Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of interferon (IFN) in the treatment of chronic myeloid leukaemia (CML) has been established. Many adverse effects have been reported, but vasospasm has been extremely rare. We report 2 CML patients who developed such complications. A 56-year-old female had been on IFN for 3 years with haematological and cytogenetic remission, when she developed an anginal syndrome followed by acute ischaemia. Coronary catheterization revealed normal arteries. After discontinuation of IFN her cardiac complaints disappeared and she needed no medication. A 61-year-old patient had been on IFN for 1 year when he presented with Raynaud's phenomenon. No evidence of collagen vascular disease could be documented. IFN discontinuation and intravenous administration of iloprost (a prostacyclin analogue) resulted in the disappearance of the vascular complications. IFN appears to have a beneficial effect on the course and prognosis of CML. However, we have to be aware of the potential complications and adverse effects which can be related to IFN. Neither our experience nor the literature provides convincing recommendations regarding the management of such patients. We suggest proceeding with IFN at lower doses, especially in those who have achieved a cytogenetic response, as our first patient.
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PMID:Interferon-induced vasospasm in chronic myeloid leukaemia. 979 41

Spontaneous mediastinal hematoma is rarely seen in hematologic malignancy. We report a case of chronic myeloid leukemia initially presenting with spontaneous hematoma and hemothorax. In addition to a detailed history, computerized tomography of the chest is important in analyzing whether an anterior mediastinal mass lesion is present. Magnetic resonance imaging is helpful in confirming the nature of a mediastinal hematoma. Trauma, vascular disease and coagulopathy should first be ruled out when making a diagnosis of spontaneous bleeding in the thorax. In our patient, the mediastinal hematoma regressed spontaneously after three months. Leukemia should be considered in the differential diagnosis of spontaneous mediastinal hematoma. In leukemia patients with spontaneous mediastinal hematoma, supportive observation and close follow-up may be better than surgery, unless massive hemorrhage or active bleeding in the thorax is suspected.
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PMID:Chronic myeloid leukemia initially presenting with spontaneous mediastinal hematoma and hemothorax. 1067 32

Advanced glycation end products (AGEs) are believed to play an important role in the development of angiopathy in diabetes mellitus. Previous reports suggested a correlation between accumulation of AGEs and production of vascular endothelial growth factor (VEGF) in human diabetic retina. However, the mechanisms involved were not revealed. In this study, we investigated the transcriptional regulation of the expression of vascular endothelial growth factor (VEGF) by AGEs, and possible involvement of reactive oxygen species (ROS) in the induction. We employed an AGE of bovine serum albumin (BSA) prepared by an incubation of BSA with D-glucose for 40 weeks and N(epsilon)-(carboxymethyl)lysine (CML), a major AGE. The expression of VEGF was induced by CML-BSA in RAW264.7 mouse macrophage-like cells. CML-BSA stimulated the DNA-binding activity of activator protein-1 (AP-1). Promoter assay showed that the induction of VEGF was dependent on AP-1. The activity of Ras/Raf-1/MEK/ERK1/2 was involved in the CML-BSA-stimulated signaling pathways to activate the AP-1 transcription with a peak at 1 h. AGE-BSA also induced VEGF mediated by AP-1, however, there was a difference of effect between AGE-BSA and CML-BSA in the activation of AP-1. AGE-BSA-stimulated AP-1 activity showed a peak at 5 h, which paralleled the formation of ROS. Reduction of AGE-BSA with NaBH(4) or addition of vitamin E attenuated the AGE-BSA-stimulated signaling pathways leading to the same pattern as for CML-BSA-stimulated signals. These results suggest an important role for AGEs in stimulation of the development of angiogenesis observed in diabetic complications, and that ROS accelerates the AGE-stimulated VEGF expression.
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PMID:Reactive oxygen species accelerate production of vascular endothelial growth factor by advanced glycation end products in RAW264.7 mouse macrophages. 1193 95

Advanced glycation end products (AGEs) play an important role in the development of angiopathy in diabetes mellitus and atherosclerosis. Here, we show that adducts of N(epsilon)-(carboxymethyl)lysine (CML), a major AGE, and bovine serum albumin (CML-BSA) stimulated gamma-glutamylcysteine synthetase (gamma-GCS), which is a key enzyme of glutathione (GSH) synthesis, in RAW264.7 mouse macrophage-like cells. CML-BSA stimulated the expression of gamma-GCS heavy subunit (h) time- and dose-dependently and concomitantly increased GSH levels. CML-BSA also stimulated DNA-binding activity of activator protein-1 (AP-1) within 3h, but the stimulatory effect decreased in 5h, and nuclear factor-kappaB (NF-kappaB) with a peak activity at 1h and the stimulatory effect diminished in 3h. Studies of luciferase activity of the gamma-GCSh promoter showed that deletion and mutagenesis of the AP-1-site abolished CML-BSA-induced up-regulation, while that of NF-kappaB-site did not affect CML-BSA-induced activity. CML-BSA also stimulated the activity of protein kinase C, Ras/Raf-1, and MEK/ERK1/2. Inhibition of ERK1/2 abolished CML-BSA-stimulated AP-1 DNA-binding activity and gamma-GCSh mRNA expression. Our results suggest that induction of gamma-GCS by CML adducts seems to increase the defense potential of cells against oxidative stress produced during glycation processes.
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PMID:Nepsilon-(Carboxymethyl)lysine induces gamma-glutamylcysteine synthetase in RAW264.7 cells. 1214 23

Gangrene of the toes and digits appears to be a rare but very severe complication of long-term hydroxyurea therapy. Nothing is known regarding the pathophysiology and the type of vascular damage leading to this syndrome. Here we report a case of a 49-year-old male presenting with gangrene of the toes of both feet 4.5 years after initiation of hydroxyurea therapy for chronic myelogenous leukemia. Blisters on the toes occurred for the first time 9 months prior to hospitalization. Successively, all ten toes showed signs of beginning gangrene with one toe removed surgically 8 months before admission. Presence of diabetes mellitus or peripheral angiopathy was ruled out and platelet counts were within the physiologic range during the last years, excluding thrombocythemia as another rare cause for gangrene in patients with myeloproliferative diseases. Whereas perimalleolar ulcerations of the legs are a more common complication of hydroxyurea, gangrene of the toes as a consequence of hydroxyurea treatment has been described previously only once in the literature. At this point in time cessation of hydroxyurea treatment appears to be the only therapeutic option, thereby avoiding further progress of gangrene in patients with chronic myelogenous leukemia treated with hydroxyurea.
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PMID:Gangrene of the toes in a patient with chronic myelogenous leukemia after long-term hydroxyurea therapy. 1222 5

Advanced glycation end products (AGEs) derived from glucose are implicated in the pathogenesis of diabetic vascular disease. However, many lines of evidence suggest that other pathways also promote AGE formation. One potential mechanism involves oxidants produced by the NADPH oxidase of neutrophils, monocytes, and macrophages. In vitro studies have demonstrated that glycolaldehyde, a product of serine oxidation, reacts with proteins to form N(epsilon)-(carboxymethyl)lysine (CML), a chemically well-characterized AGE. We used mice deficient in phagocyte NADPH oxidase (gp91-phox(-/-)) to explore the role of oxidants in AGE production in isolated neutrophils and intact animals. Activated neutrophils harvested from wild-type mice generated CML on ribonuclease A (RNase A), a model protein, by a pathway that required L-serine. CML formation by gp91-phox(-/-) neutrophils was impaired, suggesting that oxidants produced by phagocyte NADPH oxidase contribute to the cellular formation of AGEs. To determine whether these observations are physiologically relevant, we used isotope-dilution gas chromatography/mass spectrometry to quantify levels of protein-bound CML in mice suffering from acute peritoneal inflammation. Phagocytes from the gp91-phox(-/-) mice contained much lower levels of CML than those from the wild-type mice. Therefore, oxidants generated by phagocyte NADPH oxidase may play a role in AGE formation in vivo by a glucose-independent pathway.
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PMID:Production of N(epsilon)-(carboxymethyl)lysine is impaired in mice deficient in NADPH oxidase: a role for phagocyte-derived oxidants in the formation of advanced glycation end products during inflammation. 1288 33

In vitro experiments and animal models indicate that advanced glycation end products (AGEs) may play a crucial role in the vascular dysfunctions observed in patients with diabetes mellitus. These results prompted us to study subrogate markers of inflammation or vascular dysfunction in type II diabetic patients. Monocyte count and activation are dependent upon macrophage colony stimulating factors (M-CSF). Soluble vascular cell adhesion molecule (sVCAM-1) blood levels have been proposed as a marker for endothelium activation. To explore a possible relationship between these factors in diabetic patients, we measured a chemically defined AGE, N(carboxymethyl)lysine-protein (CML-protein) in a group of normal subjects (n = 55) and of diabetic patients (n = 40) using ELISA. Simultaneously, we determined M-CSF and sVCAM-1 blood levels. We found that CML-protein blood levels were significantly higher in patients with diabetes compared to non-diabetic subjects (40.2 +/- 4.7 and 7.9 +/- 0.7 pmol/mg protein respectively, p < 0.0001). M-CSF was increased while sVCAM-1 blood levels were normal in the group of diabetics. M-CSF blood level was correlated to CML-protein blood level (p < 0.05). In addition CML-protein, M-CSF and sVCAM-1 were increased in patients with micro-angiopathy. These results suggest that AGE may contribute to vascular dysfunction including microangiopathy.
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PMID:AGEs, macrophage colony stimulating factor and vascular adhesion molecule blood levels are increased in patients with diabetic microangiopathy. 1511 47

In diabetes mellitus an increased risk exists for vascular complications. A role for advanced glycation endproducts (AGEs) in the acceleration of vascular disease has been suggested. Nepsilon-(carboxymethyl)lysine (CML)- and methylglyoxal (MGO)-modified proteins have been identified as major AGEs. The interaction of these AGEs with the human endothelial cells and macrophages was studied. Changes in adhesion molecule expression, i.e. vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and E-selectin were determined by cell-bound Elisa on human endothelial cells after incubation with CML-modified albumin and MGO-modified albumin. The presence of the full-length receptor of AGEs (RAGE) and splice variants of RAGE was determined by specific RT-PCR. In addition, binding studies were performed with CML- and MGO-modified albumin to endothelial cells and P388D1 macrophages. We demonstrated that CML-albumin or MGO-albumin did not induce activation of endothelial cells as measured by the expression of adhesion molecules, while, under the same conditions, TNF-alpha did. No specific binding of CML-albumin and MGO-albumin on these cells was found. In contrast to endothelial cells, a specific binding of MGO-albumin to P388D1 macrophages was demonstrated, which could be competed by ligands of scavenger receptors. In human umbilical vein and microvascular endothelial cells we found the N-truncated and C-truncated splice variants of RAGE. In conclusion, under our experimental conditions no CML- or MGO-albumin-induced increase in adhesion molecule expression was found on endothelial cells. In agreement with this, no binding of these AGEs was found to endothelial cells. The existence of splice variants of RAGE in endothelial cells might explain the lack of interaction of extracellular AGEs with these cells.
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PMID:Interaction of Nepsilon(carboxymethyl)lysine- and methylglyoxal-modified albumin with endothelial cells and macrophages. Splice variants of RAGE may limit the responsiveness of human endothelial cells to AGEs. 1649 95

Despite the common use of immunohistochemistry in autopsy tissues, the stability of most proteins over extended time periods is unknown. The robustness of signal for 16 proteins (MMP1, MMP2, MMP3, MMP9, TIMP1, TIMP2, TIMP3, AGER, MSR, SCARB1, OLR1, CD36, LTF, LGALS3, LYZ, and DDOST) and two measures of advanced glycation end products (AGE, CML) was evaluated. Two formalin-fixed, paraffin-embedded human tissue arrays containing 16 tissues each were created to evaluate 48 hr of autolysis in a warm or cold environment. For these classes of proteins, matrix metalloproteinases and their inhibitors, scavenger receptors, and advanced glycation end product receptors, we saw no systematic diminution of signal intensity during a period of 24 hr. Analysis was performed by two independent observers and confirmed for a subset of proteins by digital analysis and Western blotting. We conclude that these classes of proteins degrade slowly and faithfully maintain their immunohistochemistry characteristics over at least a 24-hr time interval in devitalized tissues. This study supports the use of autopsy tissues with short postmortem intervals for immunohistochemical studies for diseases such as diabetic vascular disease, cancer, Alzheimer's disease, atherosclerosis, and other pathological states. This manuscript contains online supplemental material at http://www.jhc.org. Please visit this article online to view these materials.
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PMID:Robust immunohistochemical staining of several classes of proteins in tissues subjected to autolysis. 1731 10

Advanced glycation end products (AGEs) derived from glucose are implicated in the pathogenesis of diabetic vascular disease. However, their direct modulatory effects on coronary vascular tone remain unclear. We previously reported that coronary vasoconstriction was induced by acetylcholine (ACh) infusion of the isolated perfused rat heart and that sensitivity was greater in perfused hearts from streptozotocin (STZ)-induced diabetic rats than in those from age-matched controls (Kamata et al., 2008). Here, we investigated the effect of N(epsilon)-(carboxymethyl)lysine (CML), which has one of the main AGE structures, on ACh-induced vasoconstriction in perfused hearts isolated from control and diabetic rats. ACh-induced vasoconstriction was significantly greater in the STZ-induced diabetic group than in the age-matched controls. CML enhanced the ACh-induced vasoconstriction in coronary arteries from control rats, but not in those from STZ-induced diabetic rats. In the controls, the vasoconstriction induced by the calcium-channel activator Bay K 8644 was also enhanced by CML. These CML-mediated enhancements of the vasoconstrictions induced by ACh and Bay K 8644 were significantly suppressed by tempol, a superoxide dismutase mimetic. The plasma CML and glucose levels were each significantly elevated in STZ-induced diabetic rats. These findings suggest (a) that CML augments ACh-induced coronary vasoconstriction, an effect that may be attributable to increased superoxide and to activation of voltage-gated Ca(2+) channels and (b) that this modulating effect may be desensitized in the STZ-induced diabetic heart.
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PMID:Effect of N-epsilon-(carboxymethyl)lysine on coronary vasoconstriction in isolated perfused hearts from control and streptozotocin-induced diabetic rats. 1960 56


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