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Search Results: 1 - 10 of 303448 matches for " Walter J. Curran "
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Mono- or Double-Site Phosphorylation Distinctly Regulates the Proapoptotic Function of Bax
Qinhong Wang,Shi-Yong Sun,Fadlo Khuri,Walter J. Curran,Xingming Deng
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0013393
Abstract: Bax is the major multidomain proapoptotic molecule that is required for apoptosis. It has been reported that phosphorylation of Bax at serine(S) 163 or S184 activates or inactivates its proapoptotic function, respectively. To uncover the mechanism(s) by which phosphorylation regulates the proapoptotic function of Bax, a series of serine (S)→ alanine/glutamate (A/E) Bax mutants, including S163A, S184A, S163E, S184E, S163E/S184A (EA), S163A/S184E (AE), S163A/S184A (AA) and S163E/S184E (EE), were created to abrogate or mimic, respectively, either single or double-site phosphorylation. The compound Bax mutants (i.e. EA and AE) can flesh out the functional contribution of individual phosphorylation site(s). WT and each of these Bax mutants were overexpressed in Bax?/? MEF or lung cancer H157 cells and the proapoptotic activities were compared. Intriguingly, expression of any of Bax mutants containing the mutation S→A at S184 (i.e. S184A, EA or AA) represents more potent proapoptotic activity as compared to WT Bax in association with increased 6A7 epitope conformational change, mitochondrial localization/insertion and prolonged half-life. In contrast, all Bax mutants containing the mutation S→E at S184 (i.e. S184E, AE or EE) have a mobility-shift and fail to insert into mitochondrial membranes with decreased protein stability and less apoptotic activity. Unexpectedly, mutation either S→A or S→E at S163 site does not significantly affect the proapoptotic activity of Bax. These findings indicate that S184 but not S163 is the major phosphorylation site for functional regulation of Bax's activity. Therefore, manipulation of the phosphorylation status of Bax at S184 may represent a novel strategy for cancer treatment.
Stereotactic Body Radiosurgery for Spinal Metastatic Disease: An Evidence-Based Review
William A. Hall,Liza J. Stapleford,Costas G. Hadjipanayis,Walter J. Curran,Ian Crocker,Hui-Kuo G. Shu
International Journal of Surgical Oncology , 2011, DOI: 10.1155/2011/979214
Abstract: Spinal metastasis is a problem that afflicts many cancer patients. Traditionally, conventional fractionated radiation therapy and/or surgery have been the most common approaches for managing such patients. Through technical advances in radiotherapy, high dose radiation with extremely steep drop off can now be delivered to a limited target volume along the spine under image-guidance with very high precision. This procedure, known as stereotactic body radiosurgery, provides a technique to rapidly treat selected spinal metastasis patients with single- or limited-fraction treatments that have similar to superior efficacies compared with more established approaches. This review describes current treatment systems in use to deliver stereotactic body radiosurgery as well as results of some of the larger case series from a number of institutions that report outcomes of patients treated for spinal metastatic disease. These series include nearly 1400 patients and report a cumulative local control rate of 90% with myelopathy risk that is significantly less than 1%. Based on this comprehensive review of the literature, we believe that stereotactic body radiosurgery is an established treatment modality for patients with spinal metastatic disease that is both safe and highly effective. 1. Introduction Spine column tumors, both primary and metastatic lesions, are quite often seen in cancer patients. For a variety of tumors, the spine is the most common site of metastatic disease. It is estimated that 20,000–25,000 patients per year in the US develop spinal cord or root compression as a manifestation of their metastatic disease [1, 2]. Further estimates conclude that 5–10% of cancer patients will develop spinal metastasis [3]. In cancer patients with acute onset of back pain or other clinical suspicion for spinal metastatic disease, rates of spinal metastasis exceeding 25% have been reported [3, 4]. Radiotherapy has long been established as an effective treatment modality for spinal tumors [5–8]. With the advancement of image-guided radiation therapy technology, extracranial spinal radiosurgery has emerged as an effective and safe treatment modality for spinal tumors, both primary and metastatic. Extracranial radiosurgery, or stereotactic body radiosurgery (SBRS) was developed in the mid 1990s at various institutes around the world. Possibly the earliest experience describing the procedure came from the Karolinska Institute in Sweden [9]. Around the same time, Hamilton et al. published their early experience treating spinal tumors with linear accelerator-based
Targeting DNA-PKcs and ATM with miR-101 Sensitizes Tumors to Radiation
Dan Yan,Wooi Loon Ng,Xiangming Zhang,Ping Wang,Zhaobin Zhang,Yin-Yuan Mo,Hui Mao,Chunhai Hao,Jeffrey J. Olson,Walter J. Curran,Ya Wang
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0011397
Abstract: Radiotherapy kills tumor-cells by inducing DNA double strand breaks (DSBs). However, the efficient repair of tumors frequently prevents successful treatment. Therefore, identifying new practical sensitizers is an essential step towards successful radiotherapy. In this study, we tested the new hypothesis: identifying the miRNAs to target DNA DSB repair genes could be a new way for sensitizing tumors to ionizing radiation.
Phase i study of 'dose-dense' pemetrexed plus carboplatin/radiotherapy for locally advanced non-small cell lung carcinoma
Xinglei Shen, Albert DeNittis, Maria Werner-Wasik, Rita Axelrod, Paul Gilman, Thomas Meyer, Joseph Treat, Walter J Curran, Mitchell Machtay
Radiation Oncology , 2011, DOI: 10.1186/1748-717x-6-17
Abstract: Eligible patients had Stage III or IV (oligometastatic) NSCLC. Patients received XRT to 63 Gy in standard fractionation. Patients received concurrent carboplatin (AUC = 6) during weeks 1 and 5 of XRT, and pemetrexed during weeks 1, 3, 5, and 7 of XRT. The starting dose level (level 1) of pemetrexed was 300 mg/m2. Following the finding of dose limiting toxicity (DLT) in dose level 1, an amended dose level (level 1A) continued pemetrexed at 300 mg/m2, but with involved field radiation instead of extended nodal irradiation. Consolidation consisted of carboplatin (AUC = 6) and pemetrexed (500 mg/m2) q3 weeks × 2 -3 cycles.Eighteen patients were enrolled. Fourteen patients are evaluable for toxicity analysis. Of the initial 6 patients treated on dose level 1, two experienced DLTs (one grade 4 sepsis, one prolonged grade 3 esophagitis). There was one DLT (grade 5 pneumonitis) in the 8 patients treated on dose level 1A. In 16 patients evaluable for response (4 with oligometastatic stage IV disease and 12 with stage III disease), the median follow-up time is 17.8 months. Thirteen of 16 patients had in field local regional response. The actuarial median survival time was 28.6 months in all patients and 34.7 months (estimated) in stage III patients.Concurrent carboplatin with dose-dense (q2week) pemetrexed at 300 mg/m2 with involved field XRT is feasible and encouraging in patients with locally advanced and oligometastatic NSCLC.ClinicalTrials.gov NCT00330044Concurrent chemoradiation has been established as the standard of care for non-operable stage III non-small cell lung cancer (NSCLC) [1-4]. With this approach, the median survival time is approximately 17 months and about 15% of patients survive 5+ years. Concurrent combined modality therapy has improved survival over single modality or sequential therapy[1-4], but overall outcomes remain poor.The optimal chemotherapy regimen to use with concurrent radiation therapy remains uncertain. Initial studies of concurrent treatme
The prognostic value of nestin expression in newly diagnosed glioblastoma: Report from the Radiation Therapy Oncology Group
Prakash Chinnaiyan, Meihua Wang, Amyn M Rojiani, Philip J Tofilon, Arnab Chakravarti, K Kian Ang, Hua-Zhong Zhang, Elizabeth Hammond, Walter Curran, Minesh P Mehta
Radiation Oncology , 2008, DOI: 10.1186/1748-717x-3-32
Abstract: Tissue microarrays were prepared from 156 patients enrolled in these trials. These specimens were stained using a mouse monoclonal antibody specific for nestin and expression was measured by computerized quantitative image analysis using the Ariol SL-50 system. The parameters measured included both staining intensity and the relative area of expression within a specimen. This resulted into 3 categories: low, intermediate, and high nestin expression, which was then correlated with clinical outcome.A total of 153 of the 156 samples were evaluable for this study. There were no statistically significant differences between pretreatment patient characteristics and nestin expression. There was no statistically significant difference in either overall survival or progression-free survival (PFS) demonstrated, although a trend in decreased PFS was observed with high nestin expression (p = 0.06).Although the correlation of nestin expression and histologic grade in glioma is of considerable interest, the presented data does not support its prognostic value in newly diagnosed GBM. Further studies evaluating nestin expression may be more informative when studied in lower grade glioma, in the context of markers more specific to tumor stem cells, and using more recent specimens from patients treated with temozolomide in conjunction with radiation.Nestin is an intermediate filament protein that was initially identified during studies involving cellular organization of the developing rat nervous system [1]. It was described as the antigen to the monoclonal antibody Rat-401 that specifically identified transient radial glial cells, which guided neuronal migration. It was later cloned in humans and its gene product defined a distinct sixth class of intermediate filament proteins [2]. Nestin expression has been demonstrated in neuroepithelial stem cells and progenitor cells in the human brain and implicated in early stages of lineage commitment. Further, as these precursor cells differ
Inhibition of STAT3 by Niclosamide Synergizes with Erlotinib against Head and Neck Cancer
Rui Li, Shuo You, Zhongliang Hu, Zhuo G. Chen, Gabriel L. Sica, Fadlo R. Khuri, Walter J. Curran, Dong M. Shin, Xingming Deng
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0074670
Abstract: Epidermal growth factor receptor (EGFR) is extensively expressed in head and neck cancer. However, EGFR-targeted therapy has only modest efficacy in head and neck cancer, through mechanisms that are not fully understood. Here, we found that inhibition of EGFR by erlotinib stimulated phosphorylation and activation of STAT3 leading to increased Bcl2/Bcl-XL expression in head and neck cancer cells, which may dampen the therapeutic efficacy of erlotinib against head and neck cancer. Erlotinib-enhanced STAT3 phosphorylation results, at least in part, from suppression of its physiological phosphatase, PTPMeg2. Specific knockdown of STAT3 by RNA interference significantly sensitized head and neck cancer cells to erlotinib treatment. Pharmacological inhibition of STAT3 by niclosamide not only blocked erlotinib-stimulated STAT3 phosphorylation but also synergistically repressed head and neck cancer growth in vitro and in vivo. Combined inhibition of EGFR and STAT3 by erlotinib and niclosamide more effectively induced apoptosis in tumor tissues without toxicity for normal tissues. Based on our findings, treatment with erlotinib combined with niclosamide may offer an effective therapeutic approach to improve the prognosis of head and neck cancer.
Repeat Whole Brain Radiation Therapy with a Simultaneous Infield Boost: A Novel Technique for Reirradiation
William A. Hall,Roshan S. Prabhu,Ian R. Crocker,Anees Dhabban,Tomi Ogunleye,Shravan Kandula,Xiaojun Jiang,Walter J. Curran,Hui-Kuo G. Shu
Journal of Radiotherapy , 2014, DOI: 10.1155/2014/403945
Abstract: The treatment of patients who experience intracranial progression after whole brain radiation therapy (WBRT) is a clinical challenge. Novel radiation therapy delivery technologies are being applied with the objective of improving tumor and symptom control in these patients. The purpose of this study is to describe the clinical outcomes of the application of a novel technology to deliver repeat WBRT with volume modulated arc therapy (VMAT) and a simultaneous infield boost (WB-SIB) to gross disease. A total of 16 patients were initially treated with WBRT between 2000 and 2008 and then experienced intracranial progression, were treated using repeat WB-SIB, and were analyzed. The median dose for the first course of WBRT was 35?Gy (range: 30–50.4?Gy). Median time between the initial course of WBRT and repeat WB-SIB was 11.3 months. The median dose at reirradiation was 20?Gy to the whole brain with a median boost dose of 30?Gy to gross disease. A total of 2 patients demonstrated radiographic disease progression after treatment. The median overall survival (OS) time from initial diagnosis of brain metastases was 18.9 months (range: 7.1–66.6 (95% CI: 0.8–36.9)). The median OS time after initiation of reirradiation for all patients was 2.7 months (range: 0.46–14.46 (95% CI: 1.3–8.7)). Only 3 patients experienced CTCAE grade 3 fatigue. No other patients experienced any ≥ CTCAE grade 3 toxicity. This analysis reports the result of a novel RT delivery technique for the treatment of patients with recurrent brain metastases. Side effects were manageable and comparable to other conventional repeat WBRT series. Repeat WB-SIB using the VMAT RT delivery technology is feasible and appears to have acceptable short-term acute toxicity. These results may provide a foundation for further exploration of the WB-SIB technique for repeat WBRT in future prospective clinical trials. 1. Introduction Metastases to the brain occur in 25–45% of cancer patients [1]. With improving systemic treatments, cancer death rates are decreasing and patients with metastatic disease are living longer [2]. Standard treatment for patients with unresectable brain metastasis includes whole brain radiation therapy (WBRT), stereotactic radiosurgery (SRS), or a combination of both [3, 4]. Local and distant brain progression after conventional WBRT are common, occurring in 47–86% of patients [5]. Potential interventions after WBRT include surgical resection, chemotherapy, SRS, or repeat WBRT. The radiation dose given at the time of repeat WBRT generally is reduced secondary to toxicity concerns and ranges
On the detectability of HI 21-cm in MgII absorption system
S. J. Curran
Physics , 2009, DOI: 10.1111/j.1365-2966.2009.16080.x
Abstract: We investigate the effect of two important, but oft neglected, factors which can affect the detectability of HI 21-cm absorption in MgII absorption systems: The effect of line-of-sight geometry of the coverage of the background radio flux and any possible correlation between the 21-cm line strength and the rest frame equivalent width of the MgII line. Regarding the former, while the observed detection rate at small angular diameter distance ratios is a near certainty, for an unbiased sample, where either a detection or a non-detection are equally likely, at ratios > 0.8 the observed detection rate has an 8 sigma significance, suggesting that the mix of ratios values at z < 1 is correlated with the mix of detections and non-detections at low redshift, while the exclusively high values of the ratio at z > 1 contribute to the low detection rates at high redshift. In DLAs, the correlation between the 21-cm line strength and the MgII equivalent width is dominated by the velocity spread of the 21-cm line. This has recently been shown not to hold for MgII systems in general. However, we do find the significance of the correlation to increase when the MgII absorbers with MgI equivalent widths of >0.5 A are added to the DLA sample. Large values of the angular diameter distance ratio may explain why the absorbers which have similar equivalent widths to the detections remain undetected. We do, however, also find the neutral hydrogen column densities of the non-detections to be significantly lower. Applying the 21-cm line strength/equivalent width correlation to yield column densities for the MgII absorbers in which this is unmeasured, we find no evidence of a cosmological evolution in the neutral hydrogen column density.
The geometry effects of an expanding Universe on the detection of cool neutral gas at high redshift
S. J. Curran
Physics , 2012, DOI: 10.1088/2041-8205/748/1/L18
Abstract: Recent high redshift surveys for 21-cm absorption in damped Lyman-alpha absorption systems (DLAs) take the number of published searches at z > 2 to 25, the same number as at z < 2, although the detection rate at high redshift remains significantly lower (20% cf. 60%). Using the known properties of the DLAs to estimate the unknown profile widths of the 21-cm non-detections and including the limits via a survival analysis, we show that the mean spin temperature/covering factor degeneracy at high redshift is, on average, double that of the low redshift sample. This value is significantly lower than the previous factor of eight for the spin temperatures and is about the same factor as in the angular diameter distance ratios between the low and high redshift samples. That is, without the need for the several pivotal assumptions, which lead to an evolution in the spin temperature, we show that the observed distribution of 21-cm detections in DLAs can be accounted for by the geometry effects of an expanding Universe. That is, as yet there is no evidence of the spin temperature of gas rich galaxies evolving with redshift.
Defining the Pathways Underlying the Prolonged PR Interval in Atrioventricular Conduction Disease
Jerry Curran,Peter J. Mohler
PLOS Genetics , 2012, DOI: 10.1371/journal.pgen.1003154
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