Implementation of a Software Distribution Intervention to Improve Workload Balance in an Academic Pediatric Radiology Department

Journal of Digital Imaging - In our pediatric radiology department, radiographs (XR) are the shared responsibility of the body section and interpreted in addition to modality or site-specific...     

The interaction between cytoplasmic dynein and dynactin is required for fast axonal transport

Fast axonal transport is characterized by the bidirectional, microtubule-based movement of membranous organelles. Cytoplasmic dynein is necessary but not sufficient for retrograde transport directed from the synapse to the cell body. Dynactin is a heteromultimeric protein complex, enriched in neurons, that binds to both microtubules and cytoplasmic dynein. To determine whether dynactin is required for retrograde axonal transport, we examined the effects of anti-dynactin antibodies on organelle transport in extruded axoplasm. Treatment of axoplasm with antibodies to the p150^Glued subunit of dynactin resulted in a significant decrease in the velocity of microtubule-based organelle transport, with many organelles bound along microtubules. We examined the molecular mechanism of the observed inhibition of motility, and we demonstrated that antibodies to p150^Glued disrupted the binding of cytoplasmic dynein to dynactin and also inhibited the association of cytoplasmic dynein with organelles. In contrast, the anti-p150^Glued antibodies had no effect on the binding of dynactin to microtubules nor on cytoplasmic dynein-driven microtubule gliding. These results indicate that the interaction between cytoplasmic dynein and the dynactin complex is required for the axonal transport of membrane-bound vesicles and support the hypothesis that dynactin may function as a link between the organelle, the microtubule, and cytoplasmic dynein during vesicle transport.     

Alcohol dependence is related to overall internalizing psychopathology load rather than to particular internalizing disorders: evidence from a national sample

Background: Alcohol dependence is more prevalent among those with any one of several anxiety or depressive (“internalizing”) disorders than among those in the general population. However, because internalizing disorders are highly intercorrelated, it is ambiguous whether alcohol dependence is related to internalizing psychopathology components that are: (i) unique to a particular internalizing disorder (“specific”); versus (ii) shared across a number of internalizing disorders (“general”). To clarify this ambiguity, we employed structural equation and logistic models to decompose the specific versus general components of internalizing psychopathology and then related these components separately to alcohol dependence. Methods: The data were based on face‐to‐face interviews of U.S. community residents collected in the 2001 to 2002 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC; N = 43,093). Results: Both analytic approaches demonstrated that increases in the general internalizing psychopathology load are accompanied by increases in the prevalence of alcohol dependence. Once the general internalizing psychopathology load is accounted for, knowing whether a particular internalizing disorder is present or absent provides little additional information regarding the prevalence of alcohol dependence. Conclusions: The components of internalizing psychopathology that are associated with alcohol dependence are shared and cumulative among common anxiety and depressive disorders. These findings have the potential to influence clinical and scientific conceptualizations of the association between alcohol dependence and internalizing psychopathology.     

Treatment-influenced associations of PML-RARα mutations, FLT3 mutations, and additional chromosome abnormalities in relapsed acute promyelocytic leukemia

Mutations in the all-trans retinoic acid (ATRA)-targeted ligand binding domain of PML-RARα (PRα/LBD(+)) have been implicated in the passive selection of ATRA-resistant acute promyelocytic leukemia clones leading to disease relapse. Among 45 relapse patients from the ATRA/chemotherapy arm of intergroup protocol C9710, 18 patients harbored PRα/LBD(+) (40%), 7 of whom (39%) relapsed Off-ATRA selection pressure, suggesting a possible active role of PRα/LBD(+). Of 41 relapse patients coanalyzed, 15 (37%) had FMS-related tyrosine kinase 3 internal tandem duplication mutations (FLT3-ITD(+)), which were differentially associated with PRα/LBD(+) depending on ATRA treatment status at relapse: positively, On-ATRA; negatively, Off-ATRA. Thirteen of 21 patients (62%) had additional chromosome abnormalities (ACAs); all coanalyzed PRα/LBD mutant patients who relapsed off-ATRA (n = 5) had associated ACA. After relapse Off-ATRA, ACA and FLT3-ITD(+) were negatively associated and were oppositely associated with presenting white blood count and PML-RARα type: ACA, low, L-isoform; FLT3-ITD(+), high, S-isoform. These exploratory results suggest that differing PRα/LBD(+) activities may interact with FLT3-ITD(+) or ACA, that FLT3-ITD(+) and ACA are associated with different intrinsic disease progression pathways manifest at relapse Off-ATRA, and that these different pathways may be short-circuited by ATRA-selectable defects at relapse On-ATRA. ACA and certain PRα/LBD(+) were also associated with reduced postrelapse survival.     

Detection of minimal residual disease following induction immunochemotherapy predicts progression free survival in mantle cell lymphoma: final results of CALGB 59909

Background

In the present study, the prognostic impact of minimal residual disease during treatment on time to progression and overall survival was analyzed prospectively in patients with mantle cell lymphoma treated on the Cancer and Leukemia Group B 59909 clinical trial.

Design and Methods

Peripheral blood and bone marrow samples were collected during different phases of the Cancer and Leukemia Group B 59909 study for minimal residual disease analysis. Minimal residual disease status was determined by quantitative polymerase chain reaction of IgH and/or BCL-1/JH gene rearrangement. Correlation of minimal residual disease status with time to progression and overall survival was determined. In multivariable analysis, minimal residual disease, and other risk factors were correlated with time to progression.

Results

Thirty-nine patients had evaluable, sequential peripheral blood and bone marrow samples for minimal residual disease analysis. Using peripheral blood monitoring, 18 of 39 (46%) achieved molecular remission following induction therapy. The molecular remission rate increased from 46 to 74% after one course of intensification therapy. Twelve of 21 minimal residual disease positive patients (57%) progressed within three years of follow up compared to 4 of 18 (22%) molecular remission patients (P=0.049). Detection of minimal residual disease following induction therapy predicted disease progression with a hazard ratio of 3.7 (P=0.016). The 3-year probability of time to progression among those who were in molecular remission after induction chemotherapy was 82% compared to 48% in patients with detectable minimal residual disease. The prediction of time to progression by post-induction minimal residual disease was independent of other prognostic factors in multivariable analysis.

Conclusions

Detection of minimal residual disease following induction immunochemotherapy was an independent predictor of time to progression following immunochemotherapy and autologous stem cell transplantation for mantle cell lymphoma. The clinical trial was registered at ClinicalTrials.gov: {"type":"clinical-trial","attrs":{"text":"NCT00020943","term_id":"NCT00020943"}}NCT00020943.     

Quality of Depression among Suicidal Inpatient Youth

This study examined the relationship between suicidality and dependent and self-critical depression among adolescents. Ninety-six adolescents participated: 32 suicidal inpatients, 32 nonsuicidal inpatients and 32 healthy controls. The groups were matched for gender, age and education. Participants completed the Depressive Experience Questionnaire for Adolescents (DEQ-A), the Cognition Checklist (CCL), and the Multi-Attitude Suicidal Tendencies Scale (MAST). Results indicated that suicidal adolescents have significantly higher levels of self-critical and dependent depression, compared to nonsuicidal inpatients and healthy controls. The distinctive quality of depression among suicidal adolescents suggests assessment and treatment strategies for these individuals.     

Age and ethnic differences in the onset, persistence and recurrence of alcohol use disorder

Aims To estimate ethnic differences in three components of alcohol use disorder and alcohol dependence course (onset, persistence and recurrence) in a developmental framework. Design Longitudinal data from The National Epidemiologic Survey of Alcohol and Related Conditions (NESARC), collected using face‐to‐face interviews. Setting Civilian non‐institutionalized US population aged 18 years and older, with oversampling of Hispanics, blacks and those aged 18–24 years. Participants Individuals who completed both NESARC assessments, were not life‐long abstainers and were either white (n = 17 458), black (n = 4995), US‐born Hispanic (n = 2810) or Hispanic‐born outside the United States (n = 2389). Measurements Alcohol dependence (AD) and alcohol use disorder (AUD; abuse or dependence) onset, persistence and recurrence were examined using the Alcohol Use Disorders and Associated Disabilities Interview Schedule, DSM‐IV version. Findings Among men: relative to whites aged 18–29, AUD onset and persistence were elevated only in US‐born Hispanics aged 40 years and older; odds were reduced for all non‐US‐born Hispanics, older whites, most blacks and US‐born Hispanics aged 30–39. For AD, onset risk was elevated for all younger minority men and only reduced among non‐US‐born aged Hispanics 40 or older. For women: compared to young whites, non‐US‐born Hispanics were at decreased AUD and AD onset risk; AUD and AD onset and persistence were increased for older blacks and US‐born Hispanics. Conclusions In the United States, ethnic differences in alcohol disorder transitions (onset, persistence, and recurrence) vary across age, gender and whether a broad (alcohol use disorder) or narrow (alcohol dependence) alcohol definition is used. Evidence of increased risk for some transitions in minority groups suggests that attention should be paid to the course of alcohol use disorders, and that differences in prevalence should not be assumed to reflect differences in specific transitions.     

Discovery of 4-(2-(dimethylamino)ethoxy)benzohydrazide derivatives as prospective microtubule affinity regulating kinase 4 inhibitors

Microtubule affinity regulating kinase 4 (MARK4) is a Ser/Thr kinase, considered as a potential drug target for cancer, diabetes and neurodegenerative diseases. Due to its significant role in the development and progression of cancer, different in-house libraries of synthesized small molecules were screened to identify potential MARK4 inhibitors. A small library of hydrazone compounds showed a considerable binding affinity to MARK4. The selected compounds were further scrutinized using an enzyme inhibition assay and finally two hydrazone derivatives (H4 and H19) were selected that show excellent inhibition (nM range). These compounds have a strong binding affinity for MARK4 and moderate binding with human serum albumin. Anticancer studies were performed on MCF-7 and A549 cells, suggesting H4 and H19 selectively inhibit the growth of cancer cells. The IC₅₀ value of compound H4 and H19 was found to be 27.39 μM and 34.37 μM for MCF-7 cells, while for A549 cells it was 45.24 μM and 61.50 μM, respectively. These compounds inhibited the colonogenic potential of cancer cells and induced apoptosis. Overall findings reflect that hydrazones/hydrazone derivatives could be exploited as potential lead molecules for developing effective anticancer therapies via targeting MARK4.

Inhibition studies of MARK4 with selected hydrazone derivatives.