No abstract

Spontaneous senescence of cancer cells remains a puzzling and poorly understood phenomenon. Here we comprehensively characterize this process in primary epithelial ovarian cancer cells (pEOCs). Analysis of tumors from ovarian cancer patients showed an abundance of senescent cells in vivo. Further, serially passaged pEOCs become senescent after a few divisions. These senescent cultures display trace proliferation, high expression of senescence biomarkers (SA-β-Gal, γ-H2A.X), growth-arrest in the G1 phase, increased level of cyclins D1, D2, decreased cyclin B1, up-regulated p16, p21, and p53 proteins, eroded telomeres, reduced activity of telomerase, predominantly non-telomeric DNA damage, activated AKT, AP-1, and ERK1/2 signaling, diminished JNK, NF-κB, and STAT3 pathways, increased formation of reactive oxygen species, unchanged activity of antioxidants, increased oxidative damage to DNA and proteins, and dysfunctional mitochondria. Moreover, pEOC senescence is inducible by normal peritoneal mesothelium, fibroblasts, and malignant ascites via the paracrine activity of GRO-1, HGF, and TGF-β1. Collectively, pEOCs undergo spontaneous senescence in a mosaic, telomere-dependent and telomere-independent manner, plausibly in an oxidative stress-dependent mechanism. The process may also be activated by extracellular stimuli. The biological and clinical significance of pEOC senescence remains to be explored.

BackgroundMicroRNA dysregulation is a common event in leukemia. Polymorphisms in microRNA-binding sites (miRSNPs) in target genes may alter the strength of microRNA interaction with target transcripts thereby affecting protein levels. In this study we aimed at identifying miRSNPs associated with leukemia risk and assessing impact of these miRSNPs on miRNA binding to target transcripts.MethodsWe analyzed with specialized algorithms the 3′ untranslated regions of 137 leukemia-associated genes and identified 111 putative miRSNPs, of which 10 were chosen for further investigation. We genotyped patients with acute myeloid leukemia (AML, n = 87), chronic myeloid leukemia (CML, n = 140), childhood acute lymphoblastic leukemia (ALL, n = 101) and healthy controls (n = 471). Association between SNPs and leukemia risk was calculated by estimating odds ratios in the multivariate logistic regression analysis. For miRSNPs that were associated with leukemia risk we performed luciferase reporter assays to examine whether they influence miRNA binding.ResultsHere we show that variant alleles of TLX1_rs2742038 and ETV6_rs1573613 were associated with increased risk of childhood ALL (OR (95% CI) = 3.97 (1.43-11.02) and 1.9 (1.16-3.11), respectively), while PML_rs9479 was associated with decreased ALL risk (OR = 0.55 (0.36-0.86). In adult myeloid leukemias we found significant associations between the variant allele of PML_rs9479 and decreased AML risk (OR = 0.61 (0.38-0.97), and between variant alleles of IRF8_ rs10514611 and ARHGAP26_rs187729 and increased CML risk (OR = 2.4 (1.12-5.15) and 1.63 (1.07-2.47), respectively). Moreover, we observed a significant trend for an increasing ALL and CML risk with the growing number of risk genotypes with OR = 13.91 (4.38-44.11) for carriers of ≥3 risk genotypes in ALL and OR = 4.9 (1.27-18.85) for carriers of 2 risk genotypes in CML. Luciferase reporter assays revealed that the C allele of ARHGAP26_rs187729 creates an illegitimate binding site for miR-18a-3p, while the A allele of PML_rs9479 enhances binding of miR-510-5p and the C allele of ETV6_rs1573613 weakens binding of miR-34c-5p and miR-449b-5p.ConclusionsOur study implicates that microRNA-binding site polymorphisms modulate leukemia risk by interfering with the miRNA-mediated regulation. Our findings underscore the significance of variability in 3′ untranslated regions in leukemia.

The triple association between juvenile xanthogranuloma (JXG), juvenile myelomonocytic leukemia and neurofibromatosis was described in literature in about 20 cases. In this paper, the case of an 11-month-old infant boy with a disseminated JXG with unusual cytogenetic representation in the bone marrow was reported. Neurofibromatosis and juvenile myelomonocytic leukemia were excluded, just the same as other leukemias. Bone marrow and peripheral blood cytogenetic analysis revealed a karyotype with many rearrangements 46,XY,-6,der(12)t(6;12)(p21;p13),del(7)(p13p22),+9 once described in the literature as a B-acute lymphoblastic leukemia case. On the contrary, in our patient immunologic testing demonstrated a high activity of T lymphocytes, however, inflammation was excluded. To the best of our knowledge this is the first described case of systemic JXG with determined karyotype representing unusual chromosomal aberrations.

We report a case of Takayasu's disease with severe renovascular hypertension in a girl from Eritrea. In the "burn-out" phase after the erythrocyte sedimentation rate had normalized, reconstructive vascular surgery was performed as further progression of the disease seemed unlikely. However, probably due to her growth, the graft rotated and a second operation was successfully performed.