Metabolomic Signatures Differentiate Immune Responses in Avian Influenza Vaccine Recipients.

BACKGROUND: Avian influenza viruses pose significant risk to human health. Vaccines targeting the hemagglutinin of these viruses are poorly immunogenic without the use of adjuvants. METHODS: Twenty healthy men and women (18-49 years of age) were randomized to receive two doses of inactivated influenza A/H5N1 vaccine alone (IIV) or with AS03 adjuvant (IIV-AS03) one month apart. Urine and serum samples were collected on day 0 and on days 1, 3, and 7 following first vaccination and subjected to metabolomics analyses to identify metabolites, metabolic pathways, and metabolite clusters associated with immunization. RESULTS: Seventy-three differentially abundant (DA) serum and 88 urine metabolites were identified for any post-vaccination day comparison. Pathway analysis revealed enrichment of tryptophan, tyrosine and nicotinate metabolism in urine and serum among IIV-AS03 recipients. Increased urine abundance of 4-vinylphenol sulfate on Day 1 was associated with serologic response based on hemagglutination inhibition responses. In addition, 9 DA urine metabolites were identified in participants with malaise compared to those without. CONCLUSIONS: Our findings suggest that tryptophan, tyrosine, and nicotinate metabolism are upregulated among IIV-AS03 recipients compared with IIV alone. Metabolites within these pathways may serve as measures of immunogenicity and may provide mechanistic insights for adjuvanted vaccines.

Risk Factors and Outcomes of Late Posttraumatic Seizures in Combat-Related Traumatic Brain Injury.

INTRODUCTION: Post-traumatic seizures (PTSs) contribute to morbidity after traumatic brain injury (TBI). Early PTS are rare in combat casualties sustaining TBI, but the prevalence of late PTS is poorly described. We sought to define the prevalence and risk factors of late PTS in combat casualties with computed tomography evidence of TBI. METHODS: From 2010 to 2015, 687 combat casualties were transferred to a military treatment facility and included in the Department of Defense Trauma Registry. 71 patients with radiographic evidence of TBI were analyzed. Data collection included demographics, injury characteristics, interventions, medications, and outcomes. RESULTS: Of the 71 patients with evidence of TBI, 66 patients survived hospitalization and were followed. No patients had early PTS, and most received antiepileptic drugs (AEDs) for prophylaxis. At a median follow-up of 7.4 y, late PTS occurred in 25.8% of patients. Patients with late PTS were more severely injured (median Injury severity score 30 versus 24, P = 0.005) and required more blood products (18 units versus 2, P = 0.045). Patients with late PTS were more likely to have had a penetrating TBI (76.5% versus 38.8%, P = 0.01), multiple types of intracranial hemorrhage (94.1% versus 63.3%, P = 0.02), and cranial decompression (76.5% versus 28.6%, P = 0.001). Six-month Glasgow outcome scores were worse (3.5 versus 4.1 P = 0.001) in the late PTS population. No significant relationship was observed between administration of AEDs for early PTS prophylaxis and late PTS. CONCLUSIONS: Combat casualties with TBI suffering late PTS are more severely injured and require more blood products. Penetrating TBI, intracranial hemorrhage, and need for cranial decompression are correlated with late PTS, and associated with worse Glasgow Outcome Score. The administration of prophylactic AEDs for early PTS was not associated with a difference in rates of late PTS.

Non-therapeutic laparotomies in military trauma (2009-2014).

BACKGROUND: Combat casualties are frequently injured in austere settings where modern imaging modalities are unavailable. Exploratory laparotomies are often performed in these settings when there is suspicion for intra-abdominal injury. Prior studies of combat casualties reported non-therapeutic laparotomy (NTL) rates as high as 32%. Given improvements in combat casualty care over time, we evaluated NTLs performed during later years of the wars in Iraq and Afghanistan. METHODS: Military personnel with combat-related injuries (6/1/2009-12/31/2014) who underwent exploratory laparotomy based on concern for abdominal injury (i.e. not performed for proximal vascular control or fecal diversion) and were evacuated to Landstuhl Regional Medical Center (Germany) before being transferred to participating U.S. military hospitals were assessed. An NTL was defined as a negative laparotomy without substantial intra-abdominal injuries requiring repair. Characteristics, indications for laparotomy, operative findings, and outcomes were examined. RESULTS: Among 244 patients who underwent laparotomies, 41 (16.8%) had NTLs and 203 (83.2%) had therapeutic laparotomies (i.e. positive findings). Patients with NTLs had more computed tomography scans concerning for injury (48.8% vs 27.1%; p = 0.006), less penetrating injury mechanisms (43.9% vs 71.9%; p < 0.001), and lower Injury Severity Scores (26 vs 33; p = 0.003) compared to patients with therapeutic laparotomies. Patients with NTLs were also less likely to be admitted to the intensive care unit (70.7 vs 89.2% for patients with therapeutic laparotomies; p = 0.007). No patients with NTLs developed abdominal surgical site infections (SSI) compared to 16.7% of patients with therapeutic laparotomies (p = 0.002). There was no significant difference in mortality between the groups (p = 0.198). CONCLUSIONS: Our proportion of NTLs was lower than reported from earlier years during the wars in Iraq and Afghanistan. No infectious complications from NTLs (i.e. abdominal SSIs) were identified. Nevertheless, surgeons should continue to have a low threshold for exploratory laparotomy in military patients in austere settings with concern for intra-abdominal injury.

Viral Micro-RNAs Are Detected in the Early Systemic Response to Injury and Are Associated With Outcomes in Polytrauma Patients.

OBJECTIVES: To evaluate early activation of latent viruses in polytrauma patients and consider prognostic value of viral micro-RNAs in these patients. DESIGN: This was a subset analysis from a prospectively collected multicenter trauma database. Blood samples were obtained upon admission to the trauma bay (T0), and trauma metrics and recovery data were collected. SETTING: Two civilian Level 1 Trauma Centers and one Military Treatment Facility. PATIENTS: Adult polytrauma patients with Injury Severity Scores greater than or equal to 16 and available T0 plasma samples were included in this study. Patients with ICU admission greater than 14 days, mechanical ventilation greater than 7 days, or mortality within 28 days were considered to have a complicated recovery. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Polytrauma patients (n = 180) were identified, and complicated recovery was noted in 33%. Plasma samples from T0 underwent reverse transcriptase-quantitative polymerase chain reaction analysis for Kaposi's sarcoma-associated herpesvirus micro-RNAs (miR-K12_10b and miRK-12-12) and Epstein-Barr virus-associated micro-RNA (miR-BHRF-1), as well as Luminex multiplex array analysis for established mediators of inflammation. Ninety-eight percent of polytrauma patients were found to have detectable Kaposi's sarcoma-associated herpesvirus and Epstein-Barr virus micro-RNAs at T0, whereas healthy controls demonstrated 0% and 100% detection rate for Kaposi's sarcoma-associated herpesvirus and Epstein-Barr virus, respectively. Univariate analysis revealed associations between viral micro-RNAs and polytrauma patients' age, race, and postinjury complications. Multivariate least absolute shrinkage and selection operator analysis of clinical variables and systemic biomarkers at T0 revealed that interleukin-10 was the strongest predictor of all viral micro-RNAs. Multivariate least absolute shrinkage and selection operator analysis of systemic biomarkers as predictors of complicated recovery at T0 demonstrated that miR-BHRF-1, miR-K12-12, monocyte chemoattractant protein-1, and hepatocyte growth factor were independent predictors of complicated recovery with a model complicated recovery prediction area under the curve of 0.81. CONCLUSIONS: Viral micro-RNAs were detected within hours of injury and correlated with poor outcomes in polytrauma patients. Our findings suggest that transcription of viral micro-RNAs occurs early in the response to trauma and may be associated with the biological processes involved in polytrauma-induced complicated recovery.

NSQIP Based Predictors of False Negative and Indeterminate Ultrasounds in Adults With Appendicitis.

BACKGROUND: It has been well established that ultrasound (US) is the initial screening tool for children with suspected acute appendicitis. However, computed tomography (CT) has become the standard screening modality for adults presenting with abdominal pain. A recent review of National Surgical Quality Improvement Program (NSQIP) data revealed US is being utilized as a screening modality in adults. We aimed to assess the diagnostic performance of US in evaluating adults with acute appendicitis. STUDY DESIGN: The American College of Surgeons NSQIP and NSQIP Procedure Targeted Data Files were accessed and examined for all patients in 2016 and 2017 who received an US and underwent an appendectomy. The US results were then correlated to the pathology in order to determine the diagnostic performance. Additionally, we identified predictors for indeterminate and false negative US results. RESULTS: Our study included 3607 appendectomy patients of which 1135 (30%) had an indeterminate US, 683 (18%) had an US not consistent with appendicitis, and 1789 (49%) had an US consistent with appendicitis. Sensitivity and Specificity were 74.3% and 53.0%, respectively. Positive Predictive Value (PPV) and Negative Predictive Value (NPV) were 95.9% and 12.2%, respectively. On regression analysis, clinically relevant predictors for false negative and indeterminate studies included age, sex, and BMI. CONCLUSIONS: Ultrasound is an effective initial imaging modality for acute appendicitis in the adult population. Females, age >30 y, and elevated BMI were more likely to have indeterminate or false negative results. These patients may benefit from CT as their initial screening test.

The Isolated Surgeon: A Scoping Review.

BACKGROUND: Surgeons in resource-limited environments often provide care outside the expected scope of current general surgery training. Geographically isolated patients may be unwilling or unable to travel for specialty care. These same patients also present with life-threatening emergencies beyond the typical breadth of a general surgeon's practice, in hospitals with limited professional and material support. This review characterizes the unique role of isolated surgeons, so individual surgeons and health care organizations may focus professional development resources more efficiently, with the ultimate goal of improved patient care. METHODS: We performed a scoping review of the isolated surgeon, reviewing 25 years of literature regarding isolated US civilian and military surgeons. We examined emerging themes regarding the definition of an isolated surgeon, the scope of surgical practice beyond current training norms, and training gaps identified by surgeons in an isolated role. RESULTS: From 904 articles identified, we included 91 for final review. No prior definition exists for the isolated surgeon, although multiple definitions describe rural surgeons, patients, or hospitals; we propose an initial definition from consistent themes in the literature. Isolated surgeons across varied practice settings consistently performed relatively large volumes of cases of, and identified training gaps in, orthopedic, obstetric and gynecologic, urologic, and vascular surgery subspecialties. Life-threatening, "rare-but-real" cases in the above and neurosurgical disciplines are uncommon, but consistent across practice settings. CONCLUSIONS: This review represents the largest examination of the isolated surgeon in the current literature. Clarifying the identity, practice components, and training gaps of the isolated surgeon represent the first step in formalizing support for this small but critical group of surgeons and their patients.

Outcomes of Exploratory Laparotomy and Abdominal Infections Among Combat Casualties.

BACKGROUND: Abdominal injuries historically account for 13% of battlefield surgical procedures. We examined the occurrence of exploratory laparotomies and subsequent abdominal surgical site infections (SSIs) among combat casualties. METHODS: Military personnel injured during deployment (2009-2014) were included if they required a laparotomy for combat-related trauma and were evacuated to Landstuhl Regional Medical Center, Germany, before being transferred to participating US military hospitals. RESULTS: Of 4304 combat casualties, 341 (7.9%) underwent laparotomy. Including re-explorations, 1053 laparotomies (median, 2; interquartile range, 1-3; range, 1-28) were performed with 58% occurring within the combat zone. Forty-nine (14.4%) patients had abdominal SSIs (four with multiple SSIs): 27 (7.9%) with deep space SSIs, 14 (4.1%) with a deep incisional SSI, and 12 (3.5%) a superficial incisional SSI. Patients with abdominal SSIs had larger volume of blood transfusions (median, 24 versus 14 units), more laparotomies (median, 4 versus 2), and more hollow viscus injuries (74% versus 45%) than patients without abdominal SSIs. Abdominal closure occurred after 10 d for 12% of the patients with SSI versus 2% of patients without SSI. Mesh adjuncts were used to achieve fascial closure in 20.4% and 2.1% of patients with and without SSI, respectively. Survival was 98% and 96% in patients with and without SSIs, respectively. CONCLUSIONS: Less than 10% of combat casualties in the modern era required abdominal exploration and most were severely injured with hollow viscus injuries and required massive transfusions. Despite the extensive contamination from battlefield injuries, the SSI proportion is consistent with civilian rates and survival was high.

To Scan or Not to Scan: Development of a Clinical Decision Support Tool to Determine if Imaging Would Aid in the Diagnosis of Appendicitis.

BACKGROUND: Appendicitis is one of the most common surgically treated diseases in the world. CT scans are often over-utilized and ordered before a surgeon has evaluated the patient. Our aim was to develop a tool using machine learning (ML) algorithms that would help determine if there would be benefit in obtaining a CT scan prior to surgeon consultation. METHODS: Retrospective chart review of 100 randomly selected cases who underwent appendectomy and 100 randomly selected controls was completed. Variables included components of the patient's history, laboratory values, CT readings, and pathology. Pathology was used as the gold standard for appendicitis diagnosis. All variables were then used to build the ML algorithms. Random Forest (RF), Support Vector Machine (SVM), and Bayesian Network Classifiers (BNC) models with and without CT scan results were trained and compared to CT scan results alone and the Alvarado score using area under the Receiver Operator Curve (ROC), sensitivity, and specificity measures as well as calibration indices from 500 bootstrapped samples. RESULTS: Among the cases that underwent appendectomy, 88% had pathology-confirmed appendicitis. All the ML algorithms had better sensitivity, specificity, and ROC than the Alvarado score. SVM with and without CT had the best indices and could predict if imaging would aid in appendicitis diagnosis. CONCLUSION: This study demonstrated that SVM with and without CT results can be used for selective imaging in the diagnosis of appendicitis. This study serves as the initial step and proof-of-concept to externally validate these results with larger and more diverse patient population.

Correction to: Advanced Modeling to Predict Pneumonia in Combat Trauma Patients.

In the original article, the units indicated on the y-axes of Fig. 3 are incorrectly labelled. The correct label is pg/mL. Following is the corrected Fig. 3.

Advanced Modeling to Predict Pneumonia in Combat Trauma Patients.

BACKGROUND: Tools to assist clinicians in predicting pneumonia could lead to a significant decline in morbidity. Therefore, we sought to develop a model in combat trauma patients for identifying those at highest risk of pneumonia. METHODS: This was a retrospective study of 73 primarily blast-injured casualties with combat extremity wounds. Binary classification models for pneumonia prediction were developed with measurements of injury severity from the Abbreviated Injury Scale (AIS), transfusion blood products received before arrival at Walter Reed National Military Medical Center (WRNMMC), and serum protein levels. Predictive models were generated with leave-one-out-cross-validation using the variable selection method of backward elimination (BE) and the machine learning algorithms of random forests (RF) and logistic regression (LR). BE was attempted with two predictor sets: (1) all variables and (2) serum proteins alone. RESULTS: Incidence of pneumonia was 12% (n = 9). Different variable sets were produced by BE when considering all variables and just serum proteins alone. BE selected the variables ISS, AIS chest, and cryoprecipitate within the first 24 h following injury for the first predictor set 1 and FGF-basic, IL-2R, and IL-6 for predictor set 2. Using both variable sets, a RF was generated with AUCs of 0.95 and 0.87-both higher than LR algorithms. CONCLUSION: Advanced modeling allowed for the identification of clinical and biomarker data predictive of pneumonia in a cohort of predominantly blast-injured combat trauma patients. The generalizability of the models developed here will require an external validation dataset.

Outcomes of tranexamic acid administration in military trauma patients with intracranial hemorrhage: a cohort study.

BACKGROUND: Tranexamic acid (TXA) may be a useful adjunct for military patients with severe traumatic brain injury (TBI). These patients are often treated in austere settings without immediate access to neurosurgical intervention. The purpose of this study was to evaluate any association between TXA use and progression of intracranial hemorrhage (ICH), neurologic outcomes, and venous thromboembolism (VTE) in TBI. METHODS: This was a retrospective cohort study of military casualties from October 2010 to December 2015 who were transferred to a military treatment facility (MTF) in the United States. Data collected included: demographics, types of injuries, initial and interval head computerized tomography (CT) scans, Glasgow Coma Scores (GCS), and six-month Glasgow Outcome Scores (GOS). Results were stratified based on TXA administration, progression of ICH, and VTE. RESULTS: Of the 687 active duty service members reviewed, 71 patients had ICH (10.3%). Most casualties were injured in a blast (80.3%), with 36 patients (50.7%) sustaining a penetrating TBI. Mean ISS was 28.2 ± 12.3. Nine patients (12.7%) received a massive transfusion within 24 h of injury, and TXA was administered to 14 (19.7%) casualties. Patients that received TXA had lower initial reported GCS (9.2 ± 4.4 vs. 12.5 ± 3.4, p = 0.003), similar discharge GCS (13.3 ± 4.0 vs. 13.8 ± 3.2, p = 0.58), and a larger improvement between initial and discharge GCS (3.7 ± 3.9 vs. 1.3 ± 3.1, p = 0.02). However, there was no difference in mortality (7.1% vs. 7.0%, p = 1.00), progression of ICH (45.5% vs. 14.7%, p = 0.09), frequency of cranial decompression (50.0% vs. 42.1%, p = 0.76), or mean GOS (3.5 ± 0.9 vs. 3.8 ± 1.0, p = 0.13). Patients administered TXA had a higher rate of VTE (35.7% vs. 7.0%, p = 0.01). On multivariate analysis, however, TXA was not independently associated with VTE. CONCLUSIONS: Patients that received TXA were associated with an improvement in GCS but not in progression of ICH or GOS. TXA was not independently associated with VTE, although this may be related to a paucity of patients receiving TXA. Decisions about TXA administration in military casualties with ICH should be considered in the context of the availability of neurosurgical intervention as well as severity of extracranial injuries and need for massive transfusion.

Ostomy Usage for Colorectal Trauma in Combat Casualties.

INTRODUCTION: The role for diverting ostomy as a method to help reduce morbidity and mortality has been well established in the combat trauma population. However, factors that influence the type of ostomy used and which ostomies become permanent are poorly studied. We examine patterns of ostomy usage and reversal in a large series of combat trauma patients. METHODS: We performed a retrospective review of combat casualties treated at our continental U.S. military treatment facility from 2003 to 2015. All patients who underwent ostomy formation were included. Clinical and demographic factors were collected for all patients including the type of ostomy and whether or not ostomy reversal took place. Patients were grouped and analyzed based on ostomy type and by ostomy reversal. RESULTS: We identified 202 patients who had ostomies created. End colostomies were most common (N = 149) followed by loop colostomies (N = 34) and end ileostomies (N = 19). Casualties that underwent damage control laparotomy (DCL) were less likely to have a loop colostomy created (p < 0.001). Ostomy reversal occurred in 89.9% of patients. There was no difference in ostomy reversal rates by ostomy type (p = 0.080). Presence of a pelvic fracture was associated with permanent ostomy (OR = 3.28, p = 0.019), but no factor independently predicted a permanent ostomy on multivariate analysis. DISCUSSION: DCL and a severe perineal injury most strongly influence ostomy type selection. Most patients undergo colostomy reversal, and no factor independently predicted an ostomy being permanent. These findings provide a framework for understanding the issue of fecal diversion in the combat trauma population and inform military surgeons about injury patterns and treatment options.

FTY720 Effects on Inflammation and Liver Damage in a Rat Model of Renal Ischemia-Reperfusion Injury.

OBJECTIVE: Ischemia-reperfusion injury (IRI) produces systemic inflammation with the potential for causing organ failure in tissues peripheral to the initial site of injury. We speculate that treatment strategies that dampen inflammation may be therapeutically beneficial to either the initial site of injury or peripheral organs. To test this, we evaluated the impact of FTY720-induced sequestration of circulating mature lymphocytes on renal IRI and secondary organ injury. METHODS: A microvascular clamp was surgically placed around the left renal pedicle of anesthetized male Sprague-Dawley rats with either vehicle or FTY720 treatment (0.3 mg/kg) intravenously injected after 15 min of ischemia. Blood flow was restored after 60 min. Cohorts of anesthetized rats were euthanized at 6, 24, or 72 hrs with tissue samples collected for analysis. RESULTS: FTY720 treatment resulted in profound T lymphocyte reduction in peripheral blood. Histopathologic examination, clinical chemistries, and gene transcript expression measurements revealed that FTY720 treatment reduced hepatocellular degeneration, reduced serum markers of liver injury (ALT/AST), and reduced the expression of gene targets associated with IRI. CONCLUSION: These findings support an anti-inflammatory effect of FTY720 in the liver where the expression of genes associated with apoptosis, chemotaxis, and the AP-1 transcription factor was reduced. Findings presented here provide the basis for future studies evaluating FTY720 as a potential therapeutic agent to treat complications resulting from renal IRI.

Review of an emergency general surgery process improvement program at a verified military trauma center.

INTRODUCTION: Decreasing combat-based admissions to our military facility have made it difficult to maintain a robust trauma process improvement (PI) program. Since emergency general surgery (EGS) and trauma patients share similarities, we merged the care of our EGS and trauma patients into one acute care surgery (ACS) team. An EGS PI program was developed based on trauma PI principles to facilitate continued identification of opportunities for improvement despite our decline in trauma admissions. Analysis of the first 18 months of combined ACS PI data is presented. METHODS: EGS registry inclusion criteria was based on published Association for the Surgery of Trauma's recommendations. Program components and PI categories were based on our existing trauma PI program. Dedicated coordinators actively reviewed and cataloged patient care and outcomes. Deviations from standard practice patterns, unplanned interventions, and other complications were abstracted, categorized, and evaluated through levels of review similar to accepted trauma PI principles. Data for the first six quarters were collated and trends were analyzed. RESULTS: Over 18 months, 696 EGS patients met registry inclusion criteria, with 468 patients (67%) undergoing operative intervention. Over the same time, 353 trauma patients were admitted with 158 undergoing operative intervention (56.4%). Of the 696 EGS patients and 353 trauma patients, 226 (32%) and 243 (69%) PI events were identified, respectively. Common events included unplanned therapies, re-admissions, and unplanned ICU admissions. Based on analysis of all events, four new areas for improvement initiatives were identified. Results of these initiatives included implementation of a multi-disciplinary EGS PI committee, consensus protocols, and departmental and hospital-wide actions. CONCLUSION: In an 18-month period, integration of our EGS patients into a novel, combined ACS PI program facilitated recognition of an additional 226 PI events and provided a substrate for continued improvements in patient care.

Administration of FTY720 during Tourniquet-Induced Limb Ischemia Reperfusion Injury Attenuates Systemic Inflammation.

Acute ischemia-reperfusion injury (IRI) of the extremities leads to local and systemic inflammatory changes which can hinder limb function and can be life threatening. This study examined whether the administration of the T-cell sequestration agent, FTY720, following hind limb tourniquet-induced skeletal muscle IRI in a rat model would attenuate systemic inflammation and multiple end organ injury. Sprague-Dawley rats were subjected to 1 hr of ischemia via application of a rubber band tourniquet. Animals were randomized to receive an intravenous bolus of either vehicle control or FTY720 15 min after band placement. Rats (n = 10/time point) were euthanized at 6, 24, and 72 hr post-IRI. Peripheral blood as well as lung, liver, kidney, and ischemic muscle tissue was analyzed and compared between groups. FTY720 treatment markedly decreased the number of peripheral blood T cells (p < 0.05) resulting in a decreased systemic inflammatory response and lower serum creatinine levels and had a modest but significant effect in decreasing the transcription of injury-associated target genes in multiple end organs. These findings suggest that early intervention with FTY720 may benefit the treatment of IRI of the limb. Further preclinical studies are necessary to characterize the short-term and long-term beneficial effects of FTY720 following tourniquet-induced IRI.

The Effect of Copper Addition on the Activity and Stability of Iron-Based CO2 Hydrogenation Catalysts.

Iron-based CO2 catalysts have shown promise as a viable route to the production of olefins from CO2 and H2 gas. However, these catalysts can suffer from low conversion and high methane selectivity, as well as being particularly vulnerable to water produced during the reaction. In an effort to improve both the activity and durability of iron-based catalysts on an alumina support, copper (10-30%) has been added to the catalyst matrix. In this paper, the effects of copper addition on the catalyst activity and morphology are examined. The addition of 10% copper significantly increases the CO2 conversion, and decreases methane and carbon monoxide selectivity, without significantly altering the crystallinity and structure of the catalyst itself. The FeCu/K catalysts form an inverse spinel crystal phase that is independent of copper content and a metallic phase that increases in abundance with copper loading (>10% Cu). At higher loadings, copper separates from the iron oxide phase and produces metallic copper as shown by SEM-EDS. An addition of copper appears to increase the rate of the Fischer-Tropsch reaction step, as shown by modeling of the chemical kinetics and the inter- and intra-particle transport of mass and energy.

Inhibiting CARD11 translation during BCR activation by targeting the eIF4A RNA helicase.

Human diffuse large B-cell lymphomas (DLBCLs) often aberrantly express oncogenes that generally contain complex secondary structures in their 5' untranslated region (UTR). Oncogenes with complex 5'UTRs require enhanced eIF4A RNA helicase activity for translation. PDCD4 inhibits eIF4A, and PDCD4 knockout mice have a high penetrance for B-cell lymphomas. Here, we show that on B-cell receptor (BCR)-mediated p70s6K activation, PDCD4 is degraded, and eIF4A activity is greatly enhanced. We identified a subset of genes involved in BCR signaling, including CARD11, BCL10, and MALT1, that have complex 5'UTRs and encode proteins with short half-lives. Expression of these known oncogenic proteins is enhanced on BCR activation and is attenuated by the eIF4A inhibitor Silvestrol. Antigen-experienced immunoglobulin (Ig)G(+) splenic B cells, from which most DLBCLs are derived, have higher levels of eIF4A cap-binding activity and protein translation than IgM(+) B cells. Our results suggest that eIF4A-mediated enhancement of oncogene translation may be a critical component for lymphoma progression, and specific targeting of eIF4A may be an attractive therapeutic approach in the management of human B-cell lymphomas.