We used two mouse models of Huntington's disease (HD) to examine changes in glutamate receptor sensitivity and striatal electrophysiology. One model, a transgenic, consisted of mice expressing exon 1 of the human HD gene and carrying 141-157 CAG repeat sequences (R6/2 line). The second model, a CAG repeat "knockin," consisted of mice with different lengths of CAG repeats (CAG71 and CAG94 repeats). The effects of glutamate receptor activation were examined by visualizing neurons in brain slices with infrared videomicroscopy and differential interference contrast optics to determine changes in somatic area (cell swelling). Striatal and cortical neurons in both models (R6/2 and CAG94) displayed more rapid and increased swelling to N-methyl-D-aspartate (NMDA) than those in controls. This effect was specific as there were no consistent group differences after exposure to alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) or kainate (KA). Intracellular recordings revealed that resting membrane potentials (RMPs) in the R6/2 transgenics were significantly more depolarized than those in their respective controls. RMPs in CAG94 mice also were more depolarized than those in CAG71 mice or their controls in a subset of striatal neurons. Confirming previous results, R6/2 mice expressed behavioral abnormalities and nuclear inclusions. However, CAG71 and CAG94 knockins did not, suggesting that increased sensitivity to NMDA may occur early in the disease process. These findings imply that NMDA antagonists or compounds that alter sensitivity of NMDA receptors may be useful in the treatment of HD.
We used two mouse models of Huntington's disease (HD) to examine changes in glutamate receptor sensitivity and striatal electrophysiology. One model, a transgenic, consisted of mice expressing exon 1 of the human HD gene and carrying 141-157 CAG repeat sequences (R6/2 line). The second model, a CAG repeat "knockin," consisted of mice with different lengths of CAG repeats (CAG71 and CAG94 repeats). The effects of glutamate receptor activation were examined by visualizing neurons in brain slices with infrared videomicroscopy and differential interference contrast optics to determine changes in somatic area (cell swelling). Striatal and cortical neurons in both models (R6/2 and CAG94) displayed more rapid and increased swelling to N-methyl-D-aspartate (NMDA) than those in controls. This effect was specific as there were no consistent group differences after exposure to alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) or kainate (KA). Intracellular recordings revealed that resting membrane potentials (RMPs) in the R6/2 transgenics were significantly more depolarized than those in their respective controls. RMPs in CAG94 mice also were more depolarized than those in CAG71 mice or their controls in a subset of striatal neurons. Confirming previous results, R6/2 mice expressed behavioral abnormalities and nuclear inclusions. However, CAG71 and CAG94 knockins did not, suggesting that increased sensitivity to NMDA may occur early in the disease process. These findings imply that NMDA antagonists or compounds that alter sensitivity of NMDA receptors may be useful in the treatment of HD.
CCAAT/enhancer-binding proteins (C/EBPs) are a family of highly conserved transcription factors that have important roles in normal myelopoiesis as well as associated with myeloid disorders. The chronic myelogenous leukemia (CML) cell lines, KCL22 and K562, express exceptionally low levels of endogenous C/EBPs and provide a good model to test the effects of C/EBPs on myeloid differentiation. To explore the possibility that C/ EBPd can promote differentiation in BCR-ABL-positive cells, we generated stable KCL22 and K562 clones that expressed an inducible C/EBPd gene. C/EBPd expression resulted in G0/G1 proliferative arrest and a moderate increase in apoptosis of the KCL22 and the K562 cells. Within 4 days of inducing expression of C/EBPd, myeloid differentiation of the CML blast cells occurred as shown by morphologic changes and induction of secondary granule-specific genes. We also showed that during granulocytic differentiation of KCL22 cells, the C/EBPd protein was detected in immunocomplexes with both Rb and E2F1. Furthermore, expression of C/EBPd was associated with downregulation of c-Myc and cyclin E and upregulation of the cyclin-dependent kinase inhibitor p27Kip1 in both the KCL22 and K562 cell lines. These results show that expression of C/EBPd in BCR-ABLpositive leukemic cells in blast crisis is sufficient for neutrophil differentiation and point to the therapeutic potential of ectopic induction of C/EBPd in the acute phase of CML.
To our knowledge, this is the first report of an adult case of refractory PCH successfully treated with rituximab.
Allogeneic hematopoietic stem cell transplantation (allo-SCT) is potentially curative for patients with high-risk leukemia, but disease recurrence remains the leading cause of treatment failure. Our objective was to determine the impact of minimal residual disease (MRD) by any technique in adult patients with acute myeloid leukemia (AML) in morphologic first and second complete remission undergoing allo-SCT. Fifty nine patients were eligible for the study of 160 patients transplanted over ten years. For the MRD assessment we used multiparametric flow cytometry, cytogenetics and fluorescent in situ hybridization; 19 patients (32.2%) were identified as MRD positive. Patients with MRD had a consistently worse outcome over those without MRD, with 3-years leukemia-free survival (LFS) of 15.8% vs. 62.4% and overall survival (OS) of 17.5% vs. 62.3%. Relapse rate was significantly higher in MRD-positive patients; 3 years relapse rate in MRD-positive patients was 57.9% vs. 15.1% in MRD-negative patients. Detection of MRD in complete remission was associated with increased overall mortality (HR = 3.3; 95% CI: 1.45–7.57; p = 0.0044) and relapse (HR = 5.26; 95% CI: 2.0–14.0; p = 0.001), even after controlling for other risk factors. Our study showed that for patients in morphologic complete remission the presence of MRD predicts for significantly increased risk of relapse and reduced LFS and OS.
e19090 Background: Patients in rural areas have reduced access to high-quality cancer care, which contributes to rural-urban disparities in cancer mortality. Telehealth technologies can connect providers across rural and urban communities. Methods: In 2006, one author (LH) established an oncology program in Truckee, CA, a rural community with a single critical access hospital without oncology services. The program joined with 4 other facilities comprising the UC Davis Cancer Care Network, a central element being daily participation in structured virtual tumor boards addressing the four sites (colorectal, prostate, lung, & breast) that compromise ~80% of all cancer diagnoses. Remote telemedicine clinics outside the primary catchment area were also established to serve the mountain communities of Quincy, Portola, Loyalton, and South Lake Tahoe, CA. We assessed the reach and quality of the cancer program through referrals, in-migration, clinical trial accruals and accreditations. Results: The combination of virtual tumor boards and telehealth clinics associated with growth of the program to 3 medical oncologists, 1 radiation oncologist and expansion into a 20,000 ft2 facility. Total new patient visits, the percent of patients coming from zip codes outside of the primary catchment area, clinical trial enrollments, and quality accreditations steadily increased (Table). The program is accredited by the Commission on Cancer with commendation, ASTRO’s APEX, ASCO’s QOPI and CancerLinq programs, and is a G02Foundation for Lung Cancer Community Center of Excellence. Conclusions: We termed the knowledge dissemination that occurs through a telehealth connected rural oncology program involving a Comprehensive Cancer Center partner and disseminated rural telemedicine nodes a “synaptic knowledge network.” In this implementation, it enhanced the reach and quality of care as measured by volume, in-migration, clinical trial activity, and national quality accreditations. Application of synaptic knowledge networks to other rural sites is a promising strategy to reduce rural-urban disparities in cancer care. [Table: see text]
Myelodysplastic syndromes (MDS) are a diverse group of disorders characterized by disorderly and ineffective hematopoiesis. Patients suffer morbidity from associated cytopenias that result in an increased risk of infection, transfusion-dependent anemia, and bleeding. Despite the variable risk of transformation to acute leukemia, the majority of deaths are due to bone marrow failure. No truly effective treatment exists for MDS, and therapy usually focuses on reducing or preventing complications of the disease. Identification of potential cellular and molecular targets, such as epigenetic modification, has led to novel therapeutic approaches in recent years. An increasing number of diagnostic markers, prognostic parameters, and therapeutic strategies are available and becoming widely accepted.
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