Differential methylation of genes that regulate cytokine signaling in lymphoid and hematopoietic tumors.

The perturbations of the cytokine signaling pathway play an important role in lymphoid/hematopoietic tumors. Aberrant promoter methylation is the major mechanism of gene silencing in tumors. We examined 150 lymphoid/hematopoietic tumors or potential premalignant specimens, 55 control specimens and 12 EBV-transformed B lymphoblastoid cultures and 10 lymphoma/leukemia (L/L) or multiple myeloma (MM) cell lines for the methylation (and, in cell lines, of the expression status) of three genes involved in the cytokine signaling pathway. The genes were: SHP1, a protein tyrosine phosphatase; SYK, a protein kinase; and SOCS1, a suppressor of cytokine signaling. Our major findings were: (1) one or more of the three genes was frequently methylated in L/L and MM cell lines and there was good concordance (90-100%) between methylation and loss of gene expression; (2) treatment of L/L cell lines with a demethylating agent resulted in re-expression of SHP1 protein and downregulation of phosphorylated STAT3 in L/L cell lines; (3) all 55 control specimens and the lymphoblastoid cultures were negative for methylation of the three genes; (4) non-Hodgkin's lymphomas (100%), and leukemias (94%) had almost universal methylation of SHP1 and relatively less frequent (<30%) methylation of SOCS1 and SYK; (5) MM and monoclonal gammopathy of unknown significance (MGUS) had infrequent methylation of SHP1 (<20%), and occasional methylation of SOCS1 and SYK; and (6) comparable methylation frequencies for SOCS1 were observed in MM and MGUS, suggesting that SOCS1 methylation is an early event in MM pathogenesis. At least one gene was methylated in 119 of 130 (93%) of the malignant and 12 of 20 (60%) of the MGUS samples. Our findings demonstrate that the perturbations of cytokine signaling via silencing of these three genes are almost universal in lymphoid/hematopoietic tumors but the patterns of gene methylated for L/L and plasma cell dyscrasias are different.

First-year outcomes of beating heart coronary artery bypass grafting using proximal mechanical connectors.

BACKGROUND: To determine the extended results of mechanical connectors we compared the 1-year outcomes of patients having beating heart coronary artery bypass surgery with at least one sutured or mechanically connected proximal vein graft anastomosis. METHODS: From May 2001 to December 2001, 166 patients were identified as having undergone off-pump bypass grafting utilizing at least one St. Jude symmetry aortic connector (St Jude Medical Anastomotic Technology Group, St. Paul, MN). Follow-up for major adverse cardiac events (MACEs), which is defined as cardiac mortality, myocardial infarction, or revascularization of a previous target vessel, was obtained on 162 patients (97.6%). A control group of 159 patients was identified from a cohort of patients having beating heart surgery with one or more sutured proximal vein graft anastomosis in the preceding year. The MACE follow-ups were obtained in 136 patients (85.6%) by direct telephone contact. RESULTS: Patients with connectors showed an accelerated number of MACEs beginning approximately 180 days from the time of surgery and stabilizing at approximately 300 days. Logistic regression analysis identified the presence of diabetes as a significant preoperative risk factor predisposing patients to earlier onset of MACEs (p = 0.03) with an odds ratio of 2.9 (95% confidence interval, 1.1 to 7.6). Insulin dependent diabetics showed no differences between connector and control patients in the frequency or timing of MACEs. Connector patients using oral hypoglycemic agents demonstrated a significant deviation (p = 0.01) from a similar control population in the prevalence and timing of MACEs. CONCLUSIONS: Connector patients showed an increased incidence of early MACEs. These events were characterized by an increased requirement for early target vessel revascularization and were predominantly in noninsulin-dependent diabetics.