Characterizing re-triage guidelines: A scoping review of states' rules and regulations.

BACKGROUND: State guidelines for re-triage, or emergency inter-facility transfer, have never been characterized across the United States. METHODS: All 50 states' Department of Health and/or Trauma System websites were reviewed for publicly available re-triage guidelines within their rules and regulations. Communication was made via phone or email to state agencies or trauma advisory committees to obtain or confirm the absence of guidelines where public data was unavailable. Guideline criteria were abstracted and grouped into domains of Center for Disease Control Field Triage Criteria: pattern/anatomy of injury, vital signs, special populations, and mechanisms of injury. Re-triage criteria were summarized across states using median and interquartile ranges for continuous data and frequencies for categorical data. Demographic data of states with and without re-triage guidelines were compared using the Wilcoxon rank sum test. RESULTS: Re-triage guidelines were identified for 22 of 50 states (44%). Common anatomy of injury criteria included head trauma (91% of states with guidelines), spinal cord injury (82%), chest injury (77%), and pelvic injury (73%). Common vital signs criteria included Glasgow Coma Score (91% of states) ranging from 8 to 14, systolic blood pressure (36%) ranging from 90 to 100 mm Hg, and respiratory rate (23%) with all using 10 respirations/minute. Common special populations criteria included mechanical ventilation (73% of states), age (68%) ranging from <2 or >60 years, cardiac disease (59%), and pregnancy (55%). No significant demographic differences were found between states with versus without re-triage guidelines. CONCLUSION: A minority of US states have re-triage guidelines. Characterizing existing criteria can inform future guideline development.

Medical management of acute radiation syndrome.

Acute radiation syndrome (ARS) is a clinical syndrome involving four organ systems, resulting in the hematopoietic syndrome (HS), gastrointestinal subsyndrome (GIS), neurovascular subsyndrome (NVS) and cutaneous subsyndrome (CS). Since few healthcare providers have seen an ARS case, evidence-based recommendations are needed to guide medical management in a mass casualty scenario. The authors reviewed recommendations from evidence-based and narrative reviews by expert consultants to the World Health Organisation (WHO), a subsequent review of published HS cases, and infectious disease guidelines for management of febrile neutropenia. The WHO Consultancy applied a rigorous grading system to evaluate treatment strategies described in published ARS cases as of 2009, strategies to manage HS in unirradiated persons, results of ARS studies in animal models of ARS, and recommendations of prior expert panels. Major findings for HS were (a) no randomised controlled studies have been performed, (b) data are restricted by the lack of comparator groups, and (c) reports of countermeasures for management of injury to non-hematopoietic organs are often incomplete. Strength of recommendations ranged from strong to weak. Countermeasures of potential benefit include cytokines and for a subgroup of HS patients, hematopoietic stem cell transplantation. These recommendations did not change in a subsequent analysis of HS cases. Recommendations also included fluoroquinolones, bowel decontamination, serotonin receptor antagonists, loperamide and enteral nutrition for GIS; supportive care for NVS; and topical steroids, antihistamines and antibiotics, and surgical excision/grafting for CS. Also reviewed are critical care management guidelines, the role of mesenchymal stem cells for CS, the potential of a platelet-stimulating cytokine for HS, and the author's approach to clinical management of microbial infections associated with ARS based on published guidelines of infectious disease experts. Today's management of HS is supported by evidence-based guidelines. Management of non-HS subsyndromes is supported by a narrative review of the literature and recommendations of infectious disease societies.

Redox signaling by glutathione peroxidase 2 links vascular modulation to metabolic plasticity of breast cancer.

In search of redox mechanisms in breast cancer, we uncovered a striking role for glutathione peroxidase 2 (GPx2) in oncogenic signaling and patient survival. GPx2 loss stimulates malignant progression due to reactive oxygen species/hypoxia inducible factor-α (HIF1α)/VEGFA (vascular endothelial growth factor A) signaling, causing poor perfusion and hypoxia, which were reversed by GPx2 reexpression or HIF1α inhibition. Ingenuity Pathway Analysis revealed a link between GPx2 loss, tumor angiogenesis, metabolic modulation, and HIF1α signaling. Single-cell RNA analysis and bioenergetic profiling revealed that GPx2 loss stimulated the Warburg effect in most tumor cell subpopulations, except for one cluster, which was capable of oxidative phosphorylation and glycolysis, as confirmed by coexpression of phosphorylated-AMPK and GLUT1. These findings underscore a unique role for redox signaling by GPx2 dysregulation in breast cancer, underlying tumor heterogeneity, leading to metabolic plasticity and malignant progression.

Functional succinate dehydrogenase deficiency is a common adverse feature of clear cell renal cancer.

Reduced succinate dehydrogenase (SDH) activity resulting in adverse succinate accumulation was previously considered relevant only in 0.05 to 0.5% of kidney cancers associated with germline SDH mutations. Here, we sought to examine a broader role for SDH loss in kidney cancer pathogenesis/progression. We report that underexpression of SDH subunits resulting in accumulation of oncogenic succinate is a common feature in clear cell renal cell carcinoma (ccRCC) (∼80% of all kidney cancers), with a marked adverse impact on survival in ccRCC patients (n = 516). We show that SDH down-regulation is a critical brake in the TCA cycle during ccRCC pathogenesis and progression. In exploring mechanisms of SDH down-regulation in ccRCC, we report that Von Hippel-Lindau loss-induced hypoxia-inducible factor-dependent up-regulation of miR-210 causes direct inhibition of the SDHD transcript. Moreover, shallow deletion of SDHB occurs in ∼20% of ccRCC. We then demonstrate that SDH loss-induced succinate accumulation contributes to adverse loss of 5-hydroxymethylcytosine, gain of 5-methylcytosine, and enhanced invasiveness in ccRCC via inhibition of ten-eleven translocation (TET)-2 activity. Intriguingly, binding affinity between the catalytic domain of recombinant TET-2 and succinate was found to be very low, suggesting that the mechanism of succinate-induced attenuation of TET-2 activity is likely via product inhibition rather than competitive inhibition. Finally, exogenous ascorbic acid, a TET-activating demethylating agent, led to reversal of the above oncogenic effects of succinate in ccRCC cells. Collectively, our study demonstrates that functional SDH deficiency is a common adverse feature of ccRCC and not just limited to the kidney cancers associated with germline SDH mutations.

B7-H3 and PD-L1 Expression Are Prognostic Biomarkers in a Multi-racial Cohort of Patients with Colorectal Cancer.

BACKGROUND: Immunotherapy has emerged as an effective and durable treatment modality for solid cancers. However, its use in colorectal cancer (CRC) is limited to deficient mismatch repair (dMMR) tumors. As such, assessing immune regulatory proteins from the B7-CD28 family, other than PD-1, PD-L1, and CTLA-4, is critical. This study aimed to evaluate the expression of novel protein regulators in a racially diverse population of patients with CRC. METHODS: A tumor microarray was created for 214 samples from a multiracial patient population with metastatic CRC, and expression of HHLA2, B7-H3, PD-L1, CK7, CK20, and CDX2 was determined. The expression pattern was scored as 0 to 12, based on tumor tissue prevalence and the intensity. Clinical information was obtained by chart review and vital statistics from the National Death Index. Associations between low and high expression groups for each protein by race/ethnic groups were assessed, and Kaplan-Meier curves were plotted to evaluate association with survival. RESULTS: The median age at diagnosis was 61 years, with a female predominance. The majority of the patients were diagnosed with de novo metastatic disease with left-sided, moderately differentiated tumors. There were no racial disparities in the expression of any protein. Overall, a high frequency of tumors had no expression of B7-H3 (62.5%) or PD-L1 (43.5%). Low expression of both PD-L1 and B7-H3 was a significant prognostic biomarker associated with better survival (median overall survival, 43.3 months vs. 24.6 months; P < .01). CONCLUSION: In this multiracial tumor microarray of CRC samples, low PD-L1 and B7-H3 expression was associated with an improved prognosis. There was no significant variation among races with respect to the relevant CRC protein markers.

Deciphering structural bases of intestinal and hepatic selectivity in targeting pregnane X receptor with indole-based microbial mimics.

Microbial metabolite mimicry is a new concept that promises to deliver compounds that have minimal liabilities and enhanced therapeutic effects in a host. In a previous publication, we have shown that microbial metabolites of L-tryptophan, indoles, when chemically altered, yielded potent anti-inflammatory pregnane X Receptor (PXR)-targeting lead compounds, FKK5 and FKK6, targeting intestinal inflammation. Our aim in this study was to further define structure-activity relationships between indole analogs and PXR, we removed the phenyl-sulfonyl group or replaced the pyridyl residue with imidazolopyridyl of FKK6. Our results showed that while removal of the phenyl-sulfonyl group from FKK6 (now called CVK003) shifts agonist activity away from PXR towards the aryl hydrocarbon receptor (AhR), the imidazolopyridyl addition preserves PXR activity in vitro. However, when these compounds are administered to mice, that unlike the parent molecule, FKK6, they exhibit poor induction of PXR target genes in the intestines and the liver. These data suggest that modifications of FKK6 specifically in the pyridyl moiety can result in compounds with weak PXR activity in vivo. These observations are a significant step forward for understanding the structure-activity relationships (SAR) between indole mimics and receptors, PXR and AhR.

The expression of MDM2, MDM4, p53 and p21 in myeloid neoplasms and the effect of MDM2/MDM4 dual inhibitor.

p53 together with its downstream product p21 plays an important role in tumorigenesis development. MDM2 and MDM4 are two p53 regulators. We studied the expression of p53, p21, MDM2, and MDM4 in a total of 120 cases of myeloid neoplasms including MDS, AML or MDS/MPN, and control, using single and double immunohistochemical stains. We found TP53 mutations had a worse outcome in patients with AML/MDS, and p53 expression detected by immunohistochemistry had a similar prognostic value. p21 expression was strongly related to TP53 mutation status, with loss of expression in almost all TP53 mutated cases. MDM2 and MDM4 were highly expressed in hematopoietic cells in both benign and neoplastic cells. MDM2/p53 double positive cells exceeded MDM4/p53 double positive cells in neoplastic cases. Finally, we observed that p21 protein expression was up regulated upon the use of ALRN-6924 (Aileron) while no significant changes were seen in p53, MDM2 and MDM4 expression.

Monoclonal Antibodies Against Human Papillomavirus E6 and E7 Oncoproteins Inhibit Tumor Growth in Experimental Cervical Cancer.

Nearly all cases of cervical cancer are initiated by persistent infection with high-risk strains of human papillomavirus (hr-HPV). When hr-HPV integrates into the host genome, the constitutive expression of oncogenic HPV proteins E6 and E7 function to disrupt p53 and retinoblastoma regulation of cell cycle, respectively, to favor malignant transformation. HPV E6 and E7 are oncogenes found in over 99% of cervical cancer, they are also expressed in pre-neoplastic stages making these viral oncoproteins attractive therapeutic targets. Monoclonal antibodies (mAbs) represent a novel potential approach against the actions of hr-HPV E6 and E7 oncoproteins. In this report, we describe the utilization of anti-HPV E6 and HPV E7 mAbs in an experimental murine model of human cervical cancer tumors. We used differential dosing strategies of mAbs C1P5 (anti-HPV 16 E6) and TVG701Y (anti-HPV E7) administered via intraperitoneal or intratumoral injections. We compared mAbs to the action of chemotherapeutic agent Cisplatin and demonstrated the capacity of mAbs to significantly inhibit tumor growth. Furthermore, we investigated the contribution of the immune system and found increased complement deposition in both C1P5 and TVG701Y treated tumors compared to irrelevant mAb therapy. Taken together, the results suggest that anti-HPV E6 and E7 mAbs exert inhibition of tumor growth in a viral-specific manner and stimulate an immune response that could be exploited for an additional treatment options for patients.

The ZNF217 Biomarker Predicts Low- and High-Risk Oncotype DX® Recurrence Score in ER-Positive Invasive Breast Cancers.

We assessed mRNA and protein expression levels of the ZN217 oncogene in 17 clinical FFPE ER-positive invasive breast cancer specimens with known (low or high) Oncotype DX® Recurrence Scores. This study shows that mRNA or nuclear protein levels of the ZNF217 significantly correlate with Oncotype DX® Recurrence Score.

CONCEPTS OF OPERATIONS FOR A US DOSIMETRY AND BIODOSIMETRY NETWORK.

The USA must be prepared to provide a prompt, coordinated and integrated response for radiation dose and injury assessment for suspected radiation exposure, whether it involves isolated cases or mass casualties. Dose estimation for radiation accidents typically necessitates a multiple parameter diagnostics approach that includes clinical, biological and physical dosimetry to provide an early-phase radiation dose. A US Individual Dosimetry and Biodosimetry Network (US-IDBN) will increase surge capacity for civilian and military populations in a large-scale incident. The network's goal is to leverage available resources and provide an integrated biodosimetry capability, using multiple parameter diagnostics. Initial operations will be to expand an existing functional integration of two cytogenetic biodosimetry laboratories by developing Standard Operating Procedures, cross-training laboratorians, developing common calibration curves, supporting inter-comparison exercises and obtaining certification to process clinical samples. Integration with certified commercial laboratories will increase surge capacity to meet the needs of a mass-casualty incident.

Utilization of spectrins ßI and ßIII in diagnosis of hepatocellular carcinoma.

Spectrins are a group of cytoskeletal proteins which participate in many important cellular functions. It has been suggested that loss of spectrin isoforms may be associated with tumorigenesis of lymphoma, leukemia, gastric cancer and hepatocellular carcinoma (HCC). We recently reported that ßI spectrin expression was present in normal hepatocytes but lost in HCC cells, which suggested that spectrins may be helpful markers in diagnosis of HCC. In this study, using immunohistochemical staining, we further investigated the expression pattern of four spectrin isoforms (αII, ßI-III) on different benign and malignant liver tumors including focal nodular hyperplasia (FNH), hepatic adenoma (HA), HCC, and cholangiocarcinoma (CC). The results revealed that ßI spectrin was moderately to strongly positive in FNH and HA tissues, but was only weakly positive or lost in HCC cases and was weakly positive in all CC cases. In addition, the ßIII spectrin, majority of which was moderately positive in both FNH and HA tissues, was mostly lost in poorly differentiated HCC but remained at least moderately positive in most CC cases. These results suggest that spectrins ßI and ßIII may be used to differentiate well differentiated HCC from FNH or HA, and poorly differentiated HCC from CC, respectively.

An Immunoscore Using PD-L1, CD68, and Tumor-infiltrating Lymphocytes (TILs) to Predict Response to Neoadjuvant Chemotherapy in Invasive Breast Cancer.

Response to neoadjuvant chemotherapy (NAC) in invasive breast cancer (IBC) is partly regulated by the immune microenvironment. We evaluated immune checkpoint PD-L1 expression, presence of CD68+ cells of macrophage/monocytic lineage and stromal tumor-infiltrating lymphocytes (TILs) in prechemotherapy biopsies and correlated with NAC response. We studied 76 cases of IBC. Prechemotherapy biopsies with >30% TILs were considered lymphocyte-rich IBC. We performed immunohistochemistry for PD-L1 and CD68. Prechemotherapy cores showing >1% PD-L1+ immune or tumor cells were considered positive. CD68 was positive if >40% of tumor stroma contained CD68+ cells or atleast 50% of tumor cells showed infiltration by CD68+ cells. Residual Cancer burden (RCB) Score of 0/I represented excellent response to NAC and RCB II or III unfavorable response. Thirty-five patients had RCB 0/I and 41 pts RCB II/ III. TILs>30% were present in prechemotherapy biopsies in 19 pts of whom 14 showed RCB 0/I (P=0.0075). Twenty-seven cases were PD-L1+ and 20 had an RCB 0/I (P=0.0003). Twenty-two cases were CD68+ of whom 18 showed RCB 0/I (P=<0.0001) There was a significant association between TILs>30%, PD-L1+ and CD68+ expression. Using atleast one of these immunologic parameters identified 26 of 35 patients with RCB 0/I and showed a higher sensitivity for response prediction than TILs alone (40% vs. 74.3%). In conclusion we demonstrate that high numbers of CD68+ monocytic/macrophage cells and PD-L1 expression in IBC shows significant association with NAC response. An immune biomarker profile including TILs, PD-LI and CD68 is more sensitive for NAC response prediction than TILs alone.

First global consensus for evidence-based management of the hematopoietic syndrome resulting from exposure to ionizing radiation.

OBJECTIVE: Hematopoietic syndrome (HS) is a clinical diagnosis assigned to people who present with ≥ 1 new-onset cytopenias in the setting of acute radiation exposure. The World Health Organization convened a panel of experts to evaluate the evidence and develop recommendations for medical countermeasures for the management of HS in a hypothetical scenario involving the hospitalization of 100 to 200 individuals exposed to radiation. The objective of this consultancy was to develop recommendations for treatment of the HS based upon the quality of evidence. METHODS: English-language articles were identified in MEDLINE and PubMed. Reference lists of retrieved articles were distributed to panel members before the meeting and updated during the meeting. Published case series and case reports of individuals with HS, published randomized controlled trials of relevant interventions used to treat nonirradiated individuals, reports of studies in irradiated animals, and prior recommendations of subject matter experts were selected. Studies were extracted using the Grading of Recommendations Assessment Development and Evaluation (GRADE) system. In cases in which data were limited or incomplete, a narrative review of the observations was made. No randomized controlled trials of medical countermeasures have been completed for individuals with radiation-associated HS. The use of GRADE analysis of countermeasures for injury to hematopoietic tissue was restricted by the lack of comparator groups in humans. Reliance on data generated in nonirradiated humans and experimental animals was necessary. RESULTS: Based upon GRADE analysis and narrative review, a strong recommendation was made for the administration of granulocyte colony-stimulating factor or granulocyte macrophage colony-stimulating factor and a weak recommendation was made for the use of erythropoiesis-stimulating agents or hematopoietic stem cell transplantation. CONCLUSIONS: Assessment of therapeutic interventions for HS in humans exposed to nontherapeutic radiation is difficult because of the limits of the evidence.

Literature review and global consensus on management of acute radiation syndrome affecting nonhematopoietic organ systems.

OBJECTIVES: The World Health Organization convened a panel of experts to rank the evidence for medical countermeasures for management of acute radiation syndrome (ARS) in a hypothetical scenario involving the hospitalization of 100 to 200 victims. The goal of this panel was to achieve consensus on optimal management of ARS affecting nonhematopoietic organ systems based upon evidence in the published literature. METHODS: English-language articles were identified in MEDLINE and PubMed. Reference lists of retrieved articles were distributed to conferees in advance of and updated during the meeting. Published case series and case reports of ARS, publications of randomized controlled trials of relevant interventions used to treat nonirradiated individuals, reports of studies in irradiated animals, and prior recommendations of subject matter experts were selected. Studies were extracted using the Grading of Recommendations Assessment Development and Evaluation system. In cases in which data were limited or incomplete, a narrative review of the observations was made. RESULTS: No randomized controlled trials of medical countermeasures have been completed for individuals with ARS. Reports of countermeasures were often incompletely described, making it necessary to rely on data generated in nonirradiated humans and in experimental animals. A strong recommendation is made for the administration of a serotonin-receptor antagonist prophylactically when the suspected exposure is >2 Gy and topical steroids, antibiotics, and antihistamines for radiation burns, ulcers, or blisters; excision and grafting of radiation ulcers or necrosis with intractable pain; provision of supportive care to individuals with neurovascular syndrome; and administration of electrolyte replacement therapy and sedatives to individuals with significant burns, hypovolemia, and/or shock. A strong recommendation is made against the use of systemic steroids in the absence of a specific indication. A weak recommendation is made for the use of fluoroquinolones, bowel decontamination, loperamide, and enteral nutrition, and for selective oropharyngeal/digestive decontamination, blood glucose maintenance, and stress ulcer prophylaxis in critically ill patients. CONCLUSIONS: High-quality studies of therapeutic interventions in humans exposed to nontherapeutic radiation are not available, and because of ethical concerns regarding the conduct of controlled studies in humans, such studies are unlikely to emerge in the near future.

Spectrin isoforms: differential expression in normal hematopoiesis and alterations in neoplastic bone marrow disorders.

Spectrins are large, rod-like, multifunctional molecules that participate in maintaining cell structure, signal transmission, and DNA repair. Because little is known about the role of spectrins in normal hematopoiesis and leukemogenesis, we immunohistochemically stained bone marrow biopsy specimens from 81 patients for αI, αII, ßI, and ßII spectrin isoforms in normal reactive marrow (NRM), myelodysplastic syndrome, myeloproliferative neoplasm, acute myeloid leukemia (AML) with well-characterized cytogenetic abnormalities, acute erythroid leukemia (EryL), and acute megakaryoblastic leukemia (MegL). In NRM, spectrin isoforms were differentially expressed according to cell lineage: αI and ßI in erythroid precursors; αII and ßII in granulocytes; and ßI and ßII in megakaryocytes. In contrast, 18 (44%) of 41 AMLs lacked αII spectrin and/or aberrantly expressed ßI spectrin (P = .0398; Fisher exact test) and 5 (100%) of 5 EryLs expressed ßII spectrin but lacked ßI spectrin. The frequent loss and/or gain of spectrin isoforms in AMLs suggests a possible role for spectrin in leukemogenesis.

Alpha- and beta-synucleins are new diagnostic tools for acute erythroid leukemia and acute megakaryoblastic leukemia.

α-Synuclein is a key component of the Lewy body, a large globular protein complex that forms in the nervous system of patients with Parkinson disease and other dementias [1-3]. Since α-synuclein also occurs in megakaryocytic and erythroid lineages [4-7], we wondered what role synucleins had in the hematopoietic system. Therefore, we studied the expression of α-, ß-, and γ-synucleins in a comprehensive panel of patient bone marrows and leukemic cell lines. We observed under expression of α-synuclein in the megakaryocytes of myeloproliferative neoplasm (MPN), but not normal reactive marrow (NRM) or myelodysplastic syndrome (MDS). Conversely, we observed over expression of ß-synuclein in the blasts of megakaryoblastic leukemias (MegL), but not acute myeloid leukemia (AML) or erythroleukemia (EryL), suggesting that α- and ß-synucleins could be useful adjunct markers for the early detection of MDS and the differential diagnosis of EryL and MegL from other AMLs.

Patterns of spectrin expression in B-cell lymphomas: loss of spectrin isoforms is associated with nodule-forming and germinal center-related lymphomas.

Spectrins are a family of cytoskeletal proteins that organize and link membranes to subcellular motors and filaments. Although traditionally divided into erythroid and non-erythroid forms, the discovery of new spectrin isoforms in various tissues indicates that their distribution is not yet fully characterized. To our knowledge, there is no comprehensive analysis of spectrins in lymphoid malignancies. Using tumor microarrays of paraffin blocks, we immunohistochemically studied 10 lymph nodes with reactive lymphoid hyperplasia and 94 lymph nodes involved by B-cell malignant lymphoma. Expression of spectrins alphaI, alphaII, betaI, betaII, and betaIII was scored using a 20% cutoff for positive immunoperoxidase staining. All spectrin isoforms, except erythroid-specific alphaI spectrin, were detected in lymph nodes with reactive lymphoid hyperplasia. In contrast, various spectrins were lost in particular B-cell malignant lymphomas. Based on the absence of staining for one or more spectrin isoforms in at least 50% of cases, we identified three patterns: (1) loss of alphaII and betaII in follicular lymphoma, grades 2/3 and 3/3; nodular lymphocyte predominance Hodgkin's lymphoma; nodular sclerosis Hodgkin's lymphoma; (2) loss of betaI only in Burkitt lymphoma; and (3) loss of alphaII and betaI in mixed cellularity Hodgkin's lymphoma. In contrast, follicular lymphoma, grade 1/3 and diffuse large B-cell lymphoma retained spectrin in 67-100% of cases. The other lymphoma subtypes retained spectrin in greater than 50% of cases. We identified the loss of particular spectrin isoforms in B-cell malignant lymphomas that have a nodular growth pattern and/or are believed to arise from germinal center B-cells, that is follicular lymphoma, grades 2/3 and 3/3; Burkitt lymphoma; nodular sclerosis Hodgkin's lymphoma; mixed cellularity Hodgkin's lymphoma; and nodular lymphocyte predominance Hodgkin's lymphoma. The absence of particular spectrin isoforms may correlate with transformation or aggressive biologic behavior for some lymphoma subtypes.

Multivariate analysis of low-dose radiation-associated changes in cytokine gene expression profiles using microarray technology.

OBJECTIVE: The availability of microarray technology, which permits evaluation of the entire cellular transcriptome in a single experiment, has provided new insights on the function of the genome under normal and pathological conditions, as well as in response to genotoxic stimuli, including ionizing radiation. The aims of this study were to: 1) determine whether specific cytokine gene expression profiles can be delineated in individuals exposed to chronic, low-dose radiation; and 2) compare analyses from three multivariate analytic methodologies, hierarchical clustering analysis (HCA), principal component analysis (PCA), and projection pursuit (PP), in evaluating transcriptional responses in human mononuclear cells to low doses of ionizing radiation (IR), as determined by cDNA microarrays. MATERIALS AND METHODS: Total RNA isolated from mononuclear cells of 19 apparently healthy adult individuals exposed to low doses of IR ranging from 0.18 mSv to 49 mSv over a period of 11 to 13 years, as a result of the Chernobyl Nuclear Power Plant catastrophe, was reverse transcribed in the presence of radioactive dATP to generate radiolabeled complementary cDNA. Target cDNA was hybridized to human cytokine and receptor arrays and mRNA transcriptional patterns were evaluated using HCA, PCA, and PP. RESULTS: Statistical analyses of the data generated from 19 microarrays revealed distinct gene expression patterns in mononuclear cells of individuals exposed to radiation doses of greater than 10 mSv or less than 10 mSv. Genes encompassed within clusters discerned by HCA, PCA, and PP varied depending on the methodology used to analyze the microarray data. The most frequently expressed genes across all radiation doses were serine/threonine protein kinase receptor (11/19), transforming growth factor (TGF) receptor (11/19), EB13 (10/19), and CD40 ligand. CONCLUSIONS: Although our findings suggest that it may be possible to assign gene expression profiles to low-dose-irradiated individuals, we show that gene expression profiles vary, depending on the statistical method used to analyze the data. Since there is, as of yet, no consensus regarding the best method to analyze a multivariate dataset, and since discarding the raw data and repeating the experiment at a later date constitutes an unwarranted expenditure, it is important to submit microarray data to public databases where these data can be reevaluated and interpreted by investigators holding expertise in various fields within the scientific community, including radiation biology, statistics, and bioinformatics.

Development of a statewide hospital plan for radiologic emergencies.

Although general guidelines have been developed for triage of victims in the field and for hospitals to plan for a radiologic event, specific information for clinicians and administrators is not available for guidance in efficient management of radiation victims during their early encounter in the hospital. A consensus document was developed by staff members of four Connecticut hospitals, two institutions of higher learning, and the State of Connecticut Department of Environmental Protection and Office of Emergency Preparedness, with assistance of the American Society for Therapeutic Radiology and Oncology. The objective was to write a practical manual for clinicians (including radiation oncologists, emergency room physicians, and nursing staff), hospital administrators, radiation safety officers, and other individuals knowledgeable in radiation monitoring that would be useful for evaluation and management of radiation injury. The rationale for and process by which the radiation response plan was developed and implemented in the State of Connecticut are reviewed. Hospital admission pathways are described, based on classification of victims as exposed, contaminated, and/or physically injured. This manual will be of value to those involved in planning the health care response to a radiologic event.