The epithelial-to-mesenchymal transition enables carcinoma cells to acquire malignancy-associated traits and the properties of tumor-initiating cells (TICs). TICs have emerged in recent years as ...important targets for cancer therapy, owing to their ability to drive clinical relapse and enable metastasis. Here, we propose a strategy to eliminate mesenchymal TICs by inducing their conversion to more epithelial counterparts that have lost tumor-initiating ability. We report that increases in intracellular levels of the second messenger, adenosine 3',5'-monophosphate, and the subsequent activation of protein kinase A (PKA) induce a mesenchymal-to-epithelial transition (MET) in mesenchymal human mammary epithelial cells. PKA activation triggers epigenetic reprogramming of TICs by the histone demethylase PHF2, which promotes their differentiation and loss of tumor-initiating ability. This study provides proof-of-principle for inducing an MET as differentiation therapy for TICs and uncovers a role for PKA in enforcing and maintaining the epithelial state.
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BFBNIB, NMLJ, NUK, ODKLJ, PNG, SAZU, UL, UM, UPUK
In certain regions of the United States, there has been a dramatic proliferation of trauma centers. The goal of our study was to evaluate transport times during this period of trauma center ...proliferation.
Aggregated data summarizing level I trauma center admissions in Arizona between 2009 and 2018 were provided to our institution by the Arizona Department of Health Services. We evaluated patient demographics, transport times, and injury severity for both rural and urban injuries.
Data included statistics summarizing 266,605 level I trauma admissions in the state of Arizona. The number of state-designated trauma centers during this time increased from 14 to 47, with level I centers increasing from 8 to 13. Slight decreases in mean Injury Severity Score (rural, 9.4 vs. 8.4; urban, 7.9 vs. 7.0) were observed over this period. Median transport time for cases transported from the injury scene directly to a level I center remained stable in urban areas at 0.9 hours in both 2009 and 2018. In rural areas, transport times for these cases were approximately double but also stable, with median times of 1.8 and 1.9 hours. Transport times for cases requiring interfacility transfer before admission at a level I center increased by 0.3 hours for urban injuries (5.3-5.6 hours) and 0.9 hours for rural injuries (5.6-6.5 hours).
Despite the threefold increase in the number of state-designated trauma centers, transport time has not decreased in urban or rural areas. This finding highlights the need for regulatory oversight regarding the number and geographic placement of state-designated trauma centers.
Care management, level IV, Epidemiological, level III.
Patients undergoing surgical resection of primary breast tumors confront a risk for metastatic recurrence that peaks sharply 12 to 18 months after surgery. The cause of early metastatic relapse in ...breast cancer has long been debated, with many ascribing these relapses to the natural progression of the disease. Others have proposed that some aspect of surgical tumor resection triggers the outgrowth of otherwise-dormant metastases, leading to the synchronous pattern of relapse. Clinical data cannot distinguish between these hypotheses, and previous experimental approaches have not provided clear answers. Such uncertainty hinders the development and application of therapeutic approaches that could potentially reduce early metastatic relapse. We describe an experimental model system that definitively links surgery and the subsequent wound-healing response to the outgrowth of tumor cells at distant anatomical sites. Specifically, we find that the systemic inflammatory response induced after surgery promotes the emergence of tumors whose growth was otherwise restricted by a tumor-specific T cell response. Furthermore, we demonstrate that perioperative anti-inflammatory treatment markedly reduces tumor outgrowth in this model, suggesting that similar approaches might substantially reduce early metastatic recurrence in breast cancer patients.
The epithelial-mesenchymal transition program becomes activated during malignant progression and can enrich for cancer stem cells (CSCs). We report that inhibition of protein kinase C α (PKCα) ...specifically targets CSCs but has little effect on non-CSCs. The formation of CSCs from non-stem cells involves a shift from EGFR to PDGFR signaling and results in the PKCα-dependent activation of FRA1. We identified an AP-1 molecular switch in which c-FOS and FRA1 are preferentially utilized in non-CSCs and CSCs, respectively. PKCα and FRA1 expression is associated with the aggressive triple-negative breast cancers, and the depletion of FRA1 results in a mesenchymal-epithelial transition. Hence, identifying molecular features that shift between cell states can be exploited to target signaling components critical to CSCs.
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•Inhibition of PKCα preferentially targets breast cancer stem cells•Activation of an EMT program induces a shift from EGFR to PDGFR signaling•Activation of an AP-1 molecular switch involves c-FOS and FRA1 in CSCs•FRA1 is required for the EMT phenotype and tumor-initiation ability
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Ventilator-associated pneumonia is a well-acknowledged complication after hospitalization for injury or surgical emergency. The contribution to the literature on this topic by Dr Timothy Fabian and ...the Memphis group at the Elvis Presley Trauma Center resulted in the contemporary recognition that the diagnosis and management of pneumonia is an essential component of surgical critical care. During three decades, the Memphis group, under Dr Fabian’s leadership, performed numerous clinical studies that led to the publication of over 40 articles concerning the epidemiology, diagnosis, and treatment of pneumonia after injury. The purpose of this review is to survey the consecutive studies from Memphis specifically that led to the development of a clinical pathway that has stood the test of time. Examination of the research output during this period provides a case study in how bedside clinical research can inform clinical practice and is a model for applied science in the intensive care unit.
Background Standard hemodynamic evaluation of patients in shock may underestimate severity of hemorrhage given physiologic compensation. Blood lactate (BL) is an important adjunct in characterizing ...shock, and point-of-care devices are currently available for use in the prehospital (PH) setting. The objective of this study was to determine if BL levels have better predictive value when compared with systolic blood pressure (SBP) for identifying patients with an elevated risk of significant transfusion and mortality in a hemodynamically indeterminant cohort. Study Design We selected trauma patients admitted to a level I trauma center over a 9-year period with SBP between 90 and 110 mmHg. The predictive capability of initial emergency department (ED) BL for needing ≥6 units packed RBCs within 24 hours postinjury and mortality was compared with PH-SBP and ED-SBP by comparing estimated area under the receiver operator curve (AUC). Results We identified 2,413 patients with ED-SBP and 787 patients with PH-SBP and ED-BL. ED-BL was statistically better than PH-SBP (p = 0.0025) and ED-SBP (p < 0.0001) in predicting patients who will need ≥ 6 U packed RBCs within 24 hours postinjury (AUC: ED-BL, 0.72 vs PH-SBP, 0.61; ED-BL, 0.76 vs ED-SBP, 0.60). ED-BL was also a better predictor than both PH-SBP (p = 0.0235) and ED-SBP (p < 0.0001) for mortality (AUC: ED-BL, 0.74 vs PH-SBP, 0.60; ED-BL, 0.76 vs ED-SBP, 0.61). Conclusions ED-BL is a better predictor than SBP in identifying patients requiring significant transfusion and mortality in this cohort with indeterminant SBP. These findings suggest that point-of-care BL measurements could improve trauma triage and better identify patients for enrollment in interventional trials. Further studies using BL measurement in the PH environment are warranted.
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GEOZS, NUK, OILJ, SBCE, SBJE, UL, UPUK
IMPORTANCE: Severely injured patients experiencing hemorrhagic shock often require massive transfusion. Earlier transfusion with higher blood product ratios (plasma, platelets, and red blood cells), ...defined as damage control resuscitation, has been associated with improved outcomes; however, there have been no large multicenter clinical trials. OBJECTIVE: To determine the effectiveness and safety of transfusing patients with severe trauma and major bleeding using plasma, platelets, and red blood cells in a 1:1:1 ratio compared with a 1:1:2 ratio. DESIGN, SETTING, AND PARTICIPANTS: Pragmatic, phase 3, multisite, randomized clinical trial of 680 severely injured patients who arrived at 1 of 12 level I trauma centers in North America directly from the scene and were predicted to require massive transfusion between August 2012 and December 2013. INTERVENTIONS: Blood product ratios of 1:1:1 (338 patients) vs 1:1:2 (342 patients) during active resuscitation in addition to all local standard-of-care interventions (uncontrolled). MAIN OUTCOMES AND MEASURES: Primary outcomes were 24-hour and 30-day all-cause mortality. Prespecified ancillary outcomes included time to hemostasis, blood product volumes transfused, complications, incidence of surgical procedures, and functional status. RESULTS: No significant differences were detected in mortality at 24 hours (12.7% in 1:1:1 group vs 17.0% in 1:1:2 group; difference, −4.2% 95% CI, −9.6% to 1.1%; P = .12) or at 30 days (22.4% vs 26.1%, respectively; difference, −3.7% 95% CI, −10.2% to 2.7%; P = .26). Exsanguination, which was the predominant cause of death within the first 24 hours, was significantly decreased in the 1:1:1 group (9.2% vs 14.6% in 1:1:2 group; difference, −5.4% 95% CI, −10.4% to −0.5%; P = .03). More patients in the 1:1:1 group achieved hemostasis than in the 1:1:2 group (86% vs 78%, respectively; P = .006). Despite the 1:1:1 group receiving more plasma (median of 7 U vs 5 U, P < .001) and platelets (12 U vs 6 U, P < .001) and similar amounts of red blood cells (9 U) over the first 24 hours, no differences between the 2 groups were found for the 23 prespecified complications, including acute respiratory distress syndrome, multiple organ failure, venous thromboembolism, sepsis, and transfusion-related complications. CONCLUSIONS AND RELEVANCE: Among patients with severe trauma and major bleeding, early administration of plasma, platelets, and red blood cells in a 1:1:1 ratio compared with a 1:1:2 ratio did not result in significant differences in mortality at 24 hours or at 30 days. However, more patients in the 1:1:1 group achieved hemostasis and fewer experienced death due to exsanguination by 24 hours. Even though there was an increased use of plasma and platelets transfused in the 1:1:1 group, no other safety differences were identified between the 2 groups. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01545232
Level 1 trauma centers should provide definitive care for every aspect of injury. However, in environments that have experienced trauma center proliferation, not all level 1 centers may have the ...resources or expertise needed for every patient, necessitating transfer to another trauma center. The purpose of this study was to assess the incidence of such transfers and associated impact on patient outcome and burden on the receiving level 1 center.
In a metropolitan area experiencing trauma center proliferation, we performed a 5.5-year review of patient transfers to an established level 1 (index center) from other state designated level 1 centers. American College of Surgeons verification level was identified for each facility. Comparisons were performed between the cohort of transferred patients and patients with similar demographics, injury patterns, and severity managed at the index center using propensity score matching.
A total of 104 patients were received from other state level 1 centers (39% American College of Surgeons level 2, 61% American College of Surgeons level 1). Nearly 70% of patients were transferred for definitive evaluation and/or management of brain, spine, or cerebrovascular injury. For 76% of this subgroup, specialty consultation was available, but the injury was deemed beyond their capability. Comparison of the transfer cohort propensity score matched to the control cohort (93 vs. 558 patients) demonstrated increased length of stay (6.5 days vs. 4.6 days, p = 0.001) and cost (US $36,027 vs. US $30,654, p = 0.033) associated with the transfer cohort, with similar mortality (12.1% vs. 9.7%, p = 0.492).
The number of level 1 to level 1 transfers observed imply a disparity in resources and capability among level 1 trauma centers in the region. The majority of transfers were for neurosurgical care, suggestive of a deficit of adequate neurosurgical coverage in the setting of trauma center proliferation. Both patients and established trauma centers bear the burden for these transfers with respect to increased cost and length of stay.
Care management, level IV.
Pelvic fractures are common and potentially life-threatening. Pelvic circumferential compression devices (PCCD) can temporize hemorrhage, but more invasive strategies that involve femoral access may ...be necessary for definitive treatment. The aim of our study was to evaluate the efficacy of PCCDs reducing open book pelvic fractures when utilizing commonly described modifications and placement adjustments that allow for access to the femoral vasculature.
Open book pelvic fractures were created in adult cadavers. Three commercially available PCCDs were used to reduce fractures. The binders were properly placed, moved caudally, or moved cranially and modified. Fracture reduction rates were then recorded.
The pelvic fracture was completely reduced with every PCCD tested when properly placed. Reduction rates decreased with improper placement and modifications.
Modifying PCCD placement to allow femoral access decreased the effectiveness of these devices Clinicians should be aware of this possibility when caring for critically injured trauma patients with pelvic fractures.
•Properly placed pelvic binders reduced open book pelvic fractures 100% of the time.•Modification to binder position, with or without modification to the pelvic binder itself, is required for femoral access.•Successfully reduced open book pelvic fractures decreased with binder modifications.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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