Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019045 (hemoglobinopathies)
 2,704 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sarcoma associated with osteonecrosis or bone infarction is a rare but well-documented pathological event. In this report, a 69-year-old man with sickle cell trait presented with malignant fibrous histiocytoma (MFH) in his distal tibia. The resected tumor was found in association with a large medullary infarct that extended 10 cm proximal from the tumor site. Bone infarcts can be caused by a number of processes including corticosteroid overuse, alcoholism, dysbarism, and hemoglobinopathies such as sickle cell disease. Patients with sickle cell anemia often develop osteonecrosis, but osteonecrosis has also been reported in people with sickle cell trait, albeit much more rarely. Our patient is only the third reported case of infarct-related bone sarcoma in a patient with sickle cell trait. Bone infarction may be a rare though serious consequence of sickle cell trait.
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PMID:Malignant fibrous histiocytoma arising within a bone infarct in a patient with sickle cell trait. 1476 78

Abnormalities of hemoglobin synthesis are usually inherited but may also arise as a secondary manifestation of another disease, most commonly hematologic neoplasia. Acquired hemoglobin disorders can be seen in any population and are not restricted to areas of the world with high incidences of inherited hemoglobinopathies. In fact, the acquired hemoglobinopathies may be more readily recognized where inherited hemoglobin abnormalities are rare and less likely to cause diagnostic confusion. Acquired alpha-thalassemia is the best characterized of the acquired red blood cell disorders in patients with hematologic malignancy, and it is almost always associated with a myelodysplastic syndrome (MDS). At least 2 molecular mechanisms for acquired alpha-thalassemia are now recognized: acquired deletion of the alpha-globin gene cluster limited to the neoplastic clone and, more commonly, inactivating somatic mutations of the trans-acting chromatin-associated factor ATRX, which cause dramatic down-regulation of alpha-globin gene expression. Here we review the clinical, hematologic, and molecular genetic features of alpha-thalassemia arising in a clonal myeloid disorder, and we discuss howATRX might affect gene expression in normal and abnormal hematopoiesis through epigenetic mechanisms.
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PMID:Acquired alpha-thalassemia in association with myelodysplastic syndrome and other hematologic malignancies. 1535 26

Allogeneic bone marrow or blood stem cell transplantation (BMT) represents an important therapeutic tool for the treatment of an otherwise incurable broad spectrum of malignant and non-malignant diseases. Until recently, BMT was used primarily to replace a malignant, genetically abnormal or deficient immunohematopoietic compartment and therefore, highly toxic myeloablative regimens were considered mandatory for more effective eradication of all undesirable host-derived hematopoietic cells, including stem cells and their progeny. Our preclinical and ongoing clinical studies indicated that much more effective eradication of host immunohematopoietic system cells can be mediated by donor lymphocytes in the process of adoptive allogeneic cell therapy following BMT. Thus, eradication of all malignant cells, especially in patients with CML and, to a lesser extent, in patients with other hematologic malignancies can be accomplished despite complete resistance of puch tumor cells to maximally tolerated doses of chemoradiotherapy. Our cumulative experience suggested that graft-versus-malignancy effects might be used as a tool for eradication of otherwise resistant tumor cells of host origin. We speculated that the therapeutic benefit of BMT may be improved by using safer conditioning for engraftment of donor stem cells induce host-versus-graft unresponsiveness to enable engraftment of donor lymphocytes for subsequent induction of graft-versus-malignancy effects, or even graft-versus-autoimmunity and graft-versus-genetically abnormal cells. In other words, focusing on more selective and smarter rather than stronger modalities. Effective BMT procedures may be accomplished without lethal conditioning of the host, using a new, well-tolerated and user-friendly non-myeloablative regimen, thus eliminating or minimizing immediate and late procedure-related toxicity and mortality. It appears that initial induction of graft tolerance, mediated by engraftment of donor stem cells, leads to durable engraftment of immunocompetent donor lymphocytes, which may be necessary for induction of effective biologic warfare against host-type immunohematopoietic cells. Consequently, stem-cell therapy following induction of transplantation tolerance by selective elimination of alloreactive donor lymphocytes may represent the treatment of choice for a wide range of otherwise incurable diseases, including cancer (hematologic malignancies and certain metastatic solid tumors), genetic disorders (hemoglobinopathies and enzyme deficiency disorders), diseases caused by self-reactive lymphocytes (autoimmune diseases such as multiple sclerosis, rheumatoid arthritis) to mention just a few. Using reduced intensity conditioning, non-myeloablative stem cell transplantation (NST) can be accomplished with no major procedure-related toxicity or mortality. Thus, NST offers the feasibility of safe stem cell transplantation and cell-mediated procedures for a large and constantly growing spectrum of clinical indications for all patients in need without lower or upper age limit. Future strategies currently under investigation include developing new approaches for control of alloreactivity of host-versus-graft and graft-versus host reactivity reactions and developing better approaches for maximizing the capacity of donor lymphocytes to eliminate cancer cells more selectively, while avoiding or minimizing GVHD for safer and more effective treatment of patients in need of BMT.
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PMID:Reduced-intensity conditioning for the treatment of malignant and life-threatening non-malignant disorders. 1538 19

Butyrate, a non-toxic short-chain fatty acid (SCFA) and inhibitor of histone deacetylase (HDAC), has potential as an anti-tumor agent because it imposes a reversible G1 block in normal cells yet induces apoptosis in tumor lines. As a potent reactivator of fetal globin transcription, butyrate is used clinically in the treatment of hemoglobinopathies. The anti-proliferative effect of butyrate and its derivatives on in vivo erythroid cell maturation, however, has limited their utility. The molecular mechanisms underlying the G1 arrest induced by butyrate and related SCFAs remain unclear. One model, drawing on tumor cell data, proposes that HDAC inhibition and subsequent transcriptional induction of cyclin-dependent kinase inhibitor (CKI) p21CIP are required. However, because of potentially confounding genetic mutations present in tumor models, we examined SCFA effects on CKIs in a non-transformed growth control model. Using murine 3T3 fibroblasts, we find p27KIP1 is also strongly induced. Unlike previously described effects of butyrate and HDAC inhibition on p21CIP, p27KIP1 induction did not occur at the transcriptional level; instead, the stability of the p27KIP1 protein increased. Other structurally unrelated HDAC inhibitors, including trichostatin A (TSA), induced p27KIP1 similarly. p27KIP1 was found in cyclin E/Cdk2 complexes, concomitant with suppression of cdk2 activity. Elevation of p27KIP1 is required for the observed G1 blockade, as p27KIP1-deficient fibroblasts were resistant to HDAC inhibition-induced arrest. These data suggest a novel activity for HDAC inhibitors and demonstrate a critical role for p27KIP1 in mediating G1 arrest in response to these drugs.
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PMID:Histone deacetylase inhibition-mediated post-translational elevation of p27KIP1 protein levels is required for G1 arrest in fibroblasts. 1538 42

DNA methylation provides a major epigenetic code (besides histone modification) of the lineage- and development-specific genes (such as regulators of differentiation in the hematopoietic lineages) that control expression of normal cells. However, DNA methylation is also involved in malignancies because aberrant methylating gene activity occurs during leukemic transformation. Thus, genes such as tumor suppressor genes, growth-regulatory genes, and adhesion molecules are often silenced in various hematopoietic malignancies by epigenetic inactivation via DNA hypermethylation. This inactivation is frequently seen not only in transformed cell lines but also in primary leukemia cells. Because this defect is amenable to reversion by pharmacologic means, agents that inhibit DNA methylation have been developed to specifically target this hypermethylation defect in leukemia and preleukemia cases. The most clinically advanced agents, the azanucleosides 5-azacytidine and 5-aza-2'-deoxycytidine (decitabine), were discovered more than 25 years ago, when their methylation-inhibitory activities, even at low concentrations, became apparent. Although both of these agents, like cytarabine, had been clinically used until then at high doses, the redevelopment of these agents for low-dose schedules has revealed very interesting clinical activities for treating myelodysplasia (MDS) and acute myeloid leukemia (AML). Because these diseases occur mostly in patients over 60 years of age, low-dose schedules with these compounds provide a very promising approach in such patient groups by virtue of their low nonhematologic toxicity profiles. In the present review, we describe the development of treatments that target DNA hypermethylation in MDS and AML, and clinical results are presented. In addition, pharmacologic DNA demethylation may be viewed as a platform for biological modification of malignant cells to become sensitized (or resensitized) to secondary signals, such as differentiating signals (retinoids, vitamin D3) and hormonal signals (eg, estrogen receptor in breast cancer cells, androgen receptor in prostate cancer cells). Finally, an in vitro synergism between the reactivating potency of demethylating agents and inhibitors of histone deacetylation has been tested in several pilot studies of AML and MDS treatment. Finally, gene reactivation by either group of compounds results in therapeutically meaningful reactivation of fetal hemoglobin in patients with severe hemoglobinopathies, extending the therapeutic range of derepressive epigenetic agents to nonmalignant hematopoietic disorders.
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PMID:DNA methylation as a therapeutic target in hematologic disorders: recent results in older patients with myelodysplasia and acute myeloid leukemia. 1548 40

Extramedullary hematopoiesis often occurs in hemoglobinopathies, hemolytic anemias, leukemias, lymphomas, and myeloproliferative disorders. Liver, spleen, and lymph nodes are frequently involved. However, extramedullary hematopoiesis may also develop in other sites such as thymus, kidney, retroperitoneum, and paravertebral areas of the thorax. Extramedullary hematopoietic masses are often microscopic and asymptomatic, but sometimes they lead to tumor-like masses. We describe massive intrathoracic extramedullary hematopoiesis in a 41-year-old man with compound heterozygosis for beta-thalassemia and sickle cell anemia and functional asplenia. We also describe a 39-year-old man with beta-thalassemia intermedia, who was initially diagnosed as having tumor masses, but was later proved, by magnetic resonance imaging, to have extramedullary erythropoietic tissue. These observations provide further support to include extramedullary hematopoiesis among the differential diagnosis of tumor-like masses in patients with hematologic diseases.
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PMID:Intrathoracic masses due to extramedullary hematopoiesis. 1554 49

Although the first studies using DNA demethylating agents at low doses in hematologic neoplasia and hemoglobinopathies were initiated more than 20 years ago, development of this type of nonintensive treatment has only been spurred in the last 6 to 8 years by the discovery of many genes that are specifically hypermethylated in cancer. These provide a powerful rationale for using azanucleosides (and other small molecules being developed for DNA demethylation) as a novel means of pharmacologic targeting of cancer cells that is distinct from low-dose chemotherapy. Encouraging response rates of about 50% in myelodysplasia with 5-azacytidine and 5-aza-2'-deoxycytidine (decitabine or DAC) have resulted in a number of phase III studies being initiated in this disorder. The development of such drugs for the treatment of acute myeloid leukemia (AML) is ongoing. While the specificity of DNA demethylation has been delineated by studying distinct genes or sets of genes, and proof-of-principle studies of in vivo methylation report demethylation and reactivation of genes like p15/INK4b and gamma-globin, responses to demethylating agents may be more complex. Specifically, so-called cancer testis antigens (CTAs) are intriguing targets for demethylation, since they are silenced in many hematopoietic disorders and may be reactivated by epigenetic therapy. Thus, demethylating agents and histone deacetylase inhibitors may also induce a T-cell-mediated antileukemic or antitumor effect.
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PMID:Epigenetic treatment of hematopoietic malignancies: in vivo targets of demethylating agents. 1621 92

Renal medullary carcinoma is an epithelial malignant tumor arising from collecting duct epithelium. The tumor is almost exclusive to young black patients with the sickle cell hemoglobinopathies, mainly sickle cell trait (SCT). Most patients present with metastatic disease and have a worse prognosis. An African-American male with sickle cell disease (HbSCD) who was diagnosed to have renal medullary carcinoma is presented here. The clinical, histologic and radiologic features of this tumor are described. In the setting of advanced disease, treatment modalities have proved largely unsuccessful. Given the shared demographic, clinical and radiographic features of these patients, awareness and early diagnosis may prove essential in improving survival.
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PMID:Renal medullary carcinoma. 1689 89

Renal medullary carcinoma (RMC) is an aggressive neoplasm occurring almost exclusively in adolescents and young adults with sickle cell (SC) hemoglobinopathies, usually sickle cell trait (SCT) or hemoglobin SC disease. The most common presentations are hematuria and flank or abdominal pain. It is a highly malignant tumor, and responses to chemotherapy are rare and transient resulting in a dismal prognosis. A high level of suspicion is necessary when evaluating at risk patients presenting with hematuria or flank pain, as currently it appears that only early diagnosis could potentially alter the outcome of this disease. We report a case of RMC in a young male patient with SCT, who presented to the emergency department with low back pain and microscopic hematuria, clinically mimicking acute obstructing urolithiasis. Our case emphasizes the need to consider alternate diagnoses when evaluating computed tomography scans for acute flank pain.
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PMID:Renal medullary carcinoma: unsuspected diagnosis at stone protocol CT. 1740 14

Priapism is a prolonged penile erection that is not associated with sexual stimulation. Although the time course has not been formally defined, it is usually considered to be one that lasts for more than 4-6 hours. Low-flow (ischemic) priapism is usually associated with sickle cell disease, hemoglobinopathies, neoplastic syndrome, anticoagulant therapy, psychotropic medication or idiopathic causes. Here, we report a case of prolonged low-flow priapism lasting for 2 weeks, which was successfully treated with the Winter procedure after several attempts of conservative treatment. Although the potency remains unclear and the patient needs a longer period of follow-up, the case reported here still shows that prolonged low-flow priapism can be successfully treated with the Winter procedure when conservative treatments fail.
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PMID:The Winter procedure as management for prolonged low-flow priapism: a case report. 1805


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