Examination of clinically-derived p210 BCR/ABL1 RhoGEF mutations in a murine bone marrow transplantation model of CML.

Expression of the p210 BCR/ABL1 fusion protein has been described in virtually all patients with chronic myelogenous leukemia (CML). Previous studies have identified a guanine nucleotide exchange factor (RhoGEF) domain within BCR that is retained in p210 BCR/ABL1. Missense mutations at residues T654 (T654K) and F547 (F547L) within this domain have been reported in a CML patient in blast crisis (BC). In this study, we have evaluated p210 BCR/ABL1 constructs that contain these substitutions in a murine bone marrow transplantation (BMT) model of CML. The mutants exhibit normal expression and tyrosine kinase activity but altered signaling. When examined in the BMT assay, mice that express the mutants exhibit earlier onset of disease but have significantly extended lifespans relative to mice that express unmodified p210 BCR/ABL1. While mice that express p210 BCR/ABL1 exhibit neutrophilia that progresses to a less differentiated phenotype at death, disease in the mutant mice is characterized by eosinophilia with no maturation arrest. This observation was confirmed in vitro using myeloid cells and was associated with enhanced p53 phosphorylation and G1/S arrest. These results suggest that residues within the RhoGEF domain of p210 BCR/ABL1 can influence disease progression.

Colonoscopy utilization in rural areas by general surgeons: An analysis of the National Ambulatory Medical Care Survey.

BACKGROUND: One in three adults above 50 years old have not been screened for colorectal cancer as of 2013.1 Rural areas have even lower screening and have more general surgeons compared to gastroenterologists,2 offering surgeons as a reservoir for necessary services. METHODS: Public data from the 2006-2015 CDC National Ambulatory Medical Care Survey was analyzed using SAS. Number of colonoscopies performed by rural general surgeons, family medicine practitioners, and other specialties were compared to their urban counterparts. RESULTS: 21.91% of rural colonoscopies were performed by general surgeons, whereas 32.87% were performed by family medicine practitioners and 45.22% by other specialties including gastroenterologists. Rural general surgeons performed a greater percentage of annual rural colonoscopies than urban general surgeons (p < 0.05). CONCLUSION: General surgeons are fulfilling the need for colonoscopy in rural areas. Improvements to current colonoscopy training guidelines are imperative, especially for physicians who practice in rural areas.

Cellular Response to Exponentially Increasing and Decreasing Dose Rates: Implications for Treatment Planning in Targeted Radionuclide Therapy.

The treatment of cancer using targeted radionuclide therapy is of interest to nuclear medicine and radiation oncology because of its potential for killing tumor cells while minimizing dose-limiting toxicities to normal tissue. The ionizing radiations emitted by radiopharmaceuticals deliver radiation absorbed doses over protracted periods of time with continuously varying dose rates. As targeted radionuclide therapy becomes a more prominent part of cancer therapy, accurate models for estimating the biologically effective dose (BED) or equieffective dose (EQD2α/ß) will become essential for treatment planning. This study examines the radiobiological impact of the dose rate increase half-time during the uptake phase of the radiopharmaceutical. MDA-MB-231 human breast cancer cells and V79 Chinese hamster lung fibroblasts were irradiated chronically with 662 keV γ rays delivered with time-varying dose rates that are clinically relevant. The temporal dose-rate patterns were: 1. acute, 2. exponential decrease with a half-time of 64 h (Td = 64 h), 3. initial exponential increase to a maximum (half time Ti = 2, 8 or 24 h) followed by exponential decrease (Td = 64 h). Cell survival assays were conducted and surviving fractions were determined. There was a marked reduction in biological effect when Ti was increased. Cell survival data were tested against existing dose-response models to assess their capacity to predict response. Currently accepted models that are used in radiation oncology overestimated BED and EQD2α/ß at low-dose rates and underestimated them at high-dose rates. This appears to be caused by an adaptive response arising as a consequence of the initial low-dose-rate phase of exposure. An adaptive response function was derived that yields more accurate BED and EQD2α/ß values over the spectrum of dose rates and absorbed doses delivered. Our experimental data demonstrate a marked increase in cell survival when the dose-rate-increase half-time is increased, thereby suggesting an adaptive response arising as a consequence of this phase of exposure. We have modified conventional radiobiological models used in the clinic for brachytherapy and external beams of radiation to account for this phenomenon and facilitate their use for treatment planning in targeted radionuclide therapy.