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1.  PX-478, an inhibitor of hypoxia-inducible factor-1α, enhances radiosensitivity of prostate carcinoma cells 
Overexpression of hypoxia-inducible factor-1α (HIF-1α) in human tumors is associated with poor prognosis and poor outcome to radiation therapy. Inhibition of HIF-1α is considered as a promising approach in cancer therapy. The purpose of this study was to test the efficacy of a novel HIF-1α inhibitor PX-478 as a radiosensitizer under normoxic and hypoxic conditions in vitro. PC3 and DU 145 prostate carcinoma cells were treated with PX-478 for 20 hr, and HIF-1α protein level and clonogenic cell survival were determined under normoxia and hypoxia. Effects of PX-478 on cell cycle distribution and phosphorylation of H2AX histone were evaluated. PX-478 decreased HIF-1α protein in PC3 and DU 145 cells. PX-478 produced cytotoxicity in both cell lines with enhanced toxicity under hypoxia for DU-145. PX-478 (20 μmol/L) enhanced the radiosensitivity of PC3 cells irradiated under normoxic and hypoxic condition with enhancement factor (EF) 1.4 and 1.56, respectively. The drug was less effective in inhibiting HIF-1α and enhancing radiosensitivity of DU 145 cells compared to PC3 cells with EF 1.13 (normoxia) and 1.25 (hypoxia) at 50 μmol/L concentration. PX-478 induced S/G2M arrest in PC3 but not in DU 145 cells. Treatment of PC3 and DU 145 cells with the drug resulted in phosphorylation of H2AX histone and prolongation of γH2AX expression in the irradiated cells. PX-478 is now undergoing Phase I clinical trials as an oral agent. Although the precise mechanism of enhancement of radiosensitivity remains to be identified, this study suggests a potential role for PX-478 as a clinical radiation enhancer.
doi:10.1002/ijc.23807
PMCID: PMC4277812  PMID: 18729192
PX-478; hypoxia; normoxia; HIF-1α; radiosensitivity
2.  Assessment of Biodosimetry Methods for a Mass-Casualty Radiological Incident: Medical Response and Management Considerations 
Health physics  2013;105(6):10.1097/HP.0b013e31829cf221.
Following a mass-casualty nuclear disaster, effective medical triage has the potential to save tens of thousands of lives. In order to best use the available scarce resources, there is an urgent need for biodosimetry tools to determine an individual’s radiation dose. Initial triage for radiation exposure will include location during the incident, symptoms, and physical examination. Stepwise triage will include point of care assessment of less than or greater than 2 Gy, followed by secondary assessment, possibly with high throughput screening, to further define an individual’s dose. Given the multisystem nature of radiation injury, it is unlikely that any single biodosimetry assay can be used as a stand-alone tool to meet the surge in capacity with the timeliness and accuracy needed. As part of the national preparedness and planning for a nuclear or radiological incident, we reviewed the primary literature to determine the capabilities and limitations of a number of biodosimetry assays currently available or under development for use in the initial and secondary triage of patients. Understanding the requirements from a response standpoint and the capability and logistics for the various assays will help inform future biodosimetry technology development and acquisition. Factors considered include: type of sample required, dose detection limit, time interval when the assay is feasible biologically, time for sample preparation and analysis, ease of use, logistical requirements, potential throughput, point-of-care capability, and the ability to support patient diagnosis and treatment within a therapeutically relevant time point.
doi:10.1097/HP.0b013e31829cf221
PMCID: PMC3810609  PMID: 24162058
Dosimetry; cytogenetics; dose assessment; emergency planning
3.  Lessons Learned from Radiation Oncology Clinical Trials 
A Workshop entitled “Lessons Learned from Radiation Oncology Trials” was held on December 7–8th, 2011 in Bethesda, MD, to present and discuss some of the recently conducted Radiation Oncology clinical trials with a focus on those that failed to refute the null hypothesis. The objectives of this Workshop were to summarize and examine the questions that these trials provoked, to assess the quality and limitations of the pre-clinical data that supported the hypotheses underlying these trials, and to consider possible solutions to these challenges for the design of future clinical trials.
Several themes emerged from the discussions, including the: a) opportunities to learn from null-hypothesis trials through tissue and imaging studies; b) value of pre-clinical data supporting the design of combinatorial therapies; c) significance of validated biomarkers; d) necessity of quality assurance in radiotherapy delivery; e) conduct of sufficiently-powered studies to address the central hypothesis; and f) importance of publishing results of the trials regardless of the outcome.
The fact that well-designed hypothesis-driven clinical trials produce null or negative results is expected given the limitations of trial design, and complexities of cancer biology. It is important to understand the reasons underlying such null results however, in order to effectively merge the technological innovations with the rapidly evolving biology for maximal patient benefit, through the design of future clinical trials.
doi:10.1158/1078-0432.CCR-13-1116
PMCID: PMC3965328  PMID: 24043463
Cancer; Null hypothesis; Radiation oncology; Radiation therapy; Randomized clinical trial
5.  Defining Molecular Signature of Pro-Immunogenic Radiotherapy Targets in Human Prostate Cancer Cells 
Radiation research  2014;182(2):139-148.
To understand the impact of clinically relevant radiation therapy (RT) on tumor immune gene expression and to utilize the changes that occur during treatment to improve cancer treatment outcome, we examined how immune response genes are modulated in prostate cancer cells of varying p53 status. LNCaP (p53 wild-type), PC3 (p53 null) and DU145 (p53 mutant) cells received a 10 Gy single dose or 1 Gy × 10 multifractionated radiation dose to simulate hypofractionated and conventionally fractionated prostate radiotherapy. Total RNA was isolated 24 h after multi-fractionated radiation treatment and single-dose treatments and subjected to microarray analysis and later validated by RT-PCR. RT-PCR was utilized to identify total-dose inflection points for significantly upregulated genes in response to multifractionated radiation therapy. Radiation-induced damage-associated molecular pattern molecules (DAMPs) and cytokine analyses were performed using bioluminescence and ELISA. Multifractionated doses activated immune response genes more robustly than single-dose treatment, with a relatively larger number of immune genes upregulated in PC3 compared to DU145 and LNCaP cells. The inflection point of multifractionated radiation-induced immune genes in PC3 cells was observed in the range of 8–10 Gy total radiation dose. Although both multifractionated and single-dose radiation-induced proinflammatory DAMPs and positively modulated the cytokine environment, the changes were of higher magnitude with multifractionated therapy. The findings of this study together with the gene expression data suggest that cells subjected to multifractionated radiation treatment would promote productive immune cell–tumor cell interactions.
doi:10.1667/RR13731.1
PMCID: PMC4216662  PMID: 25003313
6.  The International Cancer Expert Corps: A Unique Approach for Sustainable Cancer Care in Low and Lower-Middle Income Countries 
Frontiers in Oncology  2014;4:333.
The growing burden of non-communicable diseases including cancer in low- and lower-middle income countries (LMICs) and in geographic-access limited settings within resource-rich countries requires effective and sustainable solutions. The International Cancer Expert Corps (ICEC) is pioneering a novel global mentorship–partnership model to address workforce capability and capacity within cancer disparities regions built on the requirement for local investment in personnel and infrastructure. Radiation oncology will be a key component given its efficacy for cure even for the advanced stages of disease often encountered and for palliation. The goal for an ICEC Center within these health disparities settings is to develop and retain a high-quality sustainable workforce who can provide the best possible cancer care, conduct research, and become a regional center of excellence. The ICEC Center can also serve as a focal point for economic, social, and healthcare system improvement. ICEC is establishing teams of Experts with expertise to mentor in the broad range of subjects required to establish and sustain cancer care programs. The Hubs are cancer centers or other groups and professional societies in resource-rich settings that will comprise the global infrastructure coordinated by ICEC Central. A transformational tenet of ICEC is that altruistic, human-service activity should be an integral part of a healthcare career. To achieve a critical mass of mentors ICEC is working with three groups: academia, private practice, and senior mentors/retirees. While in-kind support will be important, ICEC seeks support for the career time dedicated to this activity through grants, government support, industry, and philanthropy. Providing care for people with cancer in LMICs has been a recalcitrant problem. The alarming increase in the global burden of cancer in LMICs underscores the urgency and makes this an opportune time fornovel and sustainable solutions to transform cancer care globally.
doi:10.3389/fonc.2014.00333
PMCID: PMC4237042  PMID: 25478326
health disparities; cancer; global health; underserved; non-communicable diseases
7.  Fractionated Radiation Alters Oncomir and Tumor Suppressor miRNAs in Human Prostate Cancer Cells 
Radiation research  2012;178(3):105-117.
We have previously demonstrated that prostate carcinoma cells exposed to fractionated radiation differentially expressed more genes compared to single-dose radiation. To understand the role of miRNA in regulation of radiation-induced gene expression, we analyzed miRNA expression in LNCaP, PC3 and DU145 prostate cancer cells treated with single-dose radiation and fractionated radiation by micro-array. Selected miRNAs were studied in RWPE-1 normal prostate epithelial cells by RT-PCR. Fractionated radiation significantly altered more miRNAs as compared to single-dose radiation. Downregulation of oncomiR-17-92 cluster was observed only in the p53 positive LNCaP and RWPE-1 cells treated with single-dose radiation and fractionated radiation. Comparison of miRNA and mRNA data by IPA target filter analysis revealed an inverse correlation between miR-17-92 cluster and several targets including TP53INP1 in p53 signaling pathway. The base level expressions of these miRNAs were significantly different among the cell lines and did not predict the radiation outcome. Tumor suppressor miR-34a and let-7 miRNAs were upregulated by fractionated radiation in radiosensitive LNCaP (p53 positive) and PC3 (p53-null) cells indicating that radiation-induced miRNA expression may not be regulated by p53 alone. Our data support the potential for using fractionated radiation to induce molecular targets and radiation-induced miRNAs may have a significant role in predicting radiosensitivity
PMCID: PMC4156966  PMID: 22827214
8.  The Road Not Taken and Choices in Radiation Oncology 
The Oncologist  2010;15(4):332-337.
The authors look back at the five decades of radiation oncology and consider how one's choices and decisions influence how a career is pursued and how a professional life is lived.
Accomplishments and contributions in a career in radiation oncology, and in medicine in general, involve individual choices that impact the direction of a specialty, decisions in patient care, consequences of treatment outcome, and personal satisfaction. Issues in radiation oncology include: the development and implementation of new radiation treatment technology; the use of multimodality and biologically based therapies; the role of nonradiation “energy” technologies, often by other medical specialties, including the need for quality assurance in treatment and data reporting; and the type of evidence, including appropriate study design, analysis, and rigorous long-term follow-up, that is sought before widespread implementation of a new treatment. Personal choices must weigh: the pressure from institutions—practices, departments, universities, and hospitals; the need to serve society and the underserved; the balance between individual reward and a greater mission; and the critical role of personal values and integrity, often requiring difficult and “life-defining” decisions. The impact that each of us makes in a career is perhaps more a result of character than of the specific details enumerated on one's curriculum vitae. The individual tapestry weaved by choosing the more or less traveled paths during a career results in many pathways that would be called success; however, the one path for which there is no good alternative is that of living and acting with integrity.
doi:10.1634/theoncologist.2009-S102
PMCID: PMC3227963  PMID: 20413638
Radiation oncology; Personalized medicine; Medical ethics; Medical technology
9.  Opportunities and Challenges in the Era of Molecularly Targeted Agents and Radiation Therapy 
The first annual workshop for preclinical and clinical development of radiosensitizers took place at the National Cancer Institute on August 8–9, 2012. Radiotherapy is one of the most commonly applied and effective oncologic treatments for solid tumors. It is well recognized that improved clinical efficacy of radiotherapy would make a substantive impact in clinical practice and patient outcomes. Advances in genomic technologies and high-throughput drug discovery platforms have brought a revolution in cancer treatment by providing molecularly targeted agents for various cancers. Development of predictive biomarkers directed toward specific subsets of cancers has ushered in a new era of personalized therapeutics. The field of radiation oncology stands to gain substantial benefit from these advances given the concerted effort to integrate this progress into radiation therapy. This workshop brought together expert clinicians and scientists working in various disease sites to identify the exciting opportunities and expected challenges in the development of molecularly targeted agents in combination with radiation therapy.
doi:10.1093/jnci/djt055
PMCID: PMC3733308  PMID: 23503600
10.  Exploiting sensitization windows of opportunity in hyper and hypo-fractionated radiation therapy 
Journal of Thoracic Disease  2014;6(4):287-302.
In contrast to the conventional radiotherapy/chemoradiotherapy paradigms used in the treatment of majority of cancer types, this review will describe two areas of radiobiology, hyperfractionated and hypofractionated radiation therapy, for cancer treatment focusing on application of novel concepts underlying these treatment modalities. The initial part of the review discusses the phenomenon of hyper-radiation sensitivity (HRS) at lower doses (0.1 to 0.6 Gy), describing the underlying mechanisms and how this could enhance the effects of chemotherapy, particularly, in hyperfractionated settings. The second part examines the radiobiological/physiological mechanisms underlying the effects of high-dose hypofractionated radiation therapy that can be exploited for tumor cure. These include abscopal/bystander effects, activation of immune system, endothelial cell death and effect of hypoxia with re-oxygenation. These biological properties along with targeted dose delivery and distribution to reduce normal tissue toxicity may make high-dose hypofractionation more effective than conventional radiation therapy for treatment of advanced cancers. The novel radiation physics based methods that take into consideration the tumor volume to be irradiated and normal tissue avoidance/tolerance can further improve treatment outcome and post-treatment quality of life. In conclusion, there is enough evidence to further explore novel avenues to exploit biological mechanisms from hyper-fractionation by enhancing the efficacy of chemotherapy and hypo-fractionated radiation therapy that could enhance tumor control and use imaging and technological advances to reduce toxicity.
doi:10.3978/j.issn.2072-1439.2014.01.14
PMCID: PMC3968552  PMID: 24688774
Low Doses Fractionated Radiation Therapy (LDFRT); hyper-radiation sensitivity (HRS); induced radiation resistance (IRR); hyperfractionation; chemopotentiation; stereotactic body radiation therapy (SBRT); stereotactic ablative radiosurgery (SARS); stereotactic ablative radiotherapy (SABR); stereotactic radiosurgery (SRS); spatially fractionated GRID radiotherapy (SFGRT); lattice
11.  NCI–RTOG Translational Program Strategic Guidelines for the Early-Stage Development of Radiosensitizers 
The addition of chemotherapeutic agents to ionizing radiation has improved survival in many malignancies. Cure rates may be further improved by adding novel targeted agents to current radiotherapy or radiochemotherapy regimens. Despite promising laboratory data, progress in the clinical development of new drugs with radiation has been limited. To define and address the problems involved, a collaborative effort between individuals within the translational research program of the Radiation Oncology Therapy Group and the National Cancer Institute was established. We discerned challenges to drug development with radiation including: 1) the limited relevance of preclinical work, 2) the pharmaceutical industry’s diminished interest, and 3) the important individual skills and institutional commitments required to ensure a successful program. The differences between early-phase trial designs with and without radiation are noted as substantial. The traditional endpoints for early-phase clinical trials—acute toxicity and maximum-tolerated dose—are of limited value when combining targeted agents with radiation. Furthermore, response rate is not a useful surrogate marker of activity in radiation combination trials.Consequently, a risk-stratified model for drug-dose escalation with radiation is proposed, based upon the known and estimated adverse effects. The guidelines discuss new clinical trial designs, such as the time-to-event continual reassessment method design for phase I trials, randomized phase II “screening” trials, and the use of surrogate endpoints, such as pathological response. It is hoped that by providing a clear pathway, this article will accelerate the rate of drug development with radiation.
doi:10.1093/jnci/djs472
PMCID: PMC3536642  PMID: 23231975
12.  Radiation Survivors: Understanding and exploiting the phenotype following fractionated radiation therapy 
Radiation oncology modalities such as intensity-modulated and image-guided radiation therapy can reduce the high dose to normal tissue and deliver a heterogeneous dose to tumors focusing on areas deemed at highest risk for tumor persistence. Clinical radiation oncology produces daily doses ranging from 1 to 20 Gy, with tissues being exposed to 30 or more daily fractions. Hypothesizing that cells that survive fractionated radiation therapy have a substantially different phenotype than the untreated cells, which might be exploitable for targeting with molecular therapeutics or immunotherapy, three prostate cancer cell lines (PC3, DU145 and LNCaP) and normal endothelial cells were studied to understand the biology of differential effects of multi-fraction (MF) radiation of 0.5, 1 and/or 2 Gy fraction to 10 Gy total dose, and a single dose (SD) of 5 and 10 Gy. The resulting changes in mRNA, miRNA and phosphoproteome were analyzed. Significant differences were observed in the MF radiation exposures including those from the 0.5 Gy MF that produces little cell killing. As expected, p53 function played a major role in response. Pathways modified by MF include immune response, DNA damage, cell cycle arrest, TGF-β, survival and apoptotic signal transduction. The radiation-induced stress response will set-forth a unique platform for exploiting the effects of radiation therapy as “focused biology” for cancer treatment in conjunction with molecular targeted or immunologically directed therapy. Given that more normal tissue is treated, albeit to lower doses with these newer techniques, the response of the normal tissue may also influence long-term treatment outcome.
doi:10.1158/1541-7786.MCR-12-0492
PMCID: PMC3552079  PMID: 23175523
13.  National Cancer Institute’s Cancer Disparities Research Partnership Program: Experience and Lessons Learned 
Frontiers in Oncology  2014;4:303.
Purpose: To increase access of underserved/health disparities communities to National Cancer Institute (NCI) clinical trials, the Radiation Research Program piloted a unique model – the Cancer Disparities Research Partnership (CDRP) program. CDRP targeted community hospitals with a limited past NCI funding history and provided funding to establish the infrastructure for their clinical research program.
Methods: Initially, 5-year planning phase funding was awarded to six CDRP institutions through a cooperative agreement (U56). Five were subsequently eligible to compete for 5-year implementation phase (U54) funding and three received a second award. Additionally, the NCI Center to Reduce Cancer Health Disparities supported their U56 patient navigation programs.
Results: Community-based hospitals with little or no clinical trials experience required at least a year to develop the infrastructure and establish community outreach/education and patient navigation programs before accrual to clinical trials could begin. Once established, CDRP sites increased their yearly patient accrual mainly to NCI-sponsored cooperative group trials (~60%) and Principal Investigator/mentor-initiated trials (~30%). The total number of patients accrued on all types of trials was 2,371, while 5,147 patients received navigation services.
Conclusion: Despite a historical gap in participation in clinical cancer research, underserved communities are willing/eager to participate. Since a limited number of cooperative group trials address locally advanced diseases seen in health disparities populations; this shortcoming needs to be rectified. Sustainability for these programs remains a challenge. Addressing these gaps through research and public health mechanisms may have an important impact on their health, scientific progress, and efforts to increase diversity in NCI clinical trials.
doi:10.3389/fonc.2014.00303
PMCID: PMC4217306  PMID: 25405101
cancer disparities; underserved populations; patient accrual; access to clinical trials; clinical research
14.  RESPONSE OF THE U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES IN PROTECTING CIVILIAN AMERICANS IN JAPAN DURING THE FUKUSHIMA NUCLEAR CRISIS 
Health physics  2012;102(5):10.1097/HP.0b013e31824c79e5.
Following the earthquake and tsunami in northern Japan on 11 March 2011, and the ensuing damage to the Fukushima Daiichi nuclear power plant complex, a request by the U.S. Ambassador to Japan to the U.S. Department of Health and Human Services (DHHS) Assistant Secretary for Preparedness and Response (ASPR) resulted in deployment of a five-person team of subject matter experts to the U.S. Embassy. The primary purpose of the deployment was to provide the U.S. Embassy in Tokyo with guidance on health and medical issues related to potential radiation exposure of U.S. citizens in Japan, including employees of the U.S. Department of State at consulates in Japan and American citizens living in or visiting Japan. At the request of the Government of Japan, the deployed health team also assisted Japanese experts in their public health response to the radiation incident. Over a three-week period in Japan and continuing for weeks after their return to the U.S., the team provided expertise in the areas of medical and radiation oncology, health physics, assessment of radiation dose and cancer risk, particularly to U.S. citizens living in Tokyo and the surrounding areas, food and water contamination and the acceptable limits, countermeasures to exposure such as potassium iodide (KI), the use of KI and an offered donation from the United States, evacuation and re-entry issues, and health/emergency-related communication strategies. This paper describes the various strategies used and observations made by the DHHS team during the first two months after the Fukushima crisis began.
doi:10.1097/HP.0b013e31824c79e5
PMCID: PMC3816381  PMID: 24198437
public heath; emergency response; radiation exposure; medical countermeasures; nuclear power plant
15.  mRNA Expression Profiles for Prostate Cancer following Fractionated Irradiation Are Influenced by p53 Status12 
Translational Oncology  2013;6(5):573-585.
We assessed changes in cell lines of varying p53 status after various fractionation regimens to determine if p53 influences gene expression and if multifractionated (MF) irradiation can induce molecular pathway changes. LNCaP (p53 wild-type), PC3 (p53 null), and DU145 (p53 mutant) prostate carcinoma cells received 5 and 10 Gy as single-dose (SD) or MF (0.5 Gy x 10, 1 Gy x 10, and 2 Gy x 5) irradiation to simulate hypofractionated and conventionally fractionated prostate radiotherapies, respectively. mRNA analysis revealed 978 LNCaP genes differentially expressed (greater than two-fold change, P < .05) after irradiation. Most were altered with SD (69%) and downregulated (75%). Fewer PC3 (343) and DU145 (116) genes were induced, with most upregulated (87%, 89%) and altered with MF irradiation. Gene ontology revealed immune response and interferon genes most prominently expressed after irradiation in PC3 and DU145. Cell cycle regulatory (P = 9.23 x 10-73, 14.2% of altered genes, nearly universally downregulated) and DNA replication/repair (P = 6.86 x 10-30) genes were most prominent in LNCaP. Stress response and proliferation genes were altered in all cell lines. p53-activated genes were only induced in LNCaP. Differences in gene expression exist between cell lines and after varying irradiation regimens that are p53 dependent. As the duration of changes is ≥24 hours, it may be possible to use radiation-inducible targeted therapy to enhance the efficacy of molecular targeted agents.
PMCID: PMC3804925  PMID: 24151538
16.  Redesigning Radiotherapy Quality Assurance: Opportunities to Develop an Efficient, Evidence-Based System to Support Clinical Trials 
Background
In the context of national calls for reorganizing cancer clinical trials, the National Cancer Institute (NCI) sponsored a two day workshop to examine the challenges and opportunities for optimizing radiotherapy quality assurance (QA) in clinical trial design.
Methods
Participants reviewed the current processes of clinical trial QA and noted the QA challenges presented by advanced technologies. Lessons learned from the radiotherapy QA programs of recent trials were discussed in detail. Four potential opportunities for optimizing radiotherapy QA were explored, including the use of normal tissue toxicity and tumor control metrics, biomarkers of radiation toxicity, new radiotherapy modalities like proton beam therapy, and the international harmonization of clinical trial QA.
Results
Four recommendations were made: 1) Develop a tiered (and more efficient) system for radiotherapy QA and tailor intensity of QA to clinical trial objectives. Tiers include (i) general credentialing, (ii) trial specific credentialing, and (iii) individual case review; 2) Establish a case QA repository; 3) Develop an evidence base for clinical trial QA and introduce innovative prospective trial designs to evaluate radiotherapy QA in clinical trials; and 4) Explore the feasibility of consolidating clinical trial QA in the United States.
Conclusion
Radiotherapy QA may impact clinical trial accrual, cost, outcomes and generalizability. To achieve maximum benefit, QA programs must become more efficient and evidence-based.
doi:10.1016/j.ijrobp.2011.12.080
PMCID: PMC3361528  PMID: 22425219
clinical trial design; credentialing; radiotherapy; quality assurance
17.  Gene Expression Profile of Coronary Artery cells Treated with Non-steroidal Anti-inflammatory Drugs Reveals Off-target Effects 
Non-steroidal anti-inflammatory drugs (NSAIDs) have come under scrutiny because of the gastrointestinal, renal and cardiovascular toxicity associated with prolonged use of these drugs. The purpose of this study was to identify molecular targets for NSAIDs related to cellular toxicity with a view to optimize drug efficacy in clinic. Coronary artery smooth muscle cells (CASMC) and endothelial cells (HCAEC) were treated with low (clinically achievable) and high (typically used in preclinical studies) concentrations of celecoxib (CXB), NS398 (NS) and ibuprofen (IBU) for 24h. NSAIDs-induced gene expression changes were evaluated by microarray analysis and validated by real-time RT-PCR and western blotting. The functional significance of differentially expressed genes was evaluated by Ingenuity Pathway Analysis (IPA). At high concentrations, NSAIDs altered the expression of genes regulating cell proliferation and cell death. NSAIDs also altered genes associated with cardiovascular functions including inflammation, thrombosis, fibrinolysis, coronary artery disease and hypertension. The gene expression was most impacted by IBU, CXB and NS, in that order. This study revealed that NSAIDs altered expression of an array of genes associated with cardiovascular events and emphasizes the potential for fingerprinting drugs in preclinical studies to assess the potential drug toxicity and to optimize the drug efficacy in clinical settings.
doi:10.1097/FJC.0b013e31824ba6b5
PMCID: PMC3370396  PMID: 22668799
NSAIDs; HCAEC; CASMC; Microarray; Cardiovascular genes
18.  From Mice and Men to Earth and Space: Joint NASA-NCI Workshop on Lung Cancer Risk Resulting from Space and Terrestrial Radiation 
Cancer research  2011;71(22):6926-6929.
On June 27–28, 2011 scientists from the National Cancer Institute (NCI), NASA, and academia met in Bethesda to discuss major lung cancer issues confronting each organization. For NASA – available data suggest lung cancer is the largest potential cancer risk from space travel for both men and women and quantitative risk assessment information for mission planning is needed. In space the radiation risk is from high energy and charge (HZE) nuclei (such as Fe) and high energy protons from solar flares and not from gamma radiation. By contrast the NCI is endeavoring to estimate the increased lung cancer risk from the potential wide-spread implementation of computed tomography (CT) screening in individuals at high risk for developing lung cancer based on the National Lung Cancer Screening Trial (NLST). For the latter, exposure will be x-rays from CT scans from the screening (which uses “low dose” CT scans) and also from follow-up scans used to evaluate abnormalities found during initial screening. Topics discussed included the risk of lung cancer arising after HZE particle, proton, and low dose Earth radiation exposure. The workshop examined preclinical models, epidemiology, molecular markers, “omics” technology, radiobiology issues, and lung stem cells (LSC) that relate to the development of lung cancer.
doi:10.1158/0008-5472.CAN-11-2546
PMCID: PMC3217106  PMID: 21900398
19.  Radiation Injury Treatment Network (RITN): Healthcare professionals preparing for a mass casualty radiological or nuclear incident 
Purpose
To describe the history, composition, and activities of the Radiation Injury Treatment Network (RITN). The Radiation Injury Treatment Network® is a cooperative effort of the National Marrow Donor Program and the American Society for Blood and Marrow Transplantation. The goals of RITN are to educate hematologists, oncologists, and stem cell transplant practitioners about their potential involvement in the response to a radiation incident and provide treatment expertise. Injuries to the marrow system readily occur when a victim is exposed to ionising radiation. This focus therefore leverages the expertise of these specialists who are accustomed to providing the intensive supportive care required by patients with a suppressed marrow function. Following a radiological incident, RITN centres may be asked to: Accept patient transfers to their institutions; provide treatment expertise to practitioners caring for victims at other centres; travel to other centres to provide medical expertise; or provide data on victims treated at their centres. Moving forward, it is crucial that we develop a coordinated interdisciplinary approach in planning for and responding to radiological and nuclear incidents. The ongoing efforts of radiation biologists, radiation oncologists, and health physicists can and should complement the efforts of RITN and government agencies.
Conclusion
RITN serves as a vital partner in preparedness and response efforts for potential radiological and nuclear incidents.
doi:10.3109/09553002.2011.556176
PMCID: PMC3192327  PMID: 21801106
radiation accidents; cell therapy; haematology–radiation; radiation injury; emergency response; emergency preparedness
21.  An Interventional Magnetic Resonance Imaging Technique for the Molecular Characterization of Intraprostatic Dynamic Contrast Enhancement 
Molecular Imaging  2005;4(1):63-66.
The biological characterization of an individual patient’s tumor by noninvasive imaging will have an important role in cancer care and clinical research if the molecular processes that underlie the image data are known. Spatial heterogeneity in the dynamics of magnetic resonance imaging contrast enhancement (DCE-MRI) is hypothesized to reflect variations in tumor angiogenesis. Here we demonstrate the feasibility of precisely colocalizing DCE-MRI data with the genomic and proteomic profiles of underlying biopsy tissue using a novel MRI-guided biopsy technique in patients with prostate cancer.
PMCID: PMC3299492  PMID: 15967127
Angiogenesis; molecular imaging; interventional MRI; prostate cancer; micro-array analysis
22.  Transrectal Prostate Biopsy and Fiducial Marker Placement in a Standard 1.5T Magnetic Resonance Imaging Scanner 
The Journal of Urology  2006;175(1):113-120.
Purpose
We investigated the accuracy and feasibility of a system that provides transrectal needle access to the prostate concurrent with 1.5 Tesla MRI which previously has not been possible.
Materials and Methods
In 5 patients with previously diagnosed prostate cancer, MRI guided intraprostatic placement of gold fiducial markers (4 procedures) and/or prostate biopsy (3 procedures) was performed using local anesthesia.
Results
Mean procedure duration was 76 minutes and all patients tolerated the intervention well. Procedure related adverse events included self-limited hematuria and hematochezia following 3 of 8 procedures (all resolved in less than 1 week). Mean needle placement accuracy was 1.9 mm for the fiducial marker placement studies and 1.8 mm for the biopsy procedures. Mean fiducial marker placement accuracy was 4.8 mm and the mean fiducial marker placement accuracy transverse to the needle direction was 2.6 mm. All patients who underwent the procedure were able to complete their course of radiotherapy without delay or complication.
Conclusions
While studies of clinical usefulness are warranted, transrectal 1.5 T MRI guided prostate biopsy and fiducial marker placement is feasible using this system, providing new opportunities for image guided diagnostic and therapeutic prostate interventions.
doi:10.1016/S0022-5347(05)00065-0
PMCID: PMC3299542  PMID: 16406885
magnetic resonance imaging; prostate; prostatic neoplasms; biopsy; radiology; interventional
23.  Addressing Cancer Disparities Among American Indians through Innovative Technologies and Patient Navigation: The Walking Forward Experience 
Purpose/Objective(s): American Indians (AIs) present with more advanced stages of cancer and, therefore, suffer from higher cancer mortality rates compared to non-AIs. Under the National Cancer Institute (NCI) Cancer Disparities Research Partnership (CDRP) Program, we have been researching methods of improving cancer treatment and outcomes since 2002, for AIs in Western South Dakota, through the Walking Forward (WF) Program. Materials/Methods: This program consists of (a) a culturally tailored patient navigation program that facilitated access to innovative clinical trials in conjunction with a comprehensive educational program encouraging screening and early detection, (b), surveys to evaluate barriers to access, (c) clinical trials focusing on reducing treatment length to facilitate enhanced participation using brachytherapy and intensity modulated radiotherapy (IMRT) for breast and prostate cancer, as AIs live a median of 140 miles from the cancer center, and (d) a molecular study (ataxia telangiectasia mutated) to address whether there is a specific profile that increases toxicity risks. Results: We describe the design and implementation of this program, summary of previously published results, and ongoing research to influence stage at presentation. Some of the critical outcomes include the successful implementation of a community-based research program, development of trust within tribal communities, identification of barriers, analysis of nearly 400 navigated cancer patients, clinical trial accrual rate of 10%, and total enrollment of nearly 2,500 AIs on WF research studies. Conclusion: This NCI funded pilot program has achieved some initial measures of success. A research infrastructure has been created in a community setting to address new research questions and interventions. Efforts underway to promote cancer education and screening are presented, as well as applications of the lessons learned to other health disparity populations – both nationally and internationally.
doi:10.3389/fonc.2011.00011
PMCID: PMC3355933  PMID: 22649752
patient navigation; American Indians; cancer disparities; radiation oncology
24.  NS-398, Ibuprofen and COX-2 RNAi produce significantly different gene expression profiles in prostate cancer cells 
Molecular cancer therapeutics  2009;8(1):261-273.
Cyclooxygenase-2 (COX-2) plays a significant role in tumor development and progression. Nonsteroidal anti-inflammatory drugs (NSAIDs) exhibit potent anticancer effects in vitro and in vivo by COX-2 dependent and independent mechanisms. In this study, we used microarray analysis to identify the change of expression profile regulated by a COX-2 specific NSAID NS-398 (0.01 and 0.1mM), a non-specific NSAID ibuprofen (0.1 and 1.5mM) and RNA interference-mediated COX-2 inhibition (COX-2 RNAi) in PC3 prostate cancer cells. A total of 3,362 differentially expressed genes with 2 fold change, and p<0.05 were identified. Low concentrations of NSAIDs and COX-2 RNAi altered very few genes (1-3%) compared to the higher concentration of NS-398 (17%) and ibuprofen (80%). Ingenuity Pathway Analysis (IPA) was used for distributing the differentially expressed genes into biological networks and for evaluation of functional significance. The top 3 networks for the both NSAIDs included functional categories DNA replication, recombination and repair, and gastrointestinal disease. Immune response function was specific to NS-398, and cell cycle, cellular movement were among the top functions for ibuprofen. IPA also identified renal and urological disease as a function specific for ibuprofen. This comprehensive study identified several COX-2 independent targets of NSAIDs which may help explain the antitumor and radiosensitizing effects of NSAIDs. However, none of these categories were reflected in the identified networks in PC3 cells treated with clinically relevant low concentrations of NS-398 and ibuprofen or with COX-2 RNAi suggesting the benefit to fingerprinting pre-clinical drug concentrations to improve their relevance to the clinical setting.
doi:10.1158/1535-7163.MCT-08-0928
PMCID: PMC2861287  PMID: 19139136
microarray; NSAIDs; COX-2; NS-398; ibuprofen; COX-2 RNAi
25.  MRI-GUIDED HDR PROSTATE BRACHYTHERAPY IN STANDARD 1.5T SCANNER 
Purpose:
Magnetic resonance imaging (MRI) provides superior visualization of the prostate and surrounding anatomy, making it the modality of choice for imaging the prostate gland. This pilot study was performed to determine the feasibility and dosimetric quality achieved when placing high-dose-rate prostate brachytherapy catheters under MRI guidance in a standard “closed-bore” 1.5T scanner.
Methods and Materials:
Patients with intermediate-risk and high-risk localized prostate cancer received MRI-guided high-dose-rate brachytherapy boosts before and after a course of external beam radiotherapy. Using a custom visualization and targeting program, the brachytherapy catheters were placed and adjusted under MRI guidance until satisfactory implant geometry was achieved. Inverse treatment planning was performed using high-resolution T2-weighted MRI.
Results:
Ten brachytherapy procedures were performed on 5 patients. The median percentage of volume receiving 100% of prescribed minimal peripheral dose (V100) achieved was 94% (mean, 92%; 95% confidence interval, 89–95%). The urethral V125 ranged from 0% to 18% (median, 5%), and the rectal V75 ranged from 0% to 3.1% (median, 0.3%). In all cases, lesions highly suspicious for malignancy could be visualized on the procedural MRI, and extracapsular disease was identified in 2 patients.
Conclusion:
High-dose-rate prostate brachytherapy in a standard 1.5T MRI scanner is feasible and achieves favorable dosimetry within a reasonable period with high-quality image guidance. Although the procedure was well tolerated in the acute setting, additional follow-up is required to determine the long-term safety and efficacy of this approach.
doi:10.1016/j.ijrobp.2004.01.016
PMCID: PMC2396328  PMID: 15275727
Prostate cancer; Brachytherapy; MRI; Image guidance

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