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)

Cadmium is a substantial industrial and environmental pollutant which seriously impairs erythropoiesis. Cd has been demonstrated to aggravate anemia by suppressing erythropoietin gene expression in anemic patients. As hypoxic induction of erythropoietin mRNA depends on a transcription factor, hypoxia-inducible factor 1 (HIF-1), we hypothesized that Cd suppresses the hypoxic activation of HIF-1. In hypoxic Hep3B cells, all mRNAs of various genes, which are known to be upregulated by HIF-1 activation under hypoxia, were suppressed by Cd in a dose-dependent manner. Cd inhibited the hypoxia-induced activity of luciferase in 293 cells which was transfected with a reporter plasmid carrying a hypoxia response element. By electrophoretic mobility gel shift assay, Cd inhibited the DNA-binding activity of HIF-1 in hypoxic Hep3B cells. Cd reduced the amount of HIF-1alpha protein in hypoxia, whereas it didn't affect HIF-1 alpha mRNA levels. Moreover, Cd inhibited HIF-1alpha accumulation induced by cobalt and desferrioxamine. Antioxidants and a proteasome inhibitor prevented the HIF-1alpha degradation caused by Cd. The possibility that oxidative stress mediates this action of Cd was examined. Cd didn't affect protein oxidation and reduced glutathione levels in hypoxic cells. These results indicate that Cd triggers a redox/proteasome-dependent degradation of HIF-1alpha protein, reducing HIF-1 activity and in turn suppressing the hypoxic induction of hypoxia-inducible genes.
 ...
PMID:Cadmium blocks hypoxia-inducible factor (HIF)-1-mediated response to hypoxia by stimulating the proteasome-dependent degradation of HIF-1alpha. 1086 24

Proteasome inhibitors reduce the budding of human immunodeficiency virus types 1 (HIV-1) and 2, simian immunodeficiency virus, and Rous sarcoma virus. To investigate this effect further, we examined the budding of other retroviruses from proteasome inhibitor-treated cells. The viruses tested differed in their Gag organization, late (L) domain usage, or assembly site from those previously examined. We found that proteasome inhibition decreased the budding of murine leukemia virus (plasma membrane assembly, PPPY L domain) and Mason-Pfizer monkey virus (cytoplasmic assembly, PPPY L domain), similar to the reduction observed for HIV-1. Thus, proteasome inhibitors can affect the budding of a virus that assembles within the cytoplasm. However, the budding of mouse mammary tumor virus (MMTV; cytoplasmic assembly, unknown L domain) was unaffected by proteasome inhibitors, similar to the proteasome-independent budding previously observed for equine infectious anemia virus (plasma membrane assembly, YPDL L domain). Examination of MMTV particles detected Gag-ubiquitin conjugates, demonstrating that an interaction with the ubiquitination system occurs during assembly, as previously found for other retroviruses. For all of the cell lines tested, the inhibitor treatment effectively inactivated proteasomes, as measured by the accumulation of polyubiquitinated proteins. The ubiquitination system was also inhibited, as evidenced by the loss of monoubiquitinated histones from treated cells. These results and those from other viruses show that proteasome inhibitors reduce the budding of viruses that utilize either a PPPY- or PTAP-based L domain and that this effect does not depend on the assembly site or the presence of monoubiquitinated Gag in the virion.
 ...
PMID:Retroviruses have differing requirements for proteasome function in the budding process. 1261 Jan 13

Multiple myeloma (MM) is a malignant hematologic disorder involving plasma cells. In MM, immunoglobulin is overproduced, and patients can develop skeletal, hematologic, renal, and/or neurologic complications. The exact etiology of MM is unknown. The treatment for MM includes chemotherapy, antiangiogenic medications, and, most recently, a proteasome inhibitor. Nursing care for patients with MM requires close monitoring for infections and anemia, pain control, and education about the disease and treatment options. Further understanding of the pathophysiology of MM may lead to newer treatment options for the disease.
 ...
PMID:Multiple myeloma: an overview. 1535 27

Multiple myeloma (MM), a malignancy of the plasma cells, accounts for an estimated 14% of all newly diagnosed hematologic malignancies. Advances in chemotherapy and stem cell transplantation have improved survival rates, but MM remains incurable. Bortezomib (Velcade, Millennium Pharmaceuticals, Inc., Cambridge, MA), a first-in-class proteasome inhibitor, has been approved for patients with MM who have received at least two prior treatments and have demonstrated disease progression on the most recent one. During clinical trials, most side effects were manageable with standard interventions. The most common toxicities were asthenic conditions (fatigue, malaise, and weakness), gastrointestinal disturbances (nausea, vomiting, diarrhea, and constipation), thrombocytopenia, peripheral neuropathy, pyrexia, and anemia. Supportive therapies and strategies for side-effect management can prevent worsening of these symptoms, thereby avoiding dose reductions and treatment delays. Oncology nurses play a key role in ensuring the proper and safe administration of bortezomib and often are the first to identify the signs of side effects. Patient education about anticipated side effects and close monitoring of patients can lead to symptom management interventions that are essential to patient comfort and safety.
 ...
PMID:Bortezomib, a newly approved proteasome inhibitor for the treatment of multiple myeloma: nursing implications. 1551 81

The proteasome inhibitor bortezomib has demonstrated clinical activity in patients with multiple myeloma (MM). Adverse events, including thrombocytopenia and peripheral neuropathy, have affected 30% to 60% of patients overall, and interrupted therapy in 10% to 20%. No prior toxicity data are available for Asian patients who have used bortezomib for MM. We used National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0, to review the clinical records of patients with an MM diagnosis from 25 centers in Korea. The included patients were treated with bortezomib alone or in combination with other agents, including thalidomide. Ninety-five MM patients were treated. The patients had a median age of 60 years (range, 42-77 years). The median number of previous treatments was 3 (range, 0-10), and 39% of the patients had been treated with 4 or more major classes of agents, including thalidomide (67%), and autologous stem cell transplantation (51%). Regimens included bortezomib only in 38 patients (40%), bortezomib plus dexamethasone in 34 patients (36%), and bortezomib plus a thalidomide-containing regimen in 23 patients (24%). The analysis of patient response to therapy revealed a complete response (CR) or a near-CR in 31 patients (33%) and a partial response in 30 patients (32%), for an objective response rate of 65% in 93 patients. The most common adverse events reported were thrombocytopenia (47%), sensory neuropathy (42%), anemia (31%), and leukopenia (31%). Thirteen patients (14%) stopped therapy because of adverse events (neuropathy, 8; infection, 4; diarrhea, 1). Neuropathy greater than grade 2 was more frequent in patients who received 4 or more prior therapy regimens (17/37) than in those who received 3 or fewer (14/58). In addition, therapy including thalidomide was significantly correlated with neuropathy of grades 1 to 3 (P = .001). We identified 6 therapy-related deaths (6%) within 20 days after the last dose of bortezomib. The causes of death were infection in 3 patients, disease progression in 2 patients, and suicide in 1 patient. The incidences of thrombocytopenia and neurotoxicity were similar; however, gastrointestinal toxicities were relatively low in Korean patients compared with those reported in Western studies. Significant neuropathy was associated with the number of prior regimens and combination with thalidomide. These findings provide useful information for clinicians and patients using bortezomib.
 ...
PMID:A multicenter retrospective analysis of adverse events in Korean patients using bortezomib for multiple myeloma. 1675 29

Novel therapies for multiple myeloma include the immunomodulatory drugs lenalidomide and thalidomide and the proteasome inhibitor bortezomib, which have increased response rates and survival times. However, the agents can cause myelosuppression, which, if not managed effectively, can be life threatening and interfere with optimal therapy and quality of life. The International Myeloma Foundation's Nurse Leadership Board developed a consensus statement that includes toxicity grading, strategies for monitoring and managing myelosuppression associated with novel therapies, and educational recommendations for patients and their caregivers. Although anemia, neutropenia, and thrombocytopenia are expected side effects of novel therapies for multiple myeloma, they are manageable with appropriate interventions and education.
 ...
PMID:Myelosuppression associated with novel therapies in patients with multiple myeloma: consensus statement of the IMF Nurse Leadership Board. 1849 Feb 53

In the past years, new developments have occurred both in the understanding of the biology of Waldenstrom Macroglobulinemia (WM) and in therapeutic options for WM. WM is a B-cell disorder characterized primarily by bone marrow infiltration with lymphoplasmacytic cells, along with demonstration of an IgM monoclonal gammopathy. Despite advances in therapy, WM remains incurable, with 5-6 years median overall survival of patients in symptomatic WM. Therapy is postponed for asymptomatic patients, and progressive anemia is the most common indication for initiation of treatment. The main therapeutic options include alkylating agents, nucleoside analogues, and rituximab. Studies involving combination chemotherapy are ongoing, and preliminary results are encouraging. No specific agent or regimen has been shown to be superior to another for treatment of WM. As such, novel therapeutic agents are needed for the treatment of WM. In ongoing efforts, we and others have sought to exploit advances made in the understanding of the biology of WM so as to better target therapeutics for this malignancy. These efforts have led to the development of several novel agents including the proteasome inhibitor bortezomib, and several Akt/mTor inhibitors, perifosine and Rad001, and immunomodulatory agents such as thalidomide and lenalidomide. Studies with monoclonal antibodies are ongoing and promising including the use of alemtuzumab, SGN-70, and the APRIL/BLYS blocking protein TACI-Ig atacicept. Other agents currently being tested in clinical trials include the PKC inhibitor enzastaurin, the natural product resveratrol, as well as the statin simvastatin. This report provides an update of the current preclinical studies and clinical efforts for the development of novel agents in the treatment of WM.
 ...
PMID:Waldenstrom macroglobulinemia. 1855 88

The Fanconi anemia/BRCA (FA/BRCA) DNA damage repair pathway plays a pivotal role in the cellular response to replicative stress induced by DNA alkylating agents and greatly influences drug response in cancer treatment. We recently reported that FA/BRCA genes are overexpressed and causative for drug resistance in human melphalan-resistant multiple myeloma cell lines. However, the transcriptional regulation of the FA/BRCA pathway is not understood. In this report, we describe for the first time a novel function of the NF-kappaB subunits, RelB/p50, as transcriptional activators of the FA/BRCA pathway. Specifically, our findings point to constitutive phosphorylation of IkappaB kinase alpha and subsequent alterations in FANCD2 expression and function as underlying events leading to melphalan resistance in repeatedly exposed multiple myeloma cells. Inhibiting NF-kappaB by small interfering RNA, blocking the IkappaB kinase complex with BMS-345541, or using the proteasome inhibitor bortezomib drastically reduced FA/BRCA gene expression and FANCD2 protein expression in myeloma cells, resulting in diminished DNA damage repair and enhanced melphalan sensitivity. Importantly, we also found that bortezomib decreases FA/BRCA gene expression in multiple myeloma patients. These results show for the first time that NF-kappaB transcriptionally regulates the FA/BRCA pathway and provide evidence for targeting Fanconi anemia-mediated DNA repair to enhance chemotherapeutic response and circumvent drug resistance in myeloma patients.
 ...
PMID:Targeting the Fanconi anemia/BRCA pathway circumvents drug resistance in multiple myeloma. 1993 14

Multiple myeloma (MM) is a B cell neoplasm of the bone marrow with a complex array of clinical manifestations including anemia, bone lesions, hypercalcemia, renal dysfunction, and compromised immune function. It accounts for 10%-15% of all hematologic malignancies, and 20% of deaths related to cancers of the blood and bone marrow. The diagnosis of MM is based on the presence of neoplastic plasma cells in the bone marrow or other extramedullary sites, along with evidence of disease-related organ dysfunction. Although the disease remains incurable, significant advances in both basic and translational research have enhanced understanding of disease pathogenesis and guided the development of new and more effective therapies. These agents include the immunomodulatory drugs thalidomide and lenalidomide, the proteasome inhibitor bortezomib, and other therapeutics that are currently being evaluated. This review highlights important historical landmarks in the field of MM, examines the pathogenesis and clinical manifestations of the disease, and outlines principles of both diagnosis and treatment of MM.
 ...
PMID:Multiple myeloma. 2109 Sep 65

Myeloma is a challenging blood cancer characterized by bone destruction, hypercalcaemia, renal insufficiency and anaemia. Although myeloma remains incurable, recent advancements in treatments have resulted in significant improvements in morbidity. The use of immunomodulatory drugs-thalidomide, lenalidomide, pomalidomide (in clinical trials)-and the proteasome inhibitor, bortezomib, in conjunction with conventional chemotherapy and supportive therapies, have resulted in a significant shift in approaches to treatment and an improvement in patients' quality of life. Nurses must remain up-to-date with current treatments for myeloma and their related side-effects. In addition, nurses play a key role in the coordination of a multidisciplinary approach to care for myeloma patients.
 ...
PMID:Myeloma: making sense of a complex blood cancer. 2113 23


1 2 3 4 5 Next >>