No abstract

Anaplastic lymphoma kinase (ALK), physiologically expressed only by certain neural cells, becomes highly oncogenic, when aberrantly expressed in nonneural tissues as a fusion protein with nucleophosphin (NPM) and other partners. The reason why NPM-ALK succeeds in transforming specifically CD4 + T lymphocytes remains unknown. The IL-2R common γ-chain (IL-2Rγ) is shared by receptors for several cytokines that play key roles in the maturation and growth of normal CD4 + T lymphocytes and other immune cells. We show that IL-2Rγ expression is inhibited in T-cell lymphoma cells expressing NPM-ALK kinase as a result of DNA methylation of the IL-2Rγ gene promoter. IL-2Rγ promoter methylation is induced in malignant T cells by NPM-ALK. NPM-ALK acts through STAT3, a transcription factor that binds to the IL-2Rγ gene promoter and enhances binding of DNA methyltransferases (DNMTs) to the promoter. In addition, STAT3 suppresses expression of miR-21, which selectively inhibits DNMT1 mRNA expression. Reconstitution of IL-2Rγ expression leads to loss of the NPM-ALK protein and, consequently, apoptotic cell death of the lymphoma cells. These results demonstrate that the oncogenic tyrosine kinase NPM-ALK induces epigenetic silencing of the IL-2Rγ gene and that IL-2Rγ acts as a tumor suppressor by reciprocally inhibiting expression of NPM-ALK.

Here we report that T-cell lymphomas characterized by the expression of anaplastic lymphoma kinase (ALK؉ TCL) fail to express the TNF␣ and frequently display DNA methylation of the TNF␣ gene promoter. While only a subset of the ALK؉ TCL-derived cell lines showed a high degree of the promoter methylation, all 6 showed low to nondetectable expression of the TNF␣ mRNA, and none expressed the TNF␣ protein. All 14 ALK؉ TCL tissue samples examined displayed some degree of the TNF␣ promoter methylation, which was the most prominent in the distal portion of the the promoter. Treatment with a DNA methyltransferase inhibitor, 5-aza-2-deoxy-cytidine (5-ADC), reversed the promoter methylation and led to the expression of TNF␣ mRNA and protein. Furthermore, in vitro DNA methylation of the promoter impaired its transcriptional activity in the luciferase reporter assay. This impairment was seen even if only either distal or proximal portion were methylated, with methylation of the former exerting a more profound inhibitory effect. Notably, the ALK؉ TCL cell lines uniformly expressed the type 1 TNF␣ receptor (TNF-R1) protein known to transduce the TNF␣-induced pro-apoptotic signals. Moreover, exogeneous TNF␣ inhibited growth of the ALK؉ TCL cell lines in a dose-dependent manner and induced activation of the members of the cell apoptotic pathway: Caspase 8 and caspase 3. These findings provide additional rationale for the therapeutic inhibition of DNA methyltransferases in ALK؉ TCL. They also suggest that treatment with TNF␣ may be highly effective in this type of lymphoma.

TSB-CVCs demonstrated an excellent safety profile in our study. These catheters should be preferentially utilized for arm vein preservation in advanced kidney disease. Their impact on future AVF success needs further evaluation.

Background: Patients with primary hyperoxaluria (PH) often develop kidney stones and chronic kidney disease. Noninvasive urine markers reflective of active kidney injury could be useful to gauge the effectiveness of ongoing treatments. Methods: A panel of biomarkers that reflect different nephron sites and potential mechanisms of injury (clusterin, neutrophil gelatinase-associated lipocalin (NGAL), 8-isoprostane (8IP), monocyte-chemoattractant protein 1(MCP-1), liver-type fatty acid binding protein (L-FABP), heart-type fatty acid binding protein (H-FABP), and osteopontin (OPN)) were measured in 114 urine specimens from 30 PH patients over multiple visits. Generalized estimating equations were used to assess associations between biomarkers and 24 h urine excretions, calculated proximal tubular oxalate concentration (PTOx), and eGFR. Results: Mean (±SD) age at first visit was 19.5 ± 16.6 years with an estimated glomerular filtration rate (eGFR) of 68.4 ± 21.0 ml/min/1.73m 2. After adjustment for age, sex, and eGFR, a higher urine MCP-1 concentration and MCP-1/ creatinine ratio was positively associated with CaOx supersaturation (SS). Higher urine NGAL and NGAL/creatinine as well as OPN and OPN/creatinine were associated with higher eGFR. 8IP was negatively associated with PTOx and urinary Ox, but positively associated with CaOx SS. Conclusion: In PH patients greater urine MCP-1 and 8IP excretion might reflect ongoing collecting tubule crystallization, while greater NGAL and OPN excretion may reflect preservation of kidney mass and function. CaOx crystals, rather than oxalate ion may mediate oxidative stress in hyperoxaluric conditions. Further studies are warranted to determine whether urine MCP-1 excretion predicts long term outcome or is altered in response to treatment.