naive children (78%) had detectable EBV DNA levels. Coinfection with both EBV types was less frequent in ART-treated children than in ART-naive children (odds ratio, 0.54 95% confidence interval {CI}, .30-.98; P = .042). Mean EBV DNA levels (±standard deviation) were lower in the former (3.99 ± 0.59 vs 4.22 ± 0.54 log₁₀ copies/mL; P = .006) and tended to be inversely associated with ART duration. EBV DNA levels were higher in children with an HIV-1 RNA load of > 3 log₁₀ copies/mL of blood (regression coefficient, 0.32 95%CI, .05-.59; P = .020) and correlated with circulating 16S rDNA levels (rs = 0.25 95% CI, .02-.46; P = .031). Conclusions. These findings suggest that ART, by limiting HIV-1 replication, microbial translocation, and related immune activation, prevents superinfection with both EBV types and keeps EBV viremia down, thus potentially reducing the risk of EBV-associated lymphomas.
Toll-like receptors (TLRs) and defensins (DEFs) play a crucial role in the host's innate immunity and may influence HIV-1 disease progression. We investigated the impact of TLR9 +1174G > A, 1635A > G ...and DEFβ1 -44C > G, -52G > A single nucleotide polymorphisms on the clinical outcome of 95 HIV-1-infected children. The TLR9 1635AG genotype and TLR9 G;G haplotype were associated with rapid disease progression, whereas the DEFβ1 -44CG genotype and DEFβ1 G;G haplotype correlated with a better clinical outcome.
Advanced Generalist Practice Vecchiolla, Francine J.; Roy, Ann W.; Lesser, Joan G. ...
Journal of teaching in social work,
08/2001, Letnik:
21, Številka:
3-4
Journal Article
Recenzirano
An enormous challenge faces social work educators as we prepare for the twenty-first century. Most significant is the scramble to understand and respond to contemporary challenges, notably managed ...health care and welfare reform. The authors present the conceptualization and implementation of an advanced generalist concentration curriculum. Teaching strategies and assignments in a MSW academic and field curriculum are used to illustrate the integration of knowledge necessary to a three-tiered model of practice at the micro, mezzo and macro levels. Finally, results of an alumni survey are presented that lend credence to our contention that graduates are well-prepared to function effectively in today's practice environment.
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