730 research outputs found

    Molecular prognostic markers for adult acute myeloid leukemia with normal cytogenetics

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    Acute myeloid leukemia (AML) is a heterogenous disorder that results from a block in the differentiation of hematopoietic progenitor cells along with uncontrolled proliferation. In approximately 60% of cases, specific recurrent chromosomal aberrations can be identified by modern cytogenetic techniques. This cytogenetic information is the single most important tool to classify patients at their initial diagnosis into three prognostic categories: favorable, intermediate, and poor risk. Currently, favorable risk AML patients are usually treated with contemporary chemotherapy while poor risk AML patients receive allogeneic stem cell transplantation if suitable stem cell donors exist. The largest subgroup of AML patients (~40%) have no identifiable cytogenetic abnormalities and are classified as intermediate risk. The optimal therapeutic strategies for these patients are still largely unclear. Recently, it is becoming increasingly evident that it is possible to identify a subgroup of poorer risk patients among those with normal cytogenic AML (NC-AML). Molecular risk stratification for NC-AML patients may be possible due to mutations of NPM1, FLT3, MLL, and CEBPα as well as alterations in expression levels of BAALC, MN1, ERG, and AF1q. Further prospective studies are needed to confirm if poorer risk NC-AML patients have improved clinical outcomes after more aggressive therapy

    Dosimetric Comparison of Treatment Techniques: Brachytherapy, Intensity- Modulated Radiation Therapy, and Proton Beam in Partial Breast Irradiation

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    Purpose: To perform a dosimetric comparison of 3 accelerated partial breast irradiation techniques: catheter-based brachytherapy (BT), intensity-modulated radiation therapy (IMRT), and proton beam therapy (PBT). Patients and Methods: Twelve patients with left-sided breast cancer treated with SAVI (Strut-Adjusted Volume Implant) were selected in this study. The original BT plans were compared with optimum plans using IMRT and PBT for 34 Gy (RBE) with 1.1 RBE in 10 fractions using identical parameters for target and organs at risk. Results: Significant reduction in maximum dose to the ipsilateral breast was observed with PBT and IMRT (mean 108.58% [PBT] versus 107.78% [IMRT] versus 2194.43% [BT], P = .001 for both PBT and IMRT compared to BT). The mean dose to the heart was 0%, 1.38%, and 3.85%, for PBT, IMRT, and BT, respectively (P < .001 and P = .026). The chest wall mean dose was 10.07%, 14.65%, and 29.44% for PBT, IMRT, and BT, respectively (P = .001 and .013 compared to BT). The PBT was superior in reducing the mean ipsilateral lung dose (mean 0.04% versus 2.13% versus 5.4%, P = .025 and P < .001). There was no statistically significant difference in the maximum dose to the ipsilateral lung, chest wall, 3-mm skin rind or in the mean ipsilateral breast V50% among the 3 techniques (P = .168, .405, .067, and .780, respectively). PBT exhibited the greatest mean dose homogeneity index of 4.75 compared to 7.18 for IMRT (P = .001) and 195.82 for BT (P < .001). All techniques resulted in similar dose conformality (P = .143). Conclusion: This study confirms the dosimetric feasibility of PBT and IMRT to lower dose to organs at risk while still maintaining high target dose conformality. Though the results of this comparison are promising, continued clinical research is needed to better define the role of PBT and IMRT in the accelerated partial breast irradiation treatment of early-stage breast cancer

    Immature doublecortin-positive hippocampal neurons are important for learning but not for remembering

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    It is now widely accepted that hippocampal neurogenesis underpins critical cognitive functions, such as learning and memory. To assess the behavioral importance of adult-born neurons, we developed a novel knock-in mouse model that allowed us to specifically and reversibly ablate hippocampal neurons at an immature stage. In these mice, the diphtheria toxin receptor (DTR) is expressed under control of the doublecortin (DCX) promoter, which allows for specific ablation of immature DCX-expressing neurons after administration of diphtheria toxin while leaving the neural precursor pool intact. Using a spatially challenging behavioral test (a modified version of the active place avoidance test), we present direct evidence that immature DCX-expressing neurons are required for successful acquisition of spatial learning, as well as reversal learning, but are not necessary for the retrieval of stored long-term memories. Importantly, the observed learning deficits were rescued as newly generated immature neurons repopulated the granule cell layer upon termination of the toxin treatment. Repeat (or cyclic) depletion of immature neurons reinstated behavioral deficits if the mice were challenged with a novel task. Together, these findings highlight the potential of stimulating neurogenesis as a means to enhance learning

    Derivation and Validation of an Inâ Hospital Mortality Prediction Model Suitable for Profiling Hospital Performance in Heart Failure

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    Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142499/1/jah32925_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142499/2/jah32925.pd

    Dysregulation in Subcellular Localization of Myelin Basic Protein mRNA Does Not Result in Altered Myelination in Amyotrophic Lateral Sclerosis

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    Pathological hallmarks of amyotrophic lateral sclerosis (ALS), including protein misfolding, are well established in oligodendrocytes. More recently, an RNA trafficking deficit of key myelin proteins has been suggested in oligodendrocytes in ALS but the extent to which this affects myelination and the relative contribution of this to disease pathogenesis is unclear. ALS autopsy research findings showing demyelination contrasts with the routine clinical-pathological workup of ALS cases where it is rare to see white matter abnormalities other than simple Wallerian degeneration secondary to widespread neuronal loss. To begin to address this apparent variance, we undertook a comprehensive evaluation of myelination at an RNA, protein and structural level using human pathological material from sporadic ALS patients, genetic ALS patients (harboring C9orf72 mutation) and age- and sex-matched non-neurological controls. We performed (i) quantitative spatial profiling of the mRNA transcript encoding myelin basic protein (MBP), (ii) quantification of MBP protein and (iii) the first quantitative structural assessment of myelination in ALS post-mortem specimens by electron microscopy. We show no differences in MBP protein levels or ultrastructural myelination, despite a significant dysregulation in the subcellular trafficking of MBP mRNA in ALS patients compared to controls. We therefore confirm that whilst there are cell autonomous mRNA trafficking deficits affecting oligodendrocytes in ALS, this has no effect on myelin structure

    Dysregulation in Subcellular Localization of Myelin Basic Protein mRNA Does Not Result in Altered Myelination in Amyotrophic Lateral Sclerosis

    Get PDF
    Pathological hallmarks of amyotrophic lateral sclerosis (ALS), including protein misfolding, are well established in oligodendrocytes. More recently, an RNA trafficking deficit of key myelin proteins has been suggested in oligodendrocytes in ALS but the extent to which this affects myelination and the relative contribution of this to disease pathogenesis is unclear. ALS autopsy research findings showing demyelination contrasts with the routine clinical-pathological workup of ALS cases where it is rare to see white matter abnormalities other than simple Wallerian degeneration secondary to widespread neuronal loss. To begin to address this apparent variance, we undertook a comprehensive evaluation of myelination at an RNA, protein and structural level using human pathological material from sporadic ALS patients, genetic ALS patients (harboring C9orf72 mutation) and age- and sex-matched non-neurological controls. We performed (i) quantitative spatial profiling of the mRNA transcript encoding myelin basic protein (MBP), (ii) quantification of MBP protein and (iii) the first quantitative structural assessment of myelination in ALS post-mortem specimens by electron microscopy. We show no differences in MBP protein levels or ultrastructural myelination, despite a significant dysregulation in the subcellular trafficking of MBP mRNA in ALS patients compared to controls. We therefore confirm that whilst there are cell autonomous mRNA trafficking deficits affecting oligodendrocytes in ALS, this has no effect on myelin structure.</p

    Neurologic Morbidity and Functional Independence in Adult Survivors of Childhood Cancer

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    OBJECTIVE: To examine associations between neurologic late effects and attainment of independence in adult survivors of childhood cancer treated with central nervous system (CNS)-directed therapies. METHODS: A total of 7881 survivors treated with cranial radiation therapy (n = 4051; CRT) and/or intrathecal methotrexate (n = 4193; IT MTX) ([CNS-treated]; median age [range] = 25.5 years [18-48]; time since diagnosis = 17.7 years [6.8-30.2]) and 8039 without CNS-directed therapy reported neurologic conditions including stroke, seizure, neurosensory deficits, focal neurologic dysfunction, and migraines/severe headaches. Functional independence was assessed using latent class analysis with multiple indicators (independent living, assistance with routine and personal care needs, ability to work/attend school, attainment of driver\u27s license, marital/partner status). Multivariable regression models, adjusted for age, sex, race/ethnicity, and chronic health conditions, estimated odds ratios (OR) or relative risks (RR) for associations between neurologic morbidity, functional independence, and emotional distress. RESULTS: Among CNS-treated survivors, three classes of independence were identified: (1) moderately independent, never married, and non-independent living (78.7%); (2) moderately independent, unable to drive (15.6%); and (3) non-independent (5.7%). In contrast to 50% of non-CNS-treated survivors and 60% of siblings, a fourth fully independent class of CNS-treated survivors was not identified. History of stroke (OR = 2.50, 95% CI: 1.70-3.68), seizure (OR = 9.70, 95% CI: 7.37-12.8), neurosensory deficits (OR = 2.67, 95% CI: 2.16-3.31), and focal neurologic dysfunction (OR = 3.05, 95% CI: 2.40-3.88) were associated with non-independence among CNS-treated survivors. Non-independence was associated with emotional distress symptoms. INTERPRETATION: CNS-treated survivors do not attain full independence comparable to non-CNS-treated survivors or siblings. Interventions to promote independence may be beneficial for survivors with treatment-related neurological sequalae
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