Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0038002 (splenomegaly)
 9,873 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The term congenital neutropenia (CN) has been used for a group of hematologic disorders characterized by severe neutropenia with absolute neutrophil counts (ANC) below 0.5 x 10(9)/L associated with increased susceptibility to bacterial infections. This group of diseases includes primary bone marrow failure syndromes with isolated neutropenias and neutropenias associated with metabolic or immunologic disorders or with a complex syndrome. To avoid confusion, we prefer using the term CN only for the most severe disorder among this group: severe neutropenia characterized by an early stage maturation arrest of myelopoiesis leading to bacterial infections from early infancy. This disease has originally been described as Kostmann syndrome with an autosomal recessive inheritance. Recent pathogenetic investigations have demonstrated that this clinical phenotype includes also autosomal dominant and sporadic cases with different point mutations in the neutrophil elastase gene in a subgroup of patients. Data on over 400 patients with CN collected by the Severe Chronic Neutropenia International Registry demonstrate that independent from the CN-subtype more than 90% of these patients respond to recombinant human granulocyte-colony stimulating factor (rHuG-CSF filgrastim, lenograstim) with ANC that can be maintained around 1.0 x 10(9)/L. Adverse events include mild splenomegaly, moderate thrombocytopenia, osteoporosis and malignant transformation into myelodysplastic syndrome/leukemia. Development of additional genetic aberrations, e.g., G-CSF-receptor gene mutations, monosomy 7 or ras mutations during the course of the disease indicate an underlying genetic instability leading to an increased risk of malignant transformation. If and how G-CSF treatment impacts on these adverse events remains unclear since there are no historical controls for comparison. Hematopoietic stem cell transplantation is still the only available treatment for patients refractory to G-CSF treatment.
 ...
PMID:Congenital neutropenias. 1469 35

To determine the importance of suppressor of cytokine signaling-3 (SOCS3) in the regulation of hematopoietic growth factor signaling generally, and of G-CSF-induced cellular responses specifically, we created mice in which the Socs3 gene was deleted in all hematopoietic cells. Although normal until young adulthood, these mice then developed neutrophilia and a spectrum of inflammatory pathologies. When stimulated with G-CSF in vitro, SOCS3-deficient cells of the neutrophilic granulocyte lineage exhibited prolonged STAT3 activation and enhanced cellular responses to G-CSF, including an increase in cloning frequency, survival, and proliferative capacity. Consistent with the in vitro findings, mutant mice injected with G-CSF displayed enhanced neutrophilia, progenitor cell mobilization, and splenomegaly, but unexpectedly also developed inflammatory neutrophil infiltration into multiple tissues and consequent hind-leg paresis. We conclude that SOCS3 is a key negative regulator of G-CSF signaling in myeloid cells and that this is of particular significance during G-CSF-driven emergency granulopoiesis.
 ...
PMID:SOCS3 is a critical physiological negative regulator of G-CSF signaling and emergency granulopoiesis. 1497 38

Mammalian presenilins (PS) consist of two highly homologous proteins, PS1 and PS2. Because of their indispensable activity in the gamma-secretase cleavage of amyloid precursor protein to generate Abeta peptides, inhibition of PS gamma-secretase activity is considered a potential therapy for Abeta blockage and Alzheimer's disease intervention. However, a variety of other substrates are also subject to PS-dependent processing, and it is thus imperative to understand the consequences of PS inactivation in vivo. Here we report a pivotal role of PS in hematopoiesis. Mice heterozygous for PS1 and homozygous for PS2 (PS1(+/)(-)PS2(-)(/)(-)) developed splenomegaly with severe granulocyte infiltration. This was preceded by an overrepresentation of granulocytic cells in the bone marrow and a greatly increased multipotent granulocyte-monocyte progenitor in the spleen. In contrast, hematopoietic stem cells and T- and B-lymphocytes were not affected. Importantly, treatment of wild-type splenocytes with a gamma-secretase inhibitor directly promoted the granulocyte-macrophage colony-forming unit (GM-CFU). These results establish a critical role of PS in myelopoiesis. Our finding that this activity can be directly modulated by its gamma-secretase activity has important safety implications concerning these inhibitors.
 ...
PMID:Myeloproliferative disease in mice with reduced presenilin gene dosage: effect of gamma-secretase blockage. 1512 1

We describe a 75-year-old man with neutropenia in whom bone marrow aspirate and biopsy demonstrated hemophagocytosis associated with myelodysplasia (MDS). Therapy with granulocyte-colony stimulating factor (G-CSF) and granulocyte-monocyte-colony stimulating factor (GM-CSF) caused splenomegaly and severe thrombocytopenia, which recurred upon rechallenge. We propose that myeloid growth factors may be detrimental in patients with MDS-associated hemophagocytosis.
 ...
PMID:Hemophagocytosis exacerbated by G-CSF/GM-CSF treatment in a patient with myelodysplasia. 1555 Dec 87

Protein kinase C (PKC)-epsilon, a Ca(2+)-independent, phospholipid-dependent serine/threonine kinase, is among the PKC isoforms expressed in mouse epidermis. We reported that FVB/N transgenic mouse lines that overexpress (8- or 18-fold) PKC-epsilon protein in basal epidermal cells and cells of the hair follicle develop papilloma-independent squamous cell carcinoma (SCC) elicited by 7,12-dimethylbenz(a)anthracene initiation and 12-O-tetradecanoylphorbol-13-acetate-promotion or by repeated ultraviolet radiation exposures. The susceptibility to the development of SCC was proportional to the level of expression of the PKC-epsilon transgene. We now report that PKC-epsilon FVB/N transgenic mice (line 215) that overexpress in epidermis approximately 18-fold PKC-epsilon protein more than their wild-type littermates spontaneously develop a myeloproliferative-like disease (MPD) in 100% of PKC-epsilon transgenic mice. The MPD was characterized by an excess of neutrophils and eosinophils, resulting in invasion of almost all vital organs of the mouse by 6 months of age. On gross examination these mice present with splenomegaly, hepatomegaly, and severe lymphadenopathy. Examination of the bone marrow revealed almost complete effacement by neutrophils, eosinophils, and their precursors. Furthermore, the spleen and lymph nodes were enlarged and exhibited marked extramedullary hematopoiesis. Complete pathological analysis of the second PKC-epsilon transgenic mouse (line 224) that expresses approximately eightfold PKC-epsilon protein more than their wild-type littermates revealed no remarkable findings in any of the affected organs as seen in line 215. However, peripheral blood analyses of PKC-epsilon transgenic mice indicated significant increases of neutrophils in the circulating blood in both PKC-epsilon transgenic lines. To determine whether there was an imbalance of cytokines in PKC-epsilon transgenic mice (line 215), resulting in aberrant myelopoiesis, we analyzed 17 cytokines in the peripheral blood. This analysis indicated that interleukin-5, interleukin-6, and granulocyte-colony stimulating factor were up-regulated as a function of age. The transgene PKC-epsilon was not detected in any of the affected organs (bone marrow, liver, spleen, lung) We suggest that overexpression of PKC-epsilon in the epidermis may lead to the induction of specific cytokines that may, in a paracrine mechanism, perturb normal hematopoiesis in bone marrow resulting in a granulocytic skew toward that of neutrophils and eosinophils. The susceptibility of PKC-epsilon transgenic mice to the induction of SCC and the spontaneous development of MPD are unrelated.
 ...
PMID:Overexpression of protein kinase C-{epsilon} in the mouse epidermis leads to a spontaneous myeloproliferative-like disease. 1563 5

Paraneoplastic leukemoid reaction (PLR) is a rare condition of leucocytosis in cancer patients. Here we report the rapid progression of a patient suffering from a metastasized malignant melanoma and PLR. The patient's white blood cell count exceeded 200,000 cells per mul and the serum level of Granulocyte Colony-Stimulating Factor (G-CSF) was elevated up to 780 pg/mul. A Tc-m99-labeled anti-NCA90/95 based granulocyte scan demonstrated reactive bone marrow expansion, splenomegaly and granulocyte infiltration into the tumor. KT293, a S100, gp100 and CD68 positive melanoma cell line derived from an axillary metastasis, produced large amounts of G-CSF in vitro and induced rapidly growing tumors and PLR after subcutaneous inoculation in SCID mice. In contrast to G-CSF-secreting cancer cells of other tissue origin, G-CSF-neutralizing antibodies failed to inhibit the growth of KT293 cells. In addition, KT293 cells did not express G-CSF-receptor. These observations suggest that paracrine effects of G-CSF-secretion and PLR might promote an aggressive melanoma phenotype, as seen in this patient.
 ...
PMID:Paraneoplastic leukemoid reaction and rapid progression in a patient with malignant melanoma: establishment of KT293, a novel G-CSF-secreting melanoma cell line. 1566 34

A leukemoid reaction with granulocytosis and splenomegaly has been observed in animals and humans with a variety of tumors. We have employed four color flow cytometry to characterize the leukemoid reaction induced by the transplantable mouse mammary carcinoma 4T1 in female BALB/c mice. Gr-1(+) myeloid cells with the morphology of granulocytes increased in peripheral blood from <15% pre-transplant to nearly 80% of total CD45(+) leukocytes at four weeks post-transplant. Though the granulocyte:lymphocyte ratio increased markedly, the absolute numbers of CD19(+) B lymphocytes, CD4(+) and CD8(+) T lymphocytes, and the CD4/CD8 ratio in peripheral blood did not change significantly. Femurs from tumor-bearing mice showed myeloid hyperplasia of the fatty marrow. There was a notable increase in cells with a Gr-1(dim)/CD11b(bright) immature granulocyte phenotype, and these cells were also found in peripheral blood and spleen. Spleen weights had increased 8.5-fold by four weeks post-tumor transplant, mainly due to granulocytic hyperplasia. Cultured 4T1 tumor cells constitutively expressed mRNA for the myeloid colony-stimulating factors G-CSF and GM-CSF, and IFN-gamma-inducible M-CSF transcripts were also detected. Tumors excised from mice had transcripts for G-CSF and GM-CSF, but only G-CSF protein was found in high levels in serum of tumor-bearing mice. These data demonstrate that 4T1 tumor-bearing mice exhibit a leukemoid reaction that apparently is caused by the production of colony-stimulating factors produced by the tumor. The 4T1 tumor may serve as an excellent model for the study of this reaction.
 ...
PMID:Murine mammary carcinoma 4T1 induces a leukemoid reaction with splenomegaly: association with tumor-derived growth factors. 1691 66

The use of peripheral blood stem cells (PBSC) as a source of hematopoietic stem cells is steadily increasing and has nearly supplanted bone marrow transplantation. The present article reviews mobilization of PBSC as well as the side effects. Under steady state conditions less than 0.05% of the white blood cells (WBC) are CD34+ cells. Chemotherapy results in a 5-15-fold increase of PBSC. Combining chemotherapy and growth factors increases CD34+ cells up to 6% of WBC. In the allogeneic setting, granulocyte-colony stimulating factor (G-CSF) is used alone for PBSC mobilization. Several factors affect the mobilization of PBSC: age, gender, type of growth factor, dose of the growth factor and in the autologous setting, the patient's diagnosis, chemotherapy regimen and number of previous chemotherapy cycles or radiation. Muscle and bone pain are frequent adverse events in allogeneic stem cell mobilization but are usually tolerated with the use of analgesics. Spleen enlargement followed by rupture is a serious complication in allogeneic donors. Large volume apheresis (LVL) with a processed volume of more than 4-fold of the patient's blood volume can be used to increase the CD34+ yield in patients with low CD34+ pre-counts, resulting in higher yields of CD34+ cells for transplantation. Processing of more blood in LVL is achieved by an increase of the blood flow rate and an altered anticoagulation regimen with the occurrence of more citrate reactions.
 ...
PMID:Mobilization of peripheral blood stem cells. 1798 Jun 65

The use of peripheral blood stem cells (PBSC) as a source of hematopoietic stem cells is steadily increasing and has nearly supplanted bone marrow. The present article reviews mobilization and collection of PBSC as well as its side effects. Specialized harvesting strategies such as large volume leukapheresis (LVL) and pediatric PBSC collection are included in this overview. Under steady state conditions, less than 0.05% of the white blood cells (WBC) are CD34+ cells. Chemotherapy results in a 5-15-fold increase of PBSC. Combining chemotherapy and growth factors increases CD34+ cells up to 6% of WBC. In the allogeneic setting, granulocyte-colony stimulating factor is used alone for PBSC mobilization. Several factors affect the mobilization of PBSC: age, gender, type of growth factor, dose of the growth factor and in the autologous setting, patient's diagnosis, chemotherapy regimen and number of previous chemotherapy cycles or radiation. Harvesting of PBSC can be performed with various blood cell separators using continuous or discontinuous flow technique. Continuous flow separators allow the processing of more blood compared with intermittent flow devices resulting in higher yields of CD34+ cells for transplantation. LVL can be used to increase the CD34+ yield in patients with low CD34+ pre-counts. Processing of more blood in LVL is achieved by an increase of the blood flow rate and an altered anticoagulation regimen. Specialized strategies were developed for pediatric PBSC collection considering the main limiting factors, extracorporeal volume and vascular access. Adverse events in PBSC collection can be subdivided in apheresis associated and mobilization associated side effects. Citrate reactions due to hypocalcemia are frequent during apheresis, especially in pediatric PBSC collection and LVL. Thrombocytopenia is often observed in patients after termination of apheresis due to platelet loss during PBSC harvesting. Muscle and bone pain are frequent adverse events in allogeneic stem cell mobilization but are usually tolerated under the use of analgesics. Spleen enlargement followed by rupture is a serious complication in allogeneic donors.
 ...
PMID:Mobilization and harvesting of peripheral blood stem cells. 1822 Aug 66

Felty's syndrome is regarded as a severe variant of rheumatoid arthritis (RA) that develops in less than 1% of patients with RA. It consists of a triad of RA, splenomegaly, and leukopenia, which tends to develop after a long course of RA. Treatment of neutropenia is mainly comprised of disease-modifying antirheumatic drugs including methotrexate, hydroxychloroquine, auronofin, penicillamine, glucocorticoids, and granulocyte monocyte colony stimulating factor. Recently, there has been a growing interest in the biologic agent rituximab in the treatment of Felty's syndrome. To our knowledge, only one previous case of rituximab being beneficial in the treatment of Felty's syndrome has been reported. We report the case of a 60-year-old man with Felty's syndrome in whom treatment with rituximab led to a sustained neutrophil response and marked symptomatic improvement in the form of decrease in the size of rheumatoid nodules and better pain control.
 ...
PMID:Rituximab is useful in the treatment of Felty's syndrome. 1864 32


<< Previous 1 2 3 4 5 6 7 8 9 Next >>