CTC service heterogeneity and design of a workforce calculator.

AIM: To determine the level of heterogeneity in delivery of computed tomography (CT) colonography services and develop a workforce calculator that accommodates the variation identified. MATERIALS AND METHODS: A national survey, based on the "WHO workforce indicators of staffing need", established activity standards for essential tasks in delivery of the service. From these data a workforce calculator was designed to guide the required staffing and equipment resource by service size. RESULTS: Activity standards were established as mode responses >70%. Service homogeneity was greater in areas where professional standards and guidance were available. The mean service size was 1,101. Did not attend (DNA) rates were lower where direct booking was available (p<0.0001). Service sizes were larger where radiographer reporting was embedded in reporting paradigms (p<0.024). CONCLUSION: The survey identified benefits of radiographer-led direct booking and reporting. The workforce calculator derived from the survey provides a framework to guide the resourcing of expansion while maintaining standards.

The CanPain SCI Clinical Practice Guidelines for Rehabilitation Management of Neuropathic Pain after Spinal Cord: introduction, methodology and recommendation overview.

STUDY DESIGN: Clinical practice guidelines. OBJECTIVES: The objective was to develop the first Canadian clinical practice guidelines for the management of neuropathic pain in people with spinal cord injury (SCI). SETTING: The guidelines are relevant for inpatient and outpatient SCI rehabilitation settings in Canada. METHODS: The guidelines were developed in accordance with the Appraisal of Guidelines for Research and Evaluation II tool. A Steering Committee and Working Group reviewed the relevant evidence on neuropathic pain management (encompassing screening and diagnosis, treatment and models of care) after SCI. The quality of evidence was scored using Grading of Recommendations Assessment, Development and Evaluation (GRADE). A consensus process was followed to achieve agreement on recommendations and clinical considerations. RESULTS: The Working Group developed 12 recommendations for screening and diagnosis, 12 recommendations for treatment and 5 recommendations for models of care. Important clinical considerations accompany each recommendation. CONCLUSIONS: The Working Group recommendations for the management of neuropathic pain after SCI should be used to inform practice.

The CanPain SCI Clinical Practice Guidelines for Rehabilitation Management of Neuropathic Pain after Spinal Cord: Recommendations for treatment.

STUDY DESIGN: Clinical practice guidelines. OBJECTIVES: To develop the first Canadian clinical practice guidelines for treatment of neuropathic pain in people with spinal cord injury (SCI). SETTING: The guidelines are relevant for inpatient and outpatient SCI rehabilitation settings in Canada. METHODS: The CanPainSCI Working Group reviewed the evidence for different treatment options and achieved consensus. The Working Group then developed clinical considerations for each recommendation. Recommendations for research are also included. RESULTS: Twelve recommendations were developed for the management of neuropathic pain after SCI. The recommendations address both pharmacologic and nonpharmacologic treatment modalities. CONCLUSIONS: An expert Working Group developed recommendations for the treatment of neuropathic pain after SCI that should be used to inform practice.

The CanPain SCI Clinical Practice Guideline for Rehabilitation Management of Neuropathic Pain after Spinal Cord: recommendations for model systems of care.

STUDY DESIGN: Clinical practice guidelines. OBJECTIVES: The project objectives were to develop the first Canadian recommendations on a model of care for the management of at- and below-level neuropathic pain in people with spinal cord injury (SCI). SETTING: The guidelines are relevant for inpatient and outpatient SCI rehabilitation settings in Canada. METHODS: On the basis of a review of the Accreditation Canada standards, the Steering Committee developed questions to guide the CanPainSCI Working Group when developing the recommendations. The Working Group agreed on recommendations through a consensus process. RESULTS: The Working Group developed five recommendations for the organization of neuropathic pain rehabilitation care in people with SCI. CONCLUSIONS: The Working Group recommendations for a model of care for at- and below-level neuropathic pain after SCI should be used to inform clinical practice.

The CanPain SCI Clinical Practice Guidelines for Rehabilitation Management of Neuropathic Pain after Spinal Cord: screening and diagnosis recommendations.

STUDY DESIGN: Clinical practice guidelines. OBJECTIVES: To develop the first Canadian clinical practice guidelines for screening and diagnosis of neuropathic pain in people with spinal cord injury (SCI). SETTING: The guidelines are relevant for inpatient and outpatient SCI rehabilitation settings in Canada. METHODS: The CanPainSCI Working Group reviewed evidence to address clinical questions regarding screening and diagnosis of neuropathic pain after SCI. A consensus process was followed to achieve agreement on recommendations and clinical considerations. RESULTS: Twelve recommendations, based on expert consensus, were developed for the screening and diagnosis of neuropathic pain after SCI. The recommendations address methods for assessment, documentation tools, team member accountability, frequency of screening and considerations for diagnostic investigation. Important clinical considerations accompany each recommendation. CONCLUSIONS: The expert Working Group developed recommendations for the screening and diagnosis of neuropathic pain after SCI that should be used to inform practice.

Prevention of post-dural puncture headache in parturients: a systematic review and meta-analysis.

Post-dural puncture headaches (PDPHs) present an important clinical problem. We assessed methods to decrease accidental dural punctures (ADPs) and interventions to reduce PDPH following ADP. Multiple electronic databases were searched for randomised clinical trials (RCTs) of parturients having labour epidurals, in which the studied intervention could plausibly affect ADP or PDPH, and the incidence of at least one of these was recorded. Forty RCTs (n = 11,536 epidural insertions) were included, studying combined spinal-epidurals (CSEs), loss of resistance medium, prophylactic epidural blood patches, needle bevel orientation, ultrasound-guided insertion, epidural morphine, Special Sprotte needles, acoustic-guided insertion, administration of cosyntropin, and continuous spinal analgesia. The RCTs for CSE, loss of resistance medium, and prophylactic epidural blood patches were meta-analysed. Five methods reduced PDPH: prophylactic epidural blood patch {four trials, median quality score = 2, risk difference = -0.48 [95% confidence interval (CI): -0.88 to -0.086]}, lateral positioning of the epidural needle bevel upon insertion (one trial, quality score = 1), Special Sprotte needles [one trial, quality score = 5, risk difference = -0.44 (95% CI: -0.67 to -0.21)], epidural morphine [one trial, quality score = 4, risk difference = -0.36 (95% CI -0.59 to -0.13)], and cosyntropin [one trial, quality score = 5, risk difference = -0.36 (95% CI -0.55 to -0.16)]. Several methods potentially reduce PDPH. Special Sprotte needles, epidural morphine, and cosyntropin are thus far each supported by a single, albeit good quality trial. Prophylactic blood patches are supported by three trials, but these had flawed methodology. Mostly, trials were of limited quality, and further well-conducted, large studies are needed.

Distinct effects on gene expression of chemical and genetic manipulation of the cancer epigenome revealed by a multimodality approach.

We tested the hypothesis that the effects on gene expression of altered DNA methylation by 5-aza-2'-deoxycytidine (5-aza-CdR) and genetic (DNMT knockout) manipulation of DNA are similar, and distinct from Trichostatin A (TSA)-induced chromatin decondensation. Surprisingly, the effects of 5-aza-CdR were more similar to those of TSA than to DNMT1, DNMT3B, or double DNMT somatic cell knockout. Furthermore, the effects of 5-aza-CdR were similar at one and five days exposure, suggesting active demethylation or direct influence of both drugs on the stability of methylation and/or chromatin marks. Agents that induce gene activation through hypomethylation may have unintended consequences, since nearly as many genes were downregulated as upregulated after demethylation. In addition, a 75 kb cluster of metallothionein genes was coordinately regulated.

Regional pulmonary blood flow in the lung of the chicken.

It is known that alterations in respiratory gases in birds can cause a nonhomogenous redistribution of pulmonary blood flow between the 2 separate gas-exchanging regions of the avian lung, the paleopulmo (PALEO) and neopulmo (NEO); however, the effect of alterations in respired gas content on the distribution of pulmonary blood flow in birds, such as the chicken, that possess a highly developed NEO is not known. This study used a colorimetric microsphere method to determine the effects of hypoxia and hypercapnia on the relative distribution of pulmonary blood flow in anesthetized chickens (Gallus domesticus) during control (normoxic) and experimental (hypoxic or hypercapnic) conditions, where the relative regional distribution of blood flow in the lung is expressed as the ratio NEO/PALEO. Administration of a hypoxic gas mixture (16.0% O(2)) produced a 13.4% increase in NEO/PALEO, and, administration of a hypercapnic gas mixture (5.0% CO(2)) resulted in a 27.8% increase in NEO/PALEO. Our results are consistent with a mechanism in which the regional redistribution of pulmonary blood flow is mediated by local intrapulmonary factors.

What is the impact of CT colonography interpretation by advanced practitioner radiographers on delivery of the 28 day colorectal cancer target?

INTRODUCTION: CT Colonography (CTC) is an indicated test to assess the colon and rectum for evidence of polyps and neoplasms. The advanced practitioner radiographer (APR) is increasingly involved with the entirety of the radiology pathway including procedural modification, preliminary clinical evaluation (PCE) and multi-disciplinary team (MDT) meeting notification of high risk colonic pathologies. METHODS: A retrospective audit of the Radiology Information System (RIS) was undertaken at a large secondary care centre, 12 months of data of 119 consecutive patients who had undergone CTC with summary coded reports of high risk pathology were included for analysis. Analysis of accuracy of procedural modification, PCE and impact of hypothesised earlier full radiological staging data being available for MDT discussions were measured and evaluated. RESULTS: For high risk C4b studies, just 16.67% of colonic pathology was observed during the CTC study, rising to 79% during radiographer PCE. For likely colonic neoplasm C5a studies 86% of colonic pathology was observed during the CTC study, rising to 93% during radiographer PCE. Where subsequent CT chest staging was deemed necessary following CTC by the referring team, patients had a median wait of 34 days for completion CT chest scan staging. CONCLUSION: This study supports the integration of the advanced practitioner radiographer into the entire radiological processes of a CTC, with time advantages apparent for both diagnostics, but also the decision to treat. IMPLICATIONS FOR PRACTICE: Appropriately trained radiographers are able to support CTC services to ensure delivery of an effective two-week wait diagnostic service with direct MDT liaison.

Radiation Therapy for Local Cutaneous Melanoma.

While primary treatment for melanoma consists of surgical resection and chemotherapeutics, radiation can be used as either definitive or adjuvant therapy in certain clinical scenarios. This chapter aims to explore the indications for primary definitive radiotherapy as well as adjuvant treatment following resection. Delivery, dose, fractionation, and toxicity of radiation treatment will be discussed. As our understanding of melanoma tumor biology increases, the role of radiotherapy may expand for more effective treatment of oligometastatic disease.

Current videofluoroscopy practice in the United Kingdom: A survey of imaging professionals.

INTRODUCTION: Videofluoroscopy (VFSS) is a frequently used radiological investigation for dysphagia and is conducted within a radiology setting by speech and language therapists (SLTs) working alongside imaging personnel (radiologists and/or radiographers). Previous surveys of SLT practice have reported variability in VFSS protocols and procedures. The aim of this study was to explore current clinical practice for VFSS from the perspective of imaging personnel engaged in VFSS within the United Kingdom. METHODS: A comprehensive online survey enabled exploration of current practices of imaging professionals. Target participants were diagnostic imaging personnel (radiographers and radiologists) with experience of working in VFSS clinics. Descriptive statistics describe and summarise the data alongside inferential statistics where appropriate. RESULTS: 54 survey participants represented 40 unique acute healthcare organisations in the UK, in addition to two respondents from the Republic of Ireland. The survey demonstrated high variance in clinical practice across all stages of the VFSS procedure. Clinicians were not always compliant with current UK guidelines and the roles and responsibilities of different professionals working within the clinics were often not clearly defined. CONCLUSION: Further research is required to develop new international, interprofessional VFSS guidelines to standardise service delivery for VFSS, improving diagnostic accuracy, efficiency and patient experience. IMPLICATIONS FOR PRACTICE: In the absence of VFSS guidelines for imaging personnel, practitioners should familiarise themselves with the UK Royal College of Speech and Language Therapists VFSS Position paper; IR (ME)R guidelines and DRLs for the client groups with which they work to guide clinics and improve practice. Clinicians should revisit protocols and clinical governance regarding safe practice in order to improve the quality of care within the VFSS clinic.

Clinical practice guidelines for videofluoroscopic swallowing studies: A systematic review.

INTRODUCTION: Clinical practice guidelines (CPGs) are expected to make evidence-based recommendations, thus guiding practice and reducing unwarranted variation. CPGs are particularly helpful in guiding complex procedures such as the Videofluoroscopic Swallowing Study (VFSS) for the assessment of dysphagia, but there is a suspected high level of variability among them. To explore the extent of this variation, this study aimed to systematically identify and appraise all VFSS CPGs available worldwide. METHODS: A systematic search of 3 academic databases and other sources was conducted to identify relevant CPGs; independent reviews of each CPG were undertaken by a Speech and Language Therapist and a Radiographer. Both reviewers completed a pre-determined checklist of expected professional content for each CPG. CPGs were then assessed for quality using the Appraisal of Guidance for Research & Evaluation II (AGREE II) instrument. Findings from the professional content review and the methodological quality review were synthesised to inform an assessment of suitability of each CPG to inform clinical practice. RESULTS: Seven VFSS CPGs were identified worldwide, none of which were co-designed by radiographers or aimed at a radiographer audience. Each differs in their professional content, recommendations, underpinning evidence base and professional focus. Average AGREE ll scores across the quality domains vary considerably, ranging from 93 to 22%. No CPGs scored highly on all six AGREE II domains. CONCLUSION: There is no standardisation between VFSS guidelines. Six CPGs are not recommended for clinical use; only one of the seven identified CPGs is recommended for use following significant modification. IMPLICATIONS FOR PRACTICE: The lack of a comprehensive, evidence-based guideline encourages unwarranted variation in clinical practice which potentially compromises clinical care. Further research is needed to define VFSS best practice.

DNMT1 as a molecular target in a multimodality-resistant phenotype in tumor cells.

We have previously shown that hydrogen peroxide-resistant permanent (OC-14) cells are resistant to the cytotoxicity of several exogenous oxidative and anticancer agents including H(2)O(2), etoposide, and cisplatin; and we refer to this process as an oxidative multimodality-resistant phenotype (MMRP). Furthermore, OC-14 cells contain increased activator protein 1 activity, and inhibition of activator protein 1 reversed the MMRP. In this study, we show that permanent Rat-1 cell lines genetically altered to overexpress c-Fos also displayed a similar MMRP to H(2)O(2), etoposide, and cisplatin as OC-14 cells. Gene expression analysis of the OC-14 cells and c-Fos-overexpressing cells showed increased DNMT1 expression. Where OC-14 and c-Fos-overexpressing cells were exposed to 5-aza-2'-deoxycytidine, which inhibits DNMT activity, a significant but incomplete reversal of the MMRP was observed. Thus, it seems logical to suggest that DNMT1 might be at least one target in the MMRP. Rat-1 cells genetically altered to overexpress DNMT1 were also shown to be resistant to the cytotoxicity of H(2)O(2), etoposide, and cisplatin. Finally, somatic HCT116 knockout cells that do not express either DNMT1 (DNMT1(-/-)) or DNMT3B (DNMT3B(-/-)) were shown to be more sensitive to the cytotoxicity of H(2)O(2), etoposide, and cisplatin compared with control HCT116 cells. This work is the first example of a role for the epigenome in tumor cell resistance to the cytotoxicity of exogenous oxidative (H(2)O(2)) or systemic (etoposide and cisplatin) agents and highlights a potential role for DNMT1 as a potential molecular target in cancer therapy.

Profiling microdissected epithelium and stroma to model genomic signatures for cervical carcinogenesis accommodating for covariates.

This study is the first comprehensive, integrated approach to examine grade-specific changes in gene expression along the entire neoplastic spectrum of cervical intraepithelial neoplasia (CIN) in the process of cervical carcinogenesis. This was accomplished by identifying gene expression signatures of disease progression using cDNA microarrays to analyze RNA from laser-captured microdissected epithelium and underlying stroma from normal cervix, graded CINs, cancer, and patient-matched normal cervical tissues. A separate set of samples were subsequently validated using a linear mixed model that is ideal to control for interpatient gene expression profile variation, such as age and race. These validated genes were ultimately used to propose a genomically based model of the early events in cervical neoplastic transformation. In this model, the CIN 1 transition coincides with a proproliferative/immunosuppression gene signature in the epithelium that probably represents the epithelial response to human papillomavirus infection. The CIN 2 transition coincides with a proangiogenic signature, suggesting a cooperative signaling interaction between stroma and tumor cells. Finally, the CIN 3 and squamous cell carcinoma antigen transition coincide with a proinvasive gene signature that may be a response to epithelial tumor cell overcrowding. This work strongly suggests that premalignant cells experience a series of microenvironmental stresses at the epithelium/stroma cell interface that must be overcome to progress into a transformed phenotype and identifies the order of these events in vivo and their association with specific CIN transitions.

Abdominal radiograph preliminary clinical evaluation image test bank project.

INTRODUCTION: Literature documenting preliminary clinical evaluation (PCE) commonly focuses on the evaluation of musculoskeletal radiographs. Despite this, the professional body suggest that a diagnostic radiographer should be able to provide a PCE for any radiograph. METHODS: An image bank of 30 abdominal radiographs was designed comprising of 17 abnormal cases with a range of pathologies which one could expect to encounter in the emergency department (ED). Participants' were asked to select one of four taxonomies to represent their PCE for each radiograph. Participants' answers were compared to a gold standard PCE taxonomy based on the radiological report. Inferential statistics were applied to assess for any significant different in accuracy between NHS pay bands of the participants. RESULTS: On average participants selected an abdominal radiograph PCE taxonomy with a sensitivity of 75.2% and a specificity of 75.7%. Whilst band 7 radiographers selected the most accurate abdominal radiograph PCE and had the highest area under curve (AUC), no significant difference was found in the PCE categorisation of abdominal radiographs by radiographers of all pay bands. CONCLUSION: Participants' have shown good sensitivity in recognising prominent findings on abdominal radiographs. This sensitivity is however reduced when assessing less obvious radiographic appearances, illustrating areas where additional training would be beneficial. The study provides evidence towards the consideration of an expansion of current practice regarding the implementation of a scheme of abdominal radiograph PCE. Further research with a larger cohort of participants' and a lower abnormal case prevalence would be beneficial to the limited research base.

Epigenetic silencing of novel tumor suppressors in malignant melanoma.

Malignant melanoma is a common and frequently lethal disease. Current therapeutic interventions have little effect on survival, emphasizing the need for a better understanding of the genetic, epigenetic, and phenotypic changes in melanoma formation and progression. We identified 17 genes that were not previously known to be silenced by methylation in melanoma using a microarray-based screen following treatment of melanoma cell lines with the DNA methylation inhibitor 5-Aza-2'-deoxycytidine. Eight of these genes have not been previously shown to undergo DNA methylation in any form of cancer. Three of the genes, QPCT, CYP1B1, and LXN, are densely methylated in >95% of uncultured melanoma tumor samples. Reexpression of either of two of the silenced genes, HOXB13 and SYK, resulted in reduced colony formation in vitro and diminished tumor formation in vivo, indicating that these genes function as tumor suppressors in melanoma.

Distinct effects of ionizing radiation on in vivo murine kidney and brain normal tissue gene expression.

PURPOSE: There is a growing awareness that radiation-induced normal tissue injury in late-responding organs, such as the brain, kidney, and lung, involves complex and dynamic responses between multiple cell types that not only lead to targeted cell death but also acute and chronic alterations in cell function. The specific genes involved in the acute and chronic responses of these late-responding normal tissues remain ill defined; understanding these changes is critical to understanding the mechanism of organ damage. As such, the aim of the present study was to identify candidate genes involved in the development of radiation injury in the murine kidney and brain using microarray analysis. EXPERIMENTAL DESIGN: A multimodality experimental approach combined with a comprehensive expression analysis was done to determine changes in normal murine tissue gene expression at 8 and 24 hours after irradiation. RESULTS: A comparison of the gene expression patterns in normal mouse kidney and brain was strikingly different. This observation was surprising because it has been long assumed that the changes in irradiation-induced gene expression in normal tissues are preprogrammed genetic changes that are not affected by tissue-specific origin. CONCLUSIONS: This study shows the potential of microarray analysis to identify gene expression changes in irradiated normal tissue cells and suggests how normal cells respond to the damaging effects of ionizing radiation is complex and markedly different in cells of differing origin.

Histone deacetylases in acute myeloid leukaemia show a distinctive pattern of expression that changes selectively in response to deacetylase inhibitors.

Histone deacetylase inhibitors (HDIs) are a new class of drugs with significant antileukemic activity. To explore mechanisms of disease-specific HDI activity in acute myeloid leukaemia (AML), we have characterised expression of all 18 members of the histone deacetylase family in primary AML blasts and in four control cell types, namely CD34+ progenitors from umbilical cord, either quiescent or cycling (post-culture), cycling CD34+ progenitors from GCSF-stimulated adult donors and peripheral blood mononuclear cells. Only SIRT1 was consistently overexpressed (>2 fold) in AML samples compared with all controls, while HDAC6 was overexpressed relative to adult, but not neo-natal cells. HDAC5 and SIRT4 were consistently underexpressed. AML blasts and cell lines, exposed to HDIs in culture, showed both histone hyperacetylation and, unexpectedly, specific hypermethylation of H3 lysine 4. Such treatment also modulated the pattern of HDAC expression, with strong induction of HDAC11 in all myeloid cells tested and with all inhibitors (valproate, butyrate, TSA, SAHA), and lesser, more selective, induction of HDAC9 and SIRT4. The distinct pattern of HDAC expression in AML and its response to HDIs is of relevance to the development of HDI-based therapeutic strategies and may contribute to observed patterns of clinical response and development of drug resistance.

Indomethacin-induced radiosensitization and inhibition of ionizing radiation-induced NF-kappaB activation in HeLa cells occur via a mechanism involving p38 MAP kinase.

Although ionizing radiation (IR) activates multiple cellular factors that vary depending on dose and tissue specificity, the activation of NF-kappaB appears to be a well-conserved response in tumor cells exposed to IR. Recently, it also has been demonstrated that nonsteroidal anti-inflammatory agents inhibit tumor necrosis factor and interleukin-1-induced NF-kappaB activation and act as radiosensitizing agents. These observations reinforce the growing notion that NF-kappaB may be a protective cellular factor responding to the cytotoxicity of IR and other damaging stimuli. As such, we addressed the idea and mechanism that NF-kappaB is a downstream target of the nonsteroidal anti-inflammatory agent indomethacin and is involved in the process of radiosensitization. In this study, we report that indomethacin inhibited IR-induced activation of NF-kappaB and sensitized HeLa cells to IR-induced cytotoxicity at similar concentrations. Pretreatment of HeLa cells with SB 203580, a pyridinyl imidazole compound that specifically inhibits p38 mitogen-activated protein kinase (MAPK), abrogated the ability of indomethacin to inhibit IR-induced activation of NF-kappaB and diminished the indomethacin radiosensitizing effect. In addition, the transient genetic activation of p38(MAPK) inhibited IR induction of NF-kappaB gene expression in the absence of indomethacin. Finally, permanently transfected cell lines genetically unable to activate NF-kappaB, because of expression of a dominant negative I-kappaBalpha gene, demonstrated increased sensitivity to IR-induced cytotoxicity. Taken together, these results suggest that p38 MAPK is a target involved in indomethacin-induced radiosensitization and that NF-kappaB may be one downstream target in this process.

Thioredoxin reductase as a potential molecular target for anticancer agents that induce oxidative stress.

Redox-sensitive signaling factors regulate multiple cellular processes, including proliferation, cell cycle, and prosurvival signaling cascades, suggesting their potential as molecular targets for anticancer agents. It is logical to set constraints that a molecular target should meet at least one of the following criteria: (1) inhibition of prosurvival signaling pathways; (2) inhibition of cell cycle progression; or (3) enhancement of the cytotoxic effects of anticancer agents. Therefore, we hypothesized that thioredoxin reductase 1 (TR), a component of several redox-regulated pathways, might represent a potential molecular target candidate in response to agents that induce oxidative stress. To address this issue, permanent cell lines overexpressing either the wild-type (pCXN2-myc-TR-wt) or a Cys-Ser mutant (pCXN2-myc-mTR) TR gene were used, as were parental HeLa cells treated with 1-methyl-1-propyl-2-imidazolyl disulfide (IV-2), a pharmacologic inhibitor of TR. Cells were exposed to the oxidative stressors, H2O2 and ionizing radiation (IR), and analyzed for changes in signal transduction, cell cycle, and cytotoxicity. Analysis of HeLa cells overexpressing the pCXN2-myc-TR-wt gene showed increased basal activity of nuclear factor kappaB (NFkappaB) and activator protein (AP-1), whereas HeLa cells expressing a pCXN2-myc-mTR gene and HeLa cells treated with IV-2 were unable to induce NFkappaB or AP-1 activity following H2O2 or IR exposure. Fluorescence-activated cell sorting analysis showed a marked accumulation of pCXN2-myc-mTR cells in the late G1 phase, whereas pCXN2-myc-TR-wt cells showed a decreased G1 subpopulation. Chemical inhibition of TR with IV-2 also completely inhibited cellular proliferation at concentrations between 10 and 25 micromol/L, resulting in a G1 phase cell cycle arrest consistent with the results from cells expressing the pCXN2-myc-mTR gene. Following exposure to H2O2 and IR, pCXN2-myc-mTR- and IV-2-treated cells were significantly more sensitive to oxidative stress-induced cytotoxicity as measured by clonogenic survival assays. Finally, IV-2-treated cells showed increased tumor cell death when treated with H2O2 and IR. These results identify TR as a potential target to enhance the cytotoxic effects of agents that induce oxidative stress, including IR.