Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0002871 (anemia)
 52,094 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

No immunosuppression agent is as yet available that prevents the process of chronic allograft rejection, the most critical cause of late organ allograft loss. RS61443 (mycophenolate mofetil) inhibits de novo DNA synthesis as well as diminishes expression of cell surface molecules and antibody production. As these factors seem important in the pathophysiology of the chronic phenomenon, we investigated the effects of the agent in an established model of chronic rejection of kidney allografts in a F344-to-Lewis rat strain combination. All recipients were treated for the first 10 days after engraftment with low-dose cyclosporine (1.5 mg/kg/day) to reverse an initial acute rejection episode. Since functional and morphological changes do not become manifest in this model until after 12 wk, treatment with RS61443 (15 mg/kg/day, p.o.) was either initiated at the day of grafting (Gp 1) or 8 wks thereafter (Gp 2), and continued throughout the follow-up period. Non-RS61443-treated allografted rats receiving vehicle only (Gp 3) developed progressive proteinuria after 12 wk. Peak cellular infiltration (particularly macrophages in glomeruli and perivascular areas) at 16 wk was associated with densely expressed adhesion molecules (ICAM-1 on endothelium), cytokines and growth factors (TNF-alpha and TGF-beta in glomeruli and PDGF on arterial smooth muscle cells). Interstitial fibrosis, with tubular atrophy, glomerulosclerosis, and varying degrees of intimal proliferation and luminal obliteration of vessels, progressed thereafter. In vitro binding of MNC from naive animals to chronically rejecting allografted kidneys generally confirmed the immunohistological observations, peaking at 12 wk; this binding was significantly inhibited by mAbs against specific adhesion molecules (CD11a, CD18, and ICAM-1). Serum-allospecific IgG and IgM peaked at 1-2 wk after engraftment in the control recipients, decreasing thereafter. Although IgM declined to baseline after 12 wk, low levels of allospecific IgG persisted throughout the follow-up period. In contrast, recipient treatment with RS61443 (both Gp 1 and Gp 2) allowed the allografts to function normally throughout follow-up period. Proteinuria was virtually absent, and morphological and immunohistological manifestations of the chronic process were markedly diminished. In addition, treated recipients developed no significant side effects, including leukopenia, anemia, thrombopenia, nephrotoxicity, and hepatotoxicity. It appears that this agent can safely prevent the changes of chronic rejection of kidney allografts in this rat model.
 ...
PMID:Effects of RS61443 on functional and morphological changes in chronically rejecting rat kidney allografts. 787 46

Although PDGF is not a primary hematopoietic cytokine, effects in hematopoietic cell cultures have been reported. We recently described responses of multilineage hematopoietic precursors to PDGF. The effects were shown to be neutralized by antibody to IL-1 beta and mediated by marrow macrophages that expressed PDGF receptor RNA and responded to PDGF by upregulation of IL-1 RNA. The present study was performed to determine whether constitutive expression of PDGF by hematopoietic cells would have hematopoietic consequences in vivo. Retroviral vectors containing a PDGF-B gene were constructed and infected into normal marrow cells. Irradiated mice reconstituted with infected cells consistently developed a lethal myeloproliferative syndrome with anemia, neutrophilia and monocytosis, declining hematopoiesis in marrow with shift to the spleen, and extensive infiltration of immature hematopoietic cells into the parenchymal organs and connective tissues. In addition to PDGF, the retroviral constructs expressed a neo resistance marker. Phenotypic expression patterns in fibroblasts and in hematopoietic colony-forming cells in vitro were consistent with a significant degree of interaction between the two expressed inserts. Moreover, selection of infected cells for G418 resistance significantly reduced not only the number of infected reconstituting cells but also the intensity of the evoked syndrome in vivo. The observations have important implications for projected gene therapy protocols, and identify a novel potential pathway to myeloproliferative disease.
 ...
PMID:Overexpression of PDGF-B in murine hematopoietic cells induces a lethal myeloproliferative syndrome in vivo. 830 75

The normal proto-oncogene c-fms encodes the macrophage growth factor (M-CSF) receptor involved in growth, survival, and differentiation along the monocyte-macrophage lineage of hematopoietic cell development. A major portion of our research concerns unraveling the temporal, molecular, and structural features that determine and regulate these events. Previous results indicated that c-fms can transmit a growth signal as well as a signal for differentiation in the appropriate cells. To investigate the role of the Fms tyrosine autophosphorylation sites in proliferation vs. differentiation signaling, four of these sites were disrupted and the mutant receptors expressed in a clone derived from the myeloid FDC-P1 cell line. These analyses revealed that: (1) none of the four autophosphorylation sites studied (Y697, Y706, Y721, and Y807) are essential for M-CSF-dependent proliferation of the FDC-P1 clone; (2) Y697, Y706, and Y721 sites, located in the kinase insert region of Fms, are not necessary for differentiation but their presence augments this process; and (3) the Y807 site is essential for the Fms differentiation signal: its mutation totally abrogates the differentiation of the FDC-P1 clone and conversely increases the rate of M-CSF-dependent proliferation. This suggests that the Y807 site may control a switch between growth and differentiation. The assignment of Y807 as a critical site for the reciprocal regulation of growth and differentiation may provide a paradigm for Fms involvement in leukemogenesis, and we are currently investigating the downstream signals transmitted by the tyrosine-phosphorylated 807 site. In Fms-expressing FDC-P1 cells, M-CSF stimulation results in the rapid (30 sec) tyrosine phosphorylation of Fms on the five cytoplasmic tyrosine autophosphorylation sites, and subsequent tyrosine phosphorylation of several host cell proteins occurs within 1-2 min. Complexes are formed between Fms and other signal transduction proteins such as Grb2, Shc, Sos1, and p85. In addition, a new signal transduction protein of 150 kDa is detectable in the FDC-P1 cells. The p150 is phosphorylated on tyrosine, and forms a complex with Shc and Grb2. The interaction with Shc occurs via a protein tyrosine binding (PTB) domain at the N-terminus of Shc. The p150 is not detectable in Fms signaling within fibroblasts, yet the PDGF receptor induces the tyrosine phosphorylation of a similarly sized protein. In hematopoietic cells, this protein is involved in signaling by receptors for GM-CSF, IL-3, KL, MPO, and EPO. We have now cloned a cDNA for this protein and found at least one related family member. The related family member is a Fanconia Anemia gene product, and this suggests potential ways the p150 protein may function in Fms signaling.
 ...
PMID:Growth and differentiation signals regulated by the M-CSF receptor. 898 70

A 55-year-old man with myelofibrosis was treated with natural alpha-interferon with a good hematologic response. Initially, he had anemia, leukocytosis, thrombocytosis and hepatospleomegaly. A bone marrow biopsy showed replacement with fibrosis with an increase in megakaryocytes. Natural alpha-interferon (alpha-IFN) was started at a dose of 3 x 10(6) units/day. The leukocyte and platelet counts gradually normalized, and the liver and spleen decreased in size. However, the patient complained of a dry cough and dyspnea on the 61st treatment day, when the accumulated dose of alpha-IFN treatment had reached 1.8 x 10(8) units. He subsequently developed acute respiratory failure (PaO2 < 60 mm Hg) with bilateral lung infiltrations, suggesting the occurrence of interstitial pneumonitis associated with alpha-interferon therapy. Immediately, the alpha-interferon was discontinued and high-dose methylprednisolone (1.5 g/day) was administered for 3 days. This treatment was followed by oral prednisone therapy. Steroid therapy brought about gradual improvement as suggested by a repeat radiograph. Since high levels of fibrogenic cytokines, such as PDGF and TGF-beta, have been reported in patients with myelofibrosis, it is necessary to pay attention to interstitial pneumonia as a complication in alpha-IFN therapy for myelofibrosis.
 ...
PMID:A case of interstitial pneumonitis associated with natural alpha-interferon therapy for myelofibrosis. 915 65

A 47-year-old man was admitted to our hospital in June 1997 because of nasal bleeding. He presented with anemia in addition to physical characteristics of Werner's syndrome (WS). Peripheral blood examination disclosed pancytopenia with 4% blasts. Bone marrow aspiration was a dry tap; biopsy specimens revealed myelofibrosis. Chromosomal analysis of peripheral blood revealed hypodiploidy with complex abnormalities including -5 and del(7)(q21). Serum levels of PDGF, FGF, and TGF beta 1 were normal. A diagnosis of acute myelofibrosis was made. The patient's condition became quickly deteriorated and he died of pneumonia in October 1997. In the literature, we found 6 reported cases of myelofibrosis associated with WS. Considering that only approximately 1,100 cases of WS have been reported so far, the incidence of myelofibrosis in WS seems relatively high. This case suggested a link between WS and myelofibrosis, and the mechanism of myelofibrosis in WS was discussed.
 ...
PMID:[Werner's syndrome associated with acute myelofibrosis]. 1072 41

It has been proposed that interferon-gamma (IFN) inhibits collagen synthesis in myeloproliferative disorders through an inhibitory effect on PDGF and TGF-beta. We therefore evaluated the role of IFN-gamma on bone marrow fibrosis in idiopathic myelofibrosis (IMF). After a 3-month observation period, nine patients (five female, four male), median age 64 years (range 43-72 years), received 3 x 3 mU IFN-gamma/week over 6 months and were monitored after withdrawal of IFN-gamma for further 3 months. Three out of nine patients have completed the study according to the protocol. Six patients had to be withdrawn from IFN-gamma due to the following reasons: bacterial infection (three patients), splenic infarction or deterioration of splenomegaly (one patient, each) and refusal to continue IFN-gamma (one patient). Results from seven patients treated for at least 8 weeks were considered measurable. Leukopenia, initially present in one of the evaluated patients, deteriorated during IFN-gamma treatment. This patient died during the observation period shortly after withdrawal of the therapy as a result of septicemia. Transfusion-dependent anemia, initially observed in two of the evaluated patients, deteriorated during the IFN-gamma treatment. Bone marrow fibrosis increased in three patients, whereas it remained unchanged in another and improved in a further patient. Splenomegaly improved in two patients but deteriorated markedly in one. Taking these observations together, four patients had disease progression during IFN-gamma treatment, two had stable disease and one could be qualified as a partial responder. According to these data IFN-gamma cannot be considered as a treatment option for patients with IMF.
 ...
PMID:Ineffectiveness of interferon-gamma in the treatment of idiopathic myelofibrosis: a pilot study. 1126 29

In a multi-institutional Phase II trial, we evaluated the efficacy of a platelet-derived growth factor receptor (PDGF-r) inhibitor, SU101, in patients with hormonerefractory prostate cancer. The patients received a 4-day i.v. loading dose of SU101 at 400 mg/m(2) for 4 consecutive days, followed by 10 weekly infusions at 400 mg/m(2). The primary study end points were a decline in prostate-specific antigen (PSA) and a decrease in measurable tumor. Secondary end points were time to progression and an effect on pain as measured by the Brief Pain Survey. Expression of PDGF-r was examined in both metastatic and archival primary prostate tumor samples. Forty-four patients were enrolled at four centers. The median age was 72 years, the median PSA was 223 ng/ml, and 21 patients had at least one prior chemotherapy. Thirty-nine patients are evaluable for PSA, and three patients demonstrated a PSA decline >50% from baseline (55-99.9% decrease). The median time to progression was 90 days. Of 19 patients evaluable for measurable disease, 1 patient had a partial response. Nine of 35 evaluable patients had significant improvement in pain. The most frequent adverse events were asthenia (75%), nausea (55%), anorexia (50%), and anemia (41%). PDGF-r expression was detected in 80% of the metastases and 88% of primary prostate cancers. The results of this trial may warrant further clinical studies with other PDGF-r inhibitors.
 ...
PMID:A multi-institutional phase ii study of SU101, a platelet-derived growth factor receptor inhibitor, for patients with hormone-refractory prostate cancer. 1130 25

Imatinib mesylate (IM) is a tyrosine kinase inhibitor, which inhibits phosphorylation of downstream proteins involved in BCR-ABL signal transduction. It has proved beneficial in treating patients with chronic myeloid leukaemia (CML). In addition, IM demonstrates activity against malignant cells expressing c-kit and platelet-derived growth factor receptor (PDGF-R). The activity of IM in the blastic crisis of CML and against various myeloma cell lines suggests that this drug may also target other cellular components. In the light of the important role of telomerase in malignant transformation, we evaluated the effect of IM on telomerase activity (TA) and regulation in various malignant cell lines. Imatinib mesylate caused a dose-dependent inhibition of TA (up to 90% at a concentration of 15 microM IM) in c-kit-expressing SK-N-MC (Ewing sarcoma), SK-MEL-28 (melanoma), RPMI 8226 (myeloma), MCF-7 (breast cancer) and HSC 536/N (Fanconi anaemia) cells as well as in ba/F3 (murine pro-B cells), which do not express c-kit, BCR-ABL or PDGF-R. Imatinib mesylate did not affect the activity of other DNA polymerases. Inhibition of TA was associated with 50% inhibition of proliferation. The inhibition of proliferation was associated with a decrease in the S-phase of the cell cycle and an accumulation of cells in the G2/M phase. No apoptosis was observed. Inhibition of TA was caused mainly by post-translational modifications: dephosphorylation of AKT and, to a smaller extent, by early downregulation of hTERT (the catalytic subunit of the enzyme) transcription. Other steps of telomerase regulation were not affected by IM. This study demonstrates an additional cellular target of IM, not necessarily mediated via known tyrosine kinases, that causes inhibition of TA and cell proliferation.
 ...
PMID:Imatinib mesylate (Gleevec) downregulates telomerase activity and inhibits proliferation in telomerase-expressing cell lines. 1587 Jul 11

A 56-year-old man complained of fever, anemia, thrombocytopenia and lymph node swelling. Biopsy of the lymph node demonstrated angioimmunoblastic T cell lymphoma (AITL) with the loss of normal architecture, proliferation of neoplastic T cells, small vessels mixed with eosinophils and plasma cells. Aspiration of bone marrow was dry tap, and biopsy demonstrated myelofibrosis with increased proliferation of reticulin fiber. Markedly elevated plasma levels of transforming growth factor beta1 (TGF-beta1) and soluble interleukin-2 receptor (sIL-2R) were observed, and that of platelet growth factor (PDGF) AB was slightly elevated. After chemotherapy, remission of lymphoma was achieved. The aspiration of bone marrow became possible, and the level of TGF-beta1 and PDGF AB showed normalization; thus, myelofibrosis was reversible.
 ...
PMID:Angioimmunoblastic T cell lymphoma associated with reversible myelofibrosis. 1898 38

Sickle cell anemia (SCA) associated cerebrovascular disease includes vascular remodeling, abnormal cerebral blood flow (CBF) and infarction. We studied the relationships between plasma brain derived neurotropic factor (BDNF), platelet derived growth factors (PDGF-AA and -AB/BB) and high trans-cranial Doppler (TCD) velocity, an indication of CBF velocity. Baseline plasma samples from 39 children (19 SCA with abnormal/high TCD [SATCD], 13 SCA with normal TCD [SNTCD] and 7 healthy non-SCA), were assayed for BDNF, PDGF-AA and -AB/BB plus 11 other cytokines. The sensitivity, specificity and usefulness of these biomarkers for stroke prediction was investigated. All subject groups were of similar age and gender distribution. Mean BDNF was significantly higher among SATCD than SNTCD (p=0.004) as was mean PDGF-AA (p=0.001). Similarly, mean PDGF-AA was higher among SCA subjects who developed stroke than those who did not (p=0.012). Elevated BDNF and PDGF-AA were good predictors of the presence of abnormally high CBF velocity and were both associated with severity of anemia. Elevated PDGF-AA predicted risk for stroke development. Stroke incidence and high TCD velocity were associated with elevated BDNF and PDGF-AA. These findings suggest a role for BDNF and PDGF-AA in the patho-physiological mechanism of cerebrovascular disease in SCA.
 ...
PMID:Plasma BDNF and PDGF-AA levels are associated with high TCD velocity and stroke in children with sickle cell anemia. 2270 95


1 2 Next >>