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

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

Impact of hospital volume on mortality for brain metastases treated with radiation

BACKGROUND: The impact of hospital volume on cancer patient survival has been demonstrated in the surgical literature, but sparsely for patients receiving radiation therapy (RT). This analysis addresses the impact of hospital volume on patients receiving RT for the most common central nervous system tumor: brain metastases.   MATERIALS AND METHODS: Analysis was conducted using the National Cancer Database (NCDB) from 2010–2015 for patients with metastatic brain disease from lung cancer, breast cancer, and colorectal cancer requiring RT. Hospital volume was stratified as high-volume (≥ 12 brain RT/year), moderate (5–11 RT/year), and low (< 5 RT/year). The effect of hospital volume on overall survival was assessed using a multivariable Cox regression model. RESULTS: A total of 18,841 patients [9479 (50.3%) men, 9362 (49.7%) women; median age 64 years] met the inclusion criteria. 16.7% were treated at high-volume hospitals, 36.5% at moderate-volume, and the remaining 46.8% at low-volume centers. Multivariable analysis revealed that mortality was significantly improved in high-volume centers (HR: 0.95, p = 0.039) compared with low-volume centers after accounting for multiple demographics including age, sex, race, insurance status, income, facility type, Charlson-Deyo score and receipt of palliative care. CONCLUSION: Hospitals performing 12 or more brain RT procedures per year have significantly improved survival in brain metastases patients receiving radiation as compared to lower volume hospitals. This finding, independent of additional demographics, indicates that the increased experience associated with increased volume may improve survival in this patient population

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

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

Recurrent adult-onset hypophyseal Langerhans cell histiocytosis after radiotherapy: A case report

INTRODUCTION: Langerhans cell histiocytosis is a rare disease within the adult population, with very few cases reported as solitary hypophyseal lesions in adults. Of the reported cases, most have been treated successfully with surgery, radiotherapy, and/or chemotherapy. Radiotherapy has been thought to be curative at the relatively low dose of 20Gy. Here we report a case of recurrent hypophyseal Langerhans cell histiocytosis 9 months after radiotherapy with an interval period of symptomatic and radiographic response to therapy. CASE PRESENTATION: A 50-year-old Caucasian woman who had headaches, memory difficulties, and diabetes insipidus was found to have a 2.5cm suprasellar mass. Langerhans cell histiocytosis was diagnosed following stereotactic brain biopsy. Further workup revealed no other lesions. Initial radiation treatment succeeded in shrinking the tumor and relieving clinical symptoms temporarily; however, growth and recurrence of clinical symptoms was noted at 9 months. Re-irradiation was well tolerated and the patient had no acute side effects. CONCLUSION: Isolated hypophyseal involvement by Langerhans cell histiocytosis in adults is a unique presentation of a rare disease. Although radiotherapy doses as low as 20Gy have been reported to offer control, this case demonstrates that higher doses may be warranted to ensure tumor control. With modern imaging and radiotherapy techniques higher doses should offer little increased more durable risk to surrounding critical structures