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Bortezomib and the other licensed 20S proteasome inhibitors show robust activity against liquid tumors like multiple myeloma, but have disappointed against solid tumors including ovarian cancer. Consequently, interest is mounting in alternative non-peptide based drugs targeting the proteasome's 19S regulatory particle subunit, including its ubiquitin receptor RPN13. RA183 and RA375 are more potent analogs of the prototypic inhibitor of RPN13 (iRPN13) called RA190, and they show promise for the treatment of ovarian cancer. Here we demonstrate that rendering these candidate RPN13 inhibitors chiral and asymmetric through the addition of a single methyl to the core piperidone moiety increases their potency against cancer cell lines, with the S-isomer being more active than the R-isomer. The enhanced cancer cell cytotoxicities of these compounds are associated with improved binding to RPN13 in cell lysates, ATP depletion by inhibition of glycolysis and mitochondrial electron chain transport, mitochondrial depolarization and perinuclear clustering, oxidative stress and glutathione depletion, and rapid accumulation of high molecular weight polyubiquitinated proteins with a consequent unresolved ubiquitin proteasome system (UPS) stress response. Cytotoxicity was associated with an early biomarker of apoptosis, increased surface annexin V binding. As for cisplatin, BRCA2 and ATM deficiency conferred increased sensitivity to these iRPN13s. Ubiquitination plays an important role in coordinating DNA damage repair and the iRPN13s may compromise this process by depletion of monomeric ubiquitin following its sequestration in high molecular weight polyubiquitinated protein aggregates. Indeed, a synergistic cytotoxic response was evident upon treatment of several ovarian cancer cell lines with either cisplatin or doxorubicin and our new candidate iRPN13s, suggesting that such a combination approach warrants further exploration for the treatment of ovarian cancer.

RNA tracking allows researchers to visualize RNA molecules in cells and tissues, providing important spatio-temporal information regarding RNA dynamics and function. Methods such as fluorescent in situ hybridization (FISH) and molecular beacons rely on complementary oligonucleotides to label and view endogenous transcripts. Other methods create artificial chimeric transcripts coupled with bacteriophage-derived coat proteins (e.g. MS2, λN) to tag molecules in live cells. In other approaches, endogenous RNAs are recognized by complementary RNAs complexed with noncatalytic Cas proteins. Each technique has its own set of strengths and limitations that must be considered when planning an experiment. Here, we discuss the mechanisms, advantages, and weaknesses of in situ hybridization, molecular beacons, MS2 tagging and Cas-derived systems, as well as how RNA tracking can be employed to study various aspects of molecular biology.

Objectives: To develop a desirability of outcome ranking (DOOR) scale for use in children with septic shock and determine its correlation with a decrease in 3-month postadmission health-related quality of life (HRQL) or death., Design: Secondary analysis of the Life After Pediatric Sepsis Evaluation prospective study., Setting: Twelve U.S. PICUs, 2013-2017., Patients: Children (1 mo-18 yr) with septic shock., Interventions: None., Measurements and Main Results: We applied a 7-point pediatric critical care (PCC) DOOR scale: 7: death; 6: extracorporeal life support; 5: supported by life-sustaining therapies (continuous renal replacement therapy, vasoactive, or invasive ventilation); 4: hospitalized with or 3: without organ dysfunction; 2: discharged with or 1: without new morbidity to patients by assigning the highest applicable score on specific days post-PICU admission. We analyzed Spearman rank-order correlations (95% CIs) between proximal outcomes (PCC-DOOR scale on days 7, 14, and 21, ventilator-free days, cumulative 28-day Pediatric Logistic Organ Dysfunction-2 (PELOD-2) scores, and PICU-free days) and 3-month decrease in HRQL or death. HRQL was measured by Pediatric Quality of Life Inventory 4.0 or Functional Status II-R for patients with developmental delay. Patients who died were assigned the worst possible HRQL score. PCC-DOOR scores were applied to 385 patients, median age 6 years (interquartile range 2, 13) and 177 (46%) with a complex chronic condition(s). Three-month outcomes were available for 245 patients (64%) and 42 patients (17%) died. PCC-DOOR scale on days 7, 14, and 21 demonstrated fair correlation with the primary outcome (-0.42 [-0.52, -0.31], -0.47 [-0.56, -0.36], and -0.52 [-0.61, -0.42]), similar to the correlations for cumulative 28-day PELOD-2 scores (-0.51 [-0.59, -0.41]), ventilator-free days (0.43 [0.32, 0.53]), and PICU-free days (0.46 [0.35, 0.55])., Conclusions: The PCC-DOOR scale is a feasible, practical outcome for pediatric sepsis trials and demonstrates fair correlation with decrease in HRQL or death at 3 months., Competing Interests: Dr. Logan’s institution received funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (K23HD096018) (R01HD073362 and cooperative agreements U10-HD050012, U10-HD050096, U10-HD063108, U10-HD049983 U10-HD049981, U10-HD063114, and U10-HD063106). Drs. Logan, Banks, Reeder, Meert, Zimmerman, and Maddux received support for article research from the National Institutes of Health (NIH). Drs. Banks, Bennett, and Zimmerman’s institutions received funding from the NICHD. Dr. Banks disclosed government work. Drs. Reeder and Meert’s institutions received funding from the NIH. Dr. Bennett’s institution received funding from the National Center for Advancing Translational Sciences and the National Heart, Lung, and Blood Institute. Dr. Zimmerman’s institution received funding from Immunexpress; he received funding from Elsevier Publishing. Dr. Maddux’s institution received funding from the NICHD (K23 HD096018) and the Francis Family Foundation. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Purpose: Triple-negative breast cancer (TNBC) is a heterogeneous disease. We previously showed that homologous recombination deficiency (HRD) and the DNA damage immune response (DDIR) signature are prognostic in TNBC. We hypothesized that these biomarkers reflect related but not completely interdependent biological processes, that their combined use would be prognostic, and that simultaneous assessment of the immunologic microenvironment and susceptibility to DNA damaging therapies might be able to identify subgroups with distinct therapeutic vulnerabilities., Methods: We analyzed the dual DDIR/HRD classification in 341 patients with TNBC treated with adjuvant anthracycline-based chemotherapy on the SWOG S9313 trial and corroborated our findings in The Cancer Genome Atlas breast cancer data set., Results: DDIR/HRD classification is highly prognostic in TNBC and identifies biologically and immunologically distinct subgroups. Immune-enriched DDIR+/HRD+ TNBCs have the most favorable prognosis, and DDIR+/HRD- and DDIR-/HRD+ TNBCs have favorable intermediate prognosis, despite the latter being immune-depleted. DDIR-/HRD- TNBCs have the worst prognosis and represent an internally heterogeneous group of immune-depleted chemoresistant tumors., Conclusion: Our findings propose DDIR/HRD classification as a potentially clinically relevant approach to categorize tumors on the basis of therapeutic vulnerabilities.

Objectives: Cytokine release syndrome (CRS) is a potentially lethal toxicity associated with chimeric antigen receptor T cell therapy for pediatric acute lymphoblastic leukemia (ALL). Outcomes after critical illness due to severe CRS are poorly described. Our aim was to characterize critical illness outcomes across a multicenter cohort of PICU patients with ALL and CRS., Design: Multicenter retrospective cohort study., Setting: Twenty-one PICUs contributing data to Virtual Pediatric Systems, LLC (January 2020-December 2021)., Patients: PICU patients with ALL or unclassified leukemia and CRS., Interventions: None., Measurements and Main Results: We identified 55 patients; 34 (62%) were 12 years or older, 48 (87%) were admitted from a hospital inpatient ward, and 23 (42%) received advanced organ failure support or monitoring. Fifty-one survived to PICU discharge (93%) including 19 of 23 (83%) who received advanced organ failure support or monitoring defined as receipt of noninvasive or invasive ventilation, cardiopulmonary resuscitation, extracorporeal membrane oxygenation, continuous renal replacement therapy, or placement of a tracheostomy, arterial catheter, hemodialysis catheter, or intracranial catheter. Twelve patients (22%) received invasive ventilation, nine of whom survived to PICU discharge. Two of four patients who received continuous renal replacement therapy and one of three patients who required cardiopulmonary resuscitation survived to PICU discharge. Lengths of PICU stay were median 3.0 days (interquartile range, 1.4-7.8 d) among PICU survivors, 7.8 (5.4-11.1) among those receiving advanced organ failure support or monitoring, and 7.2 days (interquartile range, 2.9-14.7 d) among nonsurvivors. Of the 51 patients who survived to PICU discharge, 48 (94%) survived the hospitalization., Conclusions: PICU patients with CRS frequently received a high level of support, and the majority survived their PICU stay and hospitalization. Additional multicenter investigations of severe CRS are necessary to inform evidence-based practice., Competing Interests: Drs. Kohler and Maddux received support for article research from the National Institutes of Health; they disclosed the off-label products use of tocilizumab, glucocorticoids, siltuximab, and anakinra. Dr. Maddux’s institution received funding from the National Institute of Child Health and Human Development (K23HD096018) and the Francis Family Foundation/Parker B. Francis Fellowship. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Background: The DNA-damage immune-response (DDIR) signature is an immune-driven gene expression signature retrospectively validated as predicting response to anthracycline-based therapy. This feasibility study prospectively evaluates the use of this assay to predict neoadjuvant chemotherapy response in early breast cancer., Methods: This feasibility study assessed the integration of a novel biomarker into clinical workflows. Tumour samples were collected from patients receiving standard of care neoadjuvant chemotherapy (FEC + /-taxane and anti-HER2 therapy as appropriate) at baseline, mid- and post-chemotherapy. Baseline DDIR signature scores were correlated with pathological treatment response. RNA sequencing was used to assess chemotherapy/response-related changes in biologically linked gene signatures., Results: DDIR signature reports were available within 14 days for 97.8% of 46 patients (13 TNBC, 16 HER2 + ve, 27 ER + HER2-ve). Positive scores predicted response to treatment (odds ratio 4.67 for RCB 0-1 disease (95% CI 1.13-15.09, P = 0.032)). DDIR positivity correlated with immune infiltration and upregulated immune-checkpoint gene expression., Conclusions: This study validates the DDIR signature as predictive of response to neoadjuvant chemotherapy which can be integrated into clinical workflows, potentially identifying a subgroup with high sensitivity to anthracycline chemotherapy. Transcriptomic data suggest induction with anthracycline-containing regimens in immune restricted, "cold" tumours may be effective for immune priming., Trial Registration: Not applicable (non-interventional study). CRUK Internal Database Number 14232., (© 2021. The Author(s).)

Purpose: The DNA damage immune response (DDIR) assay was developed in breast cancer based on biology associated with deficiencies in homologous recombination and Fanconi anemia pathways. A positive DDIR call identifies patients likely to respond to platinum-based chemotherapies in breast and esophageal cancers. In colorectal cancer, there is currently no biomarker to predict response to oxaliplatin. We tested the ability of the DDIR assay to predict response to oxaliplatin-based chemotherapy in colorectal cancer and characterized the biology in DDIR-positive colorectal cancer., Experimental Design: Samples and clinical data were assessed according to DDIR status from patients who received either 5-fluorouracil (5-FU) or 5FUFA (bolus and infusion 5-FU with folinic acid) plus oxaliplatin (FOLFOX) within the FOCUS trial ( n = 361, stage IV), or neoadjuvant FOLFOX in the FOxTROT trial ( n = 97, stage II/III). Whole transcriptome, mutation, and IHC data of these samples were used to interrogate the biology of DDIR in colorectal cancer., Results: Contrary to our hypothesis, DDIR-negative patients displayed a trend toward improved outcome for oxaliplatin-based chemotherapy compared with DDIR-positive patients. DDIR positivity was associated with microsatellite instability (MSI) and colorectal molecular subtype 1. Refinement of the DDIR signature, based on overlapping IFN-related chemokine signaling associated with DDIR positivity across colorectal cancer and breast cancer cohorts, further confirmed that the DDIR assay did not have predictive value for oxaliplatin-based chemotherapy in colorectal cancer., Conclusions: DDIR positivity does not predict improved response following oxaliplatin treatment in colorectal cancer. However, data presented here suggest the potential of the DDIR assay in identifying immune-rich tumors that may benefit from immune checkpoint blockade, beyond current use of MSI status., (©2020 American Association for Cancer Research.)

Objectives: Post-traumatic stress disorder, depression, and anxiety have all been found in parents of PICU survivors. How these research findings translate to actual use of mental health services by parents remains unknown., Design: Retrospective observational cohort study., Setting: Insurance claims data from 2006 to 2013 obtained from the IBM MarketScan Commercial Database., Patients: Parents of PICU survivors., Interventions: We examined rates of: 1) mental health diagnoses, 2) outpatient mental health visits, and 3) prescriptions for antidepressants and anxiolytics among parents, 6 months before and 6 months after their child's PICU admission, using each parent as their own control., Measurements and Main Results: Of the 95,070 parents identified, 9.5% received a new mental health diagnosis in the 6 months after their child's PICU hospitalization, which represented a 110% increase from pre-PICU rates. A smaller proportion of parents were given new prescriptions for antidepressants (3.4%) and anxiolytics (3.9%) in the 6 months after their child's PICU hospitalization. Mothers were twice as likely to receive a new mental health diagnosis and be taking a new medication than fathers in the post-PICU period. The parental diagnosis of acute stress disorder or post-traumatic stress disorder increased by 87% from the pre-PICU to the post-PICU period., Conclusions: After their child's PICU hospitalization, the proportion of parents with a new mental health diagnosis nearly doubled. Mothers were at nearly twice the risk of receiving a new mental health diagnosis and receiving a new mental health medication compared with fathers. The proportion of parents receiving mental healthcare is much lower than the proportion reporting mental health symptoms in long-term outcomes studies. Whether this indicates a gap in healthcare delivery for parents with mental health symptoms remains unknown.

Purpose: To independently validate two biomarkers, a 44-gene DNA damage immune response (DDIR) signature and stromal tumor-infiltrating lymphocytes (sTILs), as prognostic markers in patients with triple-negative breast cancer (TNBC) treated with adjuvant doxorubicin (A) and cyclophosphamide (C) in SWOG 9313., Methods: Four hundred twenty-five centrally determined patient cases with TNBC from S9313 were identified. DDIR signature was performed on RNA isolated from formalin-fixed paraffin-embedded tumor tissue, and samples were classified as DDIR negative or positive using predefined cutoffs. Evaluation of sTILs was performed as described previously. Markers were tested for prognostic value for disease-free survival (DFS) and overall survival (OS) using Cox regression models adjusted for treatment assignment, nodal status, and tumor size., Results: Among 425 patients with TNBC, 33% were node positive. DDIR was tested successfully in 90% of patients (381 of 425), 62% of which were DDIR signature positive. DDIR signature positivity was associated with improved DFS (hazard ratio [HR], 0.67; 95% CI, 0.48 to 0.92; P = .015) and OS (HR, 0.61; 95% CI, 0.43 to 0.89; P = .010). sTILs density assessment was available in 99% of patients and was associated with improved DFS (HR, 0.70; 95% CI, 0.51 to 0.96; P = .026 for sTILs density ≥ 20% v < 20%) and OS (HR, 0.59; 95% CI, 0.41 to 0.85; P = .004 for sTILs density ≥ 20% v < 20%). DDIR signature score and sTILs density were moderately correlated ( r = 0.60), which precluded statistical significance for DFS in a joint model. Three-year DFS and OS in a subgroup of patients with DDIR positivity and T1c/T2N0 disease were 88% and 94%, respectively., Conclusion: The prognostic role of sTILs and DDIR in early-stage TNBC was confirmed. DDIR signature conferred improved prognosis in two thirds of patients with TNBC treated with adjuvant AC. DDIR signature has the potential to stratify outcome and to identify patients with less projected benefit after AC chemotherapy.

Objective: Current strategies to guide selection of neoadjuvant therapy in oesophageal adenocarcinoma (OAC) are inadequate. We assessed the ability of a DNA damage immune response (DDIR) assay to predict response following neoadjuvant chemotherapy in OAC., Design: Transcriptional profiling of 273 formalin-fixed paraffin-embedded prechemotherapy endoscopic OAC biopsies was performed. All patients were treated with platinum-based neoadjuvant chemotherapy and resection between 2003 and 2014 at four centres in the Oesophageal Cancer Clinical and Molecular Stratification consortium. CD8 and programmed death ligand 1 (PD-L1) immunohistochemical staining was assessed in matched resection specimens from 126 cases. Kaplan-Meier and Cox proportional hazards regression analysis were applied according to DDIR status for recurrence-free survival (RFS) and overall survival (OS)., Results: A total of 66 OAC samples (24%) were DDIR positive with the remaining 207 samples (76%) being DDIR negative. DDIR assay positivity was associated with improved RFS (HR: 0.61; 95% CI 0.38 to 0.98; p=0.042) and OS (HR: 0.52; 95% CI 0.31 to 0.88; p=0.015) following multivariate analysis. DDIR-positive patients had a higher pathological response rate (p=0.033), lower nodal burden (p=0.026) and reduced circumferential margin involvement (p=0.007). No difference in OS was observed according to DDIR status in an independent surgery-alone dataset.DDIR-positive OAC tumours were also associated with the presence of CD8+ lymphocytes (intratumoural: p<0.001; stromal: p=0.026) as well as PD-L1 expression (intratumoural: p=0.047; stromal: p=0.025)., Conclusion: The DDIR assay is strongly predictive of benefit from DNA-damaging neoadjuvant chemotherapy followed by surgical resection and is associated with a proinflammatory microenvironment in OAC., Competing Interests: Competing interests: LAK, AMM, SMW, DPH and RK are employees of Almac Diagnostics and have patent declarations. GEL and CJS are employees of Almac Diagnostics., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: There is a clear need for assays that can predict the risk of metastatic prostate cancer following curative procedures. Importantly these assays must be analytically robust in order to provide quality data for important clinical decisions. DNA microarray based gene expression assays measure several analytes simultaneously and can present specific challenges to analytical validation. This study describes the analytical validation of one such assay designed to predict metastatic recurrence in prostate cancer using primary formalin fixed paraffin embedded tumour material., Methods: Accuracy was evaluated with a method comparison study between the assay development platform (Prostate Disease Specific Array) and an alternative platform (Xcel™ microarray) using 50 formalin-fixed, paraffin-embedded prostate cancer patient samples. An additional 70 samples were used to establish the assay reportable range. Determination of assay precision and sensitivity was performed on multiple technical replicates of three prostate cancer samples across multiple variables (operators, days, runs, reagent lots, and equipment) and RNA/cDNA inputs respectively using the appropriate linear mixed model., Results: The overall agreement between the development and alternative platform was 94.7% (95% confidence interval, 86.9-98.5%). The reportable range was determined to be 0.150 to 1.107 for core needle biopsy samples and - 0.214 to 0.844 for radical prostatectomy samples. From the precision study, the standard deviations for assay repeatability and reproducibility were 0.032 and 0.040 respectively. The sensitivity study demonstrated that a total RNA input and cDNA input of 50 ng and 3.5 μg respectively was conservative., Conclusion: The Metastatic Assay was found to be highly reproducible and precise. In conclusion the studies demonstrated an acceptable analytical performance for the assay and support its potential use in the clinic.

Background: Radiotherapy is an effective treatment of intermediate/high-risk locally advanced prostate cancer, however, >30% of patients relapse within 5 years. Clinicopathological parameters currently fail to identify patients prone to systemic relapse and those whom treatment intensification may be beneficial. The purpose of this study was to independently validate the performance of a 70-gene Metastatic Assay in a cohort of diagnostic biopsies from patients treated with radical radiotherapy and androgen deprivation therapy., Patients and Methods: A bridging cohort of prostate cancer diagnostic biopsy specimens was profiled to enable optimization of the Metastatic Assay threshold before further independent clinical validation in a cohort of diagnostic biopsies from patients treated with radical radiotherapy and androgen deprivation therapy. Multivariable Cox proportional hazard regression analysis was used to assess assay performance in predicting biochemical failure-free survival (BFFS) and metastasis-free survival (MFS)., Results: Gene expression analysis was carried out in 248 patients from the independent validation cohort and the Metastatic Assay applied. Ten-year MFS was 72% for Metastatic Assay positive patients and 94% for Metastatic Assay negative patients [HR = 3.21 (1.35-7.67); P = 0.003]. On multivariable analysis the Metastatic Assay remained predictive for development of distant metastases [HR = 2.71 (1.11-6.63); P = 0.030]. The assay retained independent prognostic performance for MFS when assessed with the Cancer of the Prostate Assessment Score (CAPRA) [HR = 3.23 (1.22-8.59); P = 0.019] whilst CAPRA itself was not significant [HR = 1.88, (0.52-6.77); P = 0.332]. A high concordance [100% (61.5-100)] for the assay result was noted between two separate foci taken from 11 tumours, whilst Gleason score had low concordance., Conclusions: The Metastatic Assay demonstrated significant prognostic performance in patients treated with radical radiotherapy both alone and independent of standard clinical and pathological variables. The Metastatic Assay could have clinical utility when deciding upon treatment intensification in high-risk patients. Genomic and clinical data are available as a public resource., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)

Background: Approximately 4-25% of patients with early prostate cancer develop disease recurrence following radical prostatectomy., Objective: To identify a molecular subgroup of prostate cancers with metastatic potential at presentation resulting in a high risk of recurrence following radical prostatectomy., Design, Setting, and Participants: Unsupervised hierarchical clustering was performed using gene expression data from 70 primary resections, 31 metastatic lymph nodes, and 25 normal prostate samples. Independent assay validation was performed using 322 radical prostatectomy samples from four sites with a mean follow-up of 50.3 months., Outcome Measurements and Statistical Analysis: Molecular subgroups were identified using unsupervised hierarchical clustering. A partial least squares approach was used to generate a gene expression assay. Relationships with outcome (time to biochemical and metastatic recurrence) were analysed using multivariable Cox regression and log-rank analysis., Results and Limitations: A molecular subgroup of primary prostate cancer with biology similar to metastatic disease was identified. A 70-transcript signature (metastatic assay) was developed and independently validated in the radical prostatectomy samples. Metastatic assay positive patients had increased risk of biochemical recurrence (multivariable hazard ratio [HR] 1.62 [1.13-2.33]; p=0.0092) and metastatic recurrence (multivariable HR=3.20 [1.76-5.80]; p=0.0001). A combined model with Cancer of the Prostate Risk Assessment post surgical (CAPRA-S) identified patients at an increased risk of biochemical and metastatic recurrence superior to either model alone (HR=2.67 [1.90-3.75]; p<0.0001 and HR=7.53 [4.13-13.73]; p<0.0001, respectively). The retrospective nature of the study is acknowledged as a potential limitation., Conclusions: The metastatic assay may identify a molecular subgroup of primary prostate cancers with metastatic potential., Patient Summary: The metastatic assay may improve the ability to detect patients at risk of metastatic recurrence following radical prostatectomy. The impact of adjuvant therapies should be assessed in this higher-risk population., (Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Despite high vaccine coverage in the United States in general, and in the State of Florida specifically, some children miss scheduled vaccines due to health system failures or vaccine refusal by their parents. Recent experiences with outbreaks in the United States suggest that geographic clustering of un(der)vaccinated populations represent a threat to the elimination status of some vaccine-preventable diseases. Immunization registries continue to expand and play an important role in efforts to track vaccine coverage and use. Using nearly 700,000 de-identified immunization records from the Florida Department of Health immunization information system (Florida SHOTS™) for children born during 2003-2014, we explored heterogeneity and potential clustering of un(der)vaccinated children in six counties in central Florida-Brevard, Lake, Orange, Oseola, Polk, and Seminole-that represent a high-risk area for importation due to family tourist attractions in the area. By zip code, we mapped the population density, the percent of children with religious exemptions, the percent of children on track or overdue for each vaccine series without and with exemptions, and the numbers of children with no recorded dose of each vaccine. Overall, we found some heterogeneity in coverage among the counties and zip codes, but relatively consistent and high coverage. We found that some children with an exemption in the system received the vaccines we analyzed, but exemption represents a clear risk factor for un(der)immunization. We identified many challenges associated with using immunization registry data for spatial analysis and potential opportunities to improve registries to better support future analyses., (© 2015 Society for Risk Analysis.)

DEK is important in regulating cellular processes including proliferation, differentiation and maintenance of stem cell phenotype. The translocation t(6;9) in Acute Myeloid Leukemia (AML), which fuses DEK with NUP214, confers a poor prognosis and a higher risk of relapse. The over-expression of DEK in AML has been reported, but different studies have shown diminished levels in pediatric and promyelocytic leukemias. This study has characterized DEK expression, in silico, using a large multi-center cohort of leukemic and normal control cases. Overall, DEK was under-expressed in AML compared to normal bone marrow (NBM). Studying specific subtypes of AML confirmed either no significant change or a significant reduction in DEK expression compared to NBM. Importantly, the similarity of DEK expression between AML and NBM was confirmed using immunohistochemistry analysis of tissue mircorarrays. In addition, stratification of AML patients based on median DEK expression levels indicated that DEK showed no effect on the overall survival of patients. DEK expression during normal hematopoiesis did reveal a relationship with specific cell types implicating a distinct function during myeloid differentiation. Whilst DEK may play a potential role in hematopoiesis, it remains to be established whether it is important for leukemagenesis, except when involved in the t(6;9) translocation., (Copyright © 2014. Published by Elsevier Inc.)

This article is a review of several of the most concerning side effects of psychotropic medications in children and adolescents. An emphasis is placed on review of the prevalence, presentation, monitoring, and evidence-based management of these side effects., (Copyright © 2012 Elsevier Inc. All rights reserved.)