ABSTRACT
Drug resistance in acute lymphoblastic leukemia (ALL) remains a major problem warranting new treatment strategies. Wnt/catenin signaling is critical for the self-renewal of normal hematopoietic progenitor cells. Deregulated Wnt signaling is evident in chronic and acute myeloid leukemia; however, little is known about ALL. Differential interaction of catenin with either the Kat3 coactivator CREBBP (CREB-binding protein (CBP)) or the highly homologous EP300 (p300) is critical to determine divergent cellular responses and provides a rationale for the regulation of both proliferation and differentiation by the Wnt signaling pathway. Usage of the coactivator CBP by catenin leads to transcriptional activation of cassettes of genes that are involved in maintenance of progenitor cell self-renewal. However, the use of the coactivator p300 leads to activation of genes involved in the initiation of differentiation. ICG-001 is a novel small-molecule modulator of Wnt/catenin signaling, which specifically binds to the N-terminus of CBP and not p300, within amino acids 1-110, thereby disrupting the interaction between CBP and catenin. Here, we report that selective disruption of the CBP/ß- and γ-catenin interactions using ICG-001 leads to differentiation of pre-B ALL cells and loss of self-renewal capacity. Survivin, an inhibitor-of-apoptosis protein, was also downregulated in primary ALL after treatment with ICG-001. Using chromatin immunoprecipitation assay, we demonstrate occupancy of the survivin promoter by CBP that is decreased by ICG-001 in primary ALL. CBP mutations have been recently identified in a significant percentage of ALL patients, however, almost all of the identified mutations reported occur C-terminal to the binding site for ICG-001. Importantly, ICG-001, regardless of CBP mutational status and chromosomal aberration, leads to eradication of drug-resistant primary leukemia in combination with conventional therapy in vitro and significantly prolongs the survival of NOD/SCID mice engrafted with primary ALL. Therefore, specifically inhibiting CBP/catenin transcription represents a novel approach to overcome relapse in ALL.
Subject(s)
Antineoplastic Agents/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Peptide Fragments/metabolism , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Pyrimidinones/pharmacology , Sialoglycoproteins/metabolism , beta Catenin/metabolism , Animals , Asparaginase/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Dexamethasone/pharmacology , Down-Regulation/drug effects , Drug Resistance, Neoplasm , Drug Synergism , Humans , Inhibitor of Apoptosis Proteins/genetics , Inhibitor of Apoptosis Proteins/metabolism , Mice , Mice, Inbred NOD , Mice, SCID , Mutation , Peptide Fragments/antagonists & inhibitors , Peptide Fragments/genetics , Sialoglycoproteins/antagonists & inhibitors , Sialoglycoproteins/genetics , Survivin , Vincristine/pharmacology , Wnt Signaling Pathway , Xenograft Model Antitumor AssaysABSTRACT
Rates of bacteremia among hospitalized patients with central venous catheters range up to 21%. Few data exist for home intravenous therapy (IVT). We studied 300 patients from two hospital-based home IVT services in 29 months. Diagnoses included 92 cases of osteomyelitis, 33 of pneumonia, 35 of malnutrition, 26 of chronic pain, and 114 of other diseases. Peripheral IVT was given to 97 patients. Mean age was 39.4 years (range, 0.3-98). Hickman, Infuse-A-Port, Broviac, Arrow triple lumen, Hohn, and peripherally inserted central catheters (PICC) were used for a mean of 44 days. Six bacteremias (one death) (2%, 4.6/10,000 catheter days), two subclavian thromboses, 13 catheter site infections, and one additional death occurred. PICC experience included 76 patients, mean age 46 years (range, 4-76), primarily with infections, chronic pain, or dehydration. Mean duration of therapy was 24 days (0-67) and was completed in 51 patients; others completed therapy with standard peripheral catheters a mean of 6 days later. Complications included 17 obstructions by clot, 11 cases of phlebitis, six catheter fractures, five punctures, two accidental removals, and one infiltration. Liquid silicone repaired holes; urokinase opened clots. Successful completion of therapy was more common in the second year, 88% versus 57%. Despite more complications, patients, home IVT nurses, and physicians preferred PICCs. We conclude that home IVT is safe via many means of access, with fewer infections than with hospital care. Such infections may be termed "nosohusial."
Subject(s)
Bacterial Infections/etiology , Catheterization/adverse effects , Home Care Services , Infusions, Intravenous/adverse effects , Adolescent , Adult , Aged , Catheterization, Central Venous/adverse effects , Catheterization, Peripheral/adverse effects , Child , Child, Preschool , Humans , Infant , Middle Aged , Sepsis/etiologyABSTRACT
The purpose of this preliminary study was twofold: (a) to explore self-care practices of 10 noninstitutionalized women who experience urinary incontinence (UI) and (b) to evaluate two instruments, the Urinary Incontinence Interview Guide and the Self-Care Responses Questionnaire. Data analysis was accomplished by data reduction and tabulation and comparison of responses from both instruments. Data are presented in a descriptive format. The most frequently reported self-care practices included regular toileting, alteration of fluid intake, exercises, weight reduction, seeking medical treatment, and protection to contain the problem. Half of the women reported embarrassment and all reported some negative feelings about UI. Recommendations are made in relation to both instruments for future use with UI research.
