NDRG4 is a novel oncogenic protein and p53 associated regulator of apoptosis in malignant meningioma cells

Aggressive meningiomas exhibit high levels of recurrence, morbidity and mortality. When surgical and radiation options are exhausted, there is need for novel molecularly-targeted therapies. We have recently identified NDRG4 overexpression in aggressive meningiomas. NDRG4 is a member of the N-Myc Downstream Regulated Gene (NDRG) family of the alpha/beta hydrolase superfamily. We have demonstrated that NDRG4 downregulation results in decreased cell proliferation, migration and invasion. In follow up to our prior studies; here we demonstrate that the predominant form of cell death following NDRG4 silencing is apoptosis, utilizing Annexin-V flow cytometry assay. We show that apoptosis caused by p53 upregulation, phosphorylation at Ser15, BAX activation, Bcl-2 and BcL-xL downregulation, mitochondrial cytochrome c release and execution of caspases following NDRG4 depletion. Sub-cellular distribution of BAX and cytochrome c indicated mitochondrial-mediated apoptosis. In addition, we carried out the fluorescence cytochemical analysis to confirm mitochondrial-mediated apoptosis by changes in mitochondrial membrane potential (Ψm), using JC-1 dye. Immunoprecipitation and immunofluorescence confirmed binding of NDRG4 to p53. In addition, we demonstrate that apoptosis is mitochondrial and p53 dependent. The proapoptotic effect of p53 was verified by the results in which a small molecule compound PFT-α, an inhibitor of p53 phosphorylation, is greatly protected against targeting NDRG4 induced apoptosis. These findings bring novel insight to the roles of NDRG4 in meningioma progression. A better understanding of this pathway and its role in meningioma carcinogenesis and cell biology is promising for the development of novel therapeutic targets for the management of aggressive meningiomas

RADIANS: A Multidisciplinary Central Nervous System Clinic Model for Radiation Oncology and Neurosurgery Practice

Background Radiation therapy for central nervous system disease commonly involves collaboration between Radiation Oncology and Neurosurgery. We describe our early experience with a multidisciplinary clinic model. Methods In 2016, the novel RADIANS (RADIation oncology And NeuroSurgery) clinic model was initiated at a community hospital. Disease and treatment demographics were collected and analyzed. Patient satisfaction was assessed via a blinded survey questionnaire. Results Forty-two patients have been seen since the inception of RADIANS. The median age was 65; and the median patient distance from RADIANS was 42.7 miles (mean = 62.6; range = 0.7–285). Half of the patients traveled >50 miles to receive care, and >80% were seen for central nervous system metastases. Of the patients receiving radiation, 75% received stereotactic radiosurgery/stereotactic body radiation therapy. The mean overall satisfaction from 0 (not satisfied) to 5 (very satisfied) was 4.8. Conclusions The RADIANS clinic model has proved viable and well-liked by patients in a community setting, with the majority of radiation therapy administered being stereotactic radiosurgery/stereotactic body radiation therapy rather than conventional fractionation

Impact of Travel Distance on Radiation Treatment Modality for Central Nervous System Disease

Background Stereotactic body radiation therapy (SBRT) has emerged as a popular alternative to conventional radiation therapy (RT) over the past 15 years. Unfortunately, the impact of patient distance from radiation treatment centers and utilization of SBRT versus conventional RT has been sparsely investigated. This report represents the first analysis of the impact of patient distance on radiation treatment modality for central nervous system (CNS) disease. Materials and Methods Since the inception of our RADIation oncology And Neuro-Surgery (RADIANS) multidisciplinary clinic at a community hospital in 2016, 27 patients have received either SBRT or conventional RT as their sole radiation treatment modality for CNS disease. Twenty-four (88.9%) presented with metastatic disease. Fisher’s exact test evaluated the relationship between patient residence from treatment (in miles) and radiation treatment modality received. Results Mean patient distance from our RADIANS clinic was 50.6 miles (median = 15.3). Twenty-one patients (77.8%) received SBRT; the remaining six received conventional RT. Mean patient distance from SBRT was 63.6 miles, and mean patient distance for conventional RT was 5.1 miles; this finding was statistically significant (p = 0.0433; 95% confidence interval = 1.9–115.1). Conclusion Our findings indicate that patients with CNS disease who receive SBRT over conventional RT are statistically more likely to reside further from treatment centers. This is similar to findings of national studies comparing proton versus photon treatment for pediatric solid malignancies. The results from our work have implications for neuro-oncology treatment and the development of community hospital-based clinic models similar to RADIANS in the future

Analysis of pre-residency research productivity, dual degree status, and gender distribution of underrepresented minorities among a current United States radiation oncology junior resident class

Background: Among the most competitive medical subspecialties, representation of underrepresented minorities (African-American race and/or Hispanic ethnicity) among resident trainees has historically been low compared to their United States Census general population representation. Research productivity and dual degree status may impact residency applicant competitiveness. To date, such an analysis has yet to be performed in Radiation Oncology. Methods: A list of radiation oncology residents from the graduating class of 2022 was obtained through internet searches. Demographics included were gender and dual degree status. Research productivity was calculated using the number of pre-residency peer-reviewed publications (PRP). Fisher's exact test was used for statistical analysis. Results: Of the 179 residents evaluated from the 2022 class, eleven (6.1%) were underrepresented minorities. Compared to the remainder of the class, underrepresented minorities had a lower proportion of men (63.6% versus 69.3%), a higher proportion of dual degrees (45.5% versus 28.6%), and a lower proportion of MD-PhD degrees (9.1% versus 17.2%). Underrepresented minorities had a higher proportion of residents with at least two PRP (72.7% versus 57.1%) and a lower proportion of residents with no PRP (18.2% versus 24.4%). None of these differences reached statistical significance (p > 0.05). Conclusion: Underrepresented minorities were comparable to the remainder of their Radiation Oncology resident class regarding gender distribution, dual degrees status, and likelihood of having at least two peer-reviewed publications cited in PubMed during the calendar year of residency application. Further studies will be needed to determine how these findings translate into future scholarly activity and post-graduate career choice

GSK-3β: A Bifunctional Role in Cell Death Pathways

Although glycogen synthase kinase-3 beta (GSK-3β) was originally named for its ability to phosphorylate glycogen synthase and regulate glucose metabolism, this multifunctional kinase is presently known to be a key regulator of a wide range of cellular functions. GSK-3β is involved in modulating a variety of functions including cell signaling, growth metabolism, and various transcription factors that determine the survival or death of the organism. Secondary to the role of GSK-3β in various diseases including Alzheimer's disease, inflammation, diabetes, and cancer, small molecule inhibitors of GSK-3β are gaining significant attention. This paper is primarily focused on addressing the bifunctional or conflicting roles of GSK-3β in both the promotion of cell survival and of apoptosis. GSK-3β has emerged as an important molecular target for drug development

The Unintended Consequences of the Restructuring of the Division of AIDS Services in New York City

The purpose of this study was to assess perceptions of the quality of services of consumers of the New York City Division of AIDS Services in restructured and pre-restructured agency settings A total of 447 consumers participated in the study. Data were collected through interviews conducted at DAS field sites around New York City between July and November of 1996, using a 77 item evaluation instrument developed by the researcher and staff from the Mayor\u27s Office on AIDS Policy Coordination On the three quality indicators, satisfaction with services, perception of the effectiveness of the caseworker, and perception of the helpfulness of the caseworker, there were no significant differences between restructured and pre-restructured sites when background factors were controlled. The failure of the restructuring effort was attributed to lack of inclusion of all stakeholders in the planning proces

Methods for the analysis of histone H3 and H4 acetylation in blood

LBH589 is one of the many histone deacetylase inhibitors (HDACi) that are currently in clinical trial. Despite their wide-spread use, there is little literature available describing the typical levels of histone acetylation in untreated peripheral blood, the treatment and storage of samples to retain optimal measurement of histone acetylation nor methods by which histone acetylation analysis may be monitored and measured during the course of a patient’s treatment. In this study, we have used cord or peripheral blood as a source of human leukocytes, performed a comparative analysis of sample processing methods and developed a flow cytometric method suitable for monitoring histone acetylation in isolated lymphocytes and liquid tumors. Western blotting and immunohistochemistry techniques have also been addressed. We have tested these methods on blood samples collected from four patients treated with LBH589 as part of an Australian Children’s Cancer Clinical Trial (CLBH589AAU03T) and show comparable results when comparing in vitro and in vivo data. This paper does not seek to correlate histone acetylation levels in peripheral blood with clinical outcome but describes methods of analysis that will be of interest to clinicians and scientists monitoring the effects of HDACi on histone acetylation in blood samples in clinical trials or in related research studies

Use of the g-index for assessment of citation-based scholarly activity of United States radiation oncology residents and subsequent choice of academic versus private practice career

Introduction: The Hirsch index (h-index) evaluates citation-based scholarly activity, but has limited ability to acknowledge those publishing a smaller number of manuscripts with exceedingly high citations. The g-index addresses this limitation by assessing the largest number of manuscripts (g) by an author cited at least (g × g) times, but has yet to be applied to radiation oncology resident productivity. Methods: A list of recent radiation oncology resident graduates (comprising 86% of the 2016 graduating class) and their post-residency career choice was compiled. The Scopus bibliometric citation database was searched to collect and calculate g-index data for each resident. Results: The mean g-index score for all resident graduates was 7.16. Residents with a PhD had significantly higher g-index scores (11.97 versus 5.80; p < 0.01), while there was no statistically significant difference in g-index scores between male and female residents. Residents choosing academic careers had higher g-index scores than those choosing private practice (9.47 versus 4.99; p < 0.01). Programs graduating at least three residents produced significantly higher g-index scores/resident than those graduating two residents, and while comprising only 25% of programs and 45% of residents, produced 60% of academic careers (p < 0.02). Conclusion: Radiation oncology resident graduates published on average a minimum of seven manuscripts cited at least 49 times. PhD-degree graduates had significantly higher g-index scores, as did residents choosing academic over private practice careers. There was no significant gender-related difference in g-index score regardless of career choice. The majority of academic careers are produced from programs graduating at least three residents