Global alterations in chromatin structure profoundly influence gene expression in thoracic neoplasms, silencing tumor suppressors while facilitating the expression of various cancer testis antigens such as NY-ESO-1. Although recent studies have shown that histone deacetylase inhibitors can potentiate tumor suppressor gene induction mediated by demethylating agents in cancer cells, the ability of these agents to augment cancer testis antigen expression have not been fully defined. The authors designed the current study to determine whether the histone deacetylase inhibitor, depsipeptide FR901228 (DP), could enhance NY-ESO-1 induction mediated by the DNA demethylating agent 5-Aza-2'-deoxycytidine (DAC) in cell lines established primarily from thoracic cancers. Quantitative reverse-transcriptase polymerase chain reaction analysis revealed that, under exposure conditions potentially achievable in clinical settings, DAC dramatically induced NY-ESO-1 expression in cultured cancer lines. DP alone mediated negligible target gene induction but significantly augmented DAC-mediated induction of NY-ESO-1. After DAC or sequential DAC-DP treatment, HLA-A*0201 cancer cells were recognized by an HLA-A*0201 CTL specific for NY-ESO-1. Although sequential DAC/DP exposure did not uniformly enhance immune recognition of target cells compared with DAC alone, this treatment mediated profound induction of apoptosis in cancer cells but not normal human bronchial epithelia. The apoptotic effects of DAC, DP, or sequential DAC-DP did not correlate in an obvious manner with histology, or the magnitude of NY-ESO-1 induction in cancer cells. Although the mechanisms have not been fully defined, sequential DAC-DP treatment may be a novel strategy to augment antitumor immunity in cancer patients.
SummaryPlatelet numbers were estimated on all 225 patients admitted with severe renal failure to the Sydney Hospital Renal Unit in a 2 year period. Serial counts were per formed to determine the circumstances under which platelet numbers were restored to normal in patients with thrombocytopenia. Measurements of 51Cr-labelled autologous or homologous platelet life span were made in 37 patients with severe renal disease and in 8 control subjects.Thrombocytopenia occurred in one quarter of all patients with renal tubular necrosis, acute or subacute glomerulonephritis, or malignant hypertension, but only in one twelfth of those with severe uraemia due to chronic renal disease. Recovery of platelet numbers followed partial relief of uraemia by dialysis or return of renal function in 24 patients. In 2 patients the platelet count rose despite no relief of uraemia, and in 14, there was no recovery from thrombocytopenia before death. Severe infection, microangiopathy and malignant disease, although present in a number of patients, were not important causes of thrombocytopenia.The life span of autologous platelets, or of compatible, normal, homologous platelets given to subjects who had never received a previous blood transfusion, was normal in severe renal failure, and there was no significant difference between patients with various types or different severities of renal disease. The survival of homologous platelets was slightly or moderately reduced when given to patients who had received a previous blood transfusion.The mean recovery of autologous 51Cr-labelled platelets prepared in acid citrate was 58%, and of homologous platelets, 41 %.Thrombocytopenia in renal failure is presumed to be mainly due to impaired platelet production caused by the biochemical affects of azotaemia. The condition should be treated by peritoneal dialysis, and, when this is impossible or ineffective, by platelet transfusion.
SummaryA novel study of dynamic blood coagulation in uraemic patients was based on the application of the variable-frequency thromboviscometer, VFTV, an advanced form of the thrombelastograph. Clotting times, rates of formation, consistencies, and rates of degradation of artificial thrombi cast at 60 and 180 cycles/min (equal to mean shear rates of 26.8 and 80 sec–1) were investigated in 35 patients and in normal controls.The study shows that there exists a profound difference in VFTV parameters between normals and patients with severe renal failure. The most significant are the rate of degradation of thrombi formed at 60 cycles/min (p < 0.001), the consistency of thrombi formed at 180 cycles/min (p < 0.005), and the total thrombus formation time at 180 cycles/min (p < 0.001). Thrombi formed at 60 cycles/min adhered to brass rather than Teflon in many patients with renal failure, in contrast to the findings in normals and in all types of patients previously tested.A division of patients into clinical subgroups (acute renal failure, non-oliguric or oliguric chronic renal failure, and long-term dialysis) shows that all these groups are quite homogeneous from the dynamic coagulation viewpoint, although the thrombus degradation rate (when coagulation proceeds at 60 cycles/min) differs significantly (p = 0.025) between the long-term dialysis group and the non-oliguric chronic renal failure group. These same groups also show a difference in their platelet count. The VFTV abnormalities of uraemia could not be correlated with either the severity of the measurable biochemical derangement or the qualitative platelet defect.An unexpected, but statistically significant, pattern appeared when patients were divided according to their ABO blood groups. The rate of degradation of the thrombus formed at 60 cycles/min differed significantly between 0 and A and between B and A blood groups (p < 0.01). The rate of formation of the white thrombus at 180 cycles/ min differed significantly (p < 0.05) between 0 and A blood groups. Simultaneously, the platelet count differed between blood groups 0 and B (p = 0.05) and between 0 and A (p < 0.005).Effect of blood groups on the VFTV parameters is evident even in the normal controls; here, the rate of degradation of the thrombus formed at 60 cycles/min showed significant difference between blood groups A and B (p < 0.005) and a smaller difference between 0 and B(0.05 < p <0.1).We consider that the demonstration that the consistency of white thrombi is twice as high in uraemic patients than in normals, and that the rate of degradation of the red-white thrombi is nearly ten-fold greater is of fundamental importance. Both these phenomena might be associated with the known platelet defects of uraemia, or with a possible further abnormalities of fibrinogen, caused by the presence of one or more of the chemical substances which accumulate in the uraemic state.
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