Intracellular Hmgb1 inhibits inflammatory nucleosome release and limits acute pancreatitis in mice

BACKGROUND & AIMS: High mobility group box 1 (HMGB1) is an abundant protein that regulates chromosome architecture and also functions as a damage-associated molecular pattern molecule. Little is known about its intracellular roles in response to tissue injury or during subsequent local and systemic inflammatory responses. We investigated the function of Hmgb1 in mice after induction of acute pancreatitis. METHODS: We utilized a Cre/LoxP system to create mice with pancreas-specific disruption in Hmbg1 (Pdx1-Cre; HMGB1(flox/flox) mice). Acute pancreatitis was induced in these mice (HMGB1(flox/flox) mice served as controls) after injection of l-arginine or cerulein. Pancreatic tissues and acinar cells were collected and analyzed by histologic, immunoblot, and immunohistochemical analyses. RESULTS: After injection of l-arginine or cerulein, Pdx1-Cre; HMGB1(flox/flox) mice developed acute pancreatitis more rapidly than controls, with increased mortality. Pancreatic tissues of these mice also had higher levels of serum amylase, acinar cell death, leukocyte infiltration, and interstitial edema than controls. Pancreatic tissues and acinar cells collected from the Pdx1-Cre; HMGB1(flox/flox) mice after l-arginine or cerulein injection demonstrated nuclear catastrophe with greater nucleosome release when compared with controls, along with increased phosphorylation/activation of RELA nuclear factor kappaB, degradation of inhibitor of kappaB, and phosphorylation of mitogen-activated protein kinase. Inhibitors of reactive oxygen species (N-acetyl-l-cysteine) blocked l-arginine-induced DNA damage, necrosis, apoptosis, release of nucleosomes, and activation of nuclear factor kappaB in pancreatic tissues and acinar cells from Pdx1-Cre; HMGB1(flox/flox) and control mice. Exogenous genomic DNA and recombinant histone H3 proteins significantly induced release of HMGB1 from mouse macrophages; administration of antibodies against H3 to mice reduced serum levels of HMGB1 and increased survival after l-arginine injection. CONCLUSIONS: In 2 mouse models of acute pancreatitis, intracellular HMGB1 appeared to prevent nuclear catastrophe and release of inflammatory nucleosomes to block inflammation. These findings indicate a role for the innate immune response in tissue damage

Systematic Review of Emotional Intelligence in Surgical Education

Introduction: Emotional intelligence (EI) was first coined in 1990 as a successful leadership skillset comprised of self-management, social awareness, and empathy. EI has wide-reaching applications to the surgical field including teamwork, patient care, and job satisfaction. Positive linkage has been made between higher EI levels in both the patient-doctor relationship and physicians in a leadership role. The purpose of our systematic review was to evaluate the use of EI in surgical education and assess whether its prevalence has grown with the general acceptance of EI in many fields including medicine. A secondary aim was to compare the incorporation of EI in surgical education to other fields of graduate medical education. Methods: A MEDLINE search was performed for publications containing both “surgery” and “emotional intelligence” with at least one term present in the title. Articles were included if EI in surgical education was considered a significant focus. The results were grouped by publication date in 5-year increments to identify temporal trends. A separate series of MEDLINE searches were performed with the phrase “emotional intelligence” in any field and either “surg*”, “internal medicine”, “pediatric”, “neurology”, “obstetric”, “gynecology”, “OBGYN”, “emergency”, and “psychiatr*” in the title with no constraints on publication date. OBGYN articles were combined in one category. Articles were included if they discussed resident education as the primary subject. Results: A total of 25 articles satisfied the MEDLINE search criteria and 7 articles satisfied inclusion criteria. These were sorted by publication date with 0, 1, and 6 articles published between 2001-2005, 2005-2010, and 2010-2015, respectively. Notable trends include: 1) EI is partially inborn, but proven to be learned; 2) Surgical residents have higher EI than the national average; 3) Educational shifts are needed to improve outcomes for the surgeon, patient, health network, and community at large. The comparative data for articles on EI and resident education showed 8 in surgery, 2 in internal medicine, 0 in pediatrics, 0 in neurology, 0 in OBGYN, 0 in emergency, and 4 in psychiatry. Conclusion: Integration of EI principles is a growing trend within surgical education. Emphasis has been placed on quantitative assessment of EI in residents and residency applicants. Further study is warranted on the integration process of EI in surgical education and its impact on patient outcomes and long-term job satisfaction

Cellular and molecular mechanisms of breast implant-associated anaplastic large cell lymphoma

Summary: Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is an emerging and highly treatable cancer of the immune system that can form around textured-surface breast implants. Although the underlying cause has yet to be elucidated, an emerging theme - linking pathogenesis to a chronic inflammatory state - continues to dominate the current literature. Specifically, the combination of increasing mutation burden and chronic inflammation leads to aberrant T-cell clonal expansion. However, the impetus remains largely unknown. Proposed mechanisms include a lipopolysaccharide endotoxin response, oncogenic transformation related to viral infection, associated trauma to the breast pocket, particulate matter digestion by capsular macrophages, chronic allergic inflammation, and genetic susceptibility. The Janus kinase-signal transducer and activator of transcription 3 (JAK-STAT3) pathway is a major signaling pathway that regulates a variety of intracellular growth and survival processes. Constitutive activation of JAK-STAT3 has been implicated in several malignancies, including lymphomas, and has recently been identified as a potential key mediator in BIA-ALCL. The purpose of this article is to review the cellular and molecular mechanisms of BIA-ALCL with a focus on the role of oncogenic JAK-STAT3 signaling in BIA-ALCL tumorigenesis and progression. Selected experimental work from the authors' group on aberrant JAK-STAT3 signaling in BIA-ALCL is also included. The authors discuss how an inflammatory microenvironment may facilitate malignant transformation through the JAK-STAT3 pathway - highlighting its potential mechanistic role. The authors' hope is that further investigation of this signaling pathway will reveal avenues for using JAK-STAT3 signaling as a prognostic indicator and novel therapeutic target in the case of advanced disease

Multi-Omic Admission-Based Prognostic Biomarkers Identified by Machine Learning Algorithms Predict Patient Recovery and 30-Day Survival in Trauma Patients

Admission-based circulating biomarkers for the prediction of outcomes in trauma patients could be useful for clinical decision support. It is unknown which molecular classes of biomolecules can contribute biomarkers to predictive modeling. Here, we analyzed a large multi-omic database of over 8500 markers (proteomics, metabolomics, and lipidomics) to identify prognostic biomarkers in the circulating compartment for adverse outcomes, including mortality and slow recovery, in severely injured trauma patients. Admission plasma samples from patients (n = 129) enrolled in the Prehospital Air Medical Plasma (PAMPer) trial were analyzed using mass spectrometry (metabolomics and lipidomics) and aptamer-based (proteomics) assays. Biomarkers were selected via Least Absolute Shrinkage and Selection Operator (LASSO) regression modeling and machine learning analysis. A combination of five proteins from the proteomic layer was best at discriminating resolvers from non-resolvers from critical illness with an Area Under the Receiver Operating Characteristic curve (AUC) of 0.74, while 26 multi-omic features predicted 30-day survival with an AUC of 0.77. Patients with traumatic brain injury as part of their injury complex had a unique subset of features that predicted 30-day survival. Our findings indicate that multi-omic analyses can identify novel admission-based prognostic biomarkers for outcomes in trauma patients. Unique biomarker discovery also has the potential to provide biologic insights

Posterior epidural migration of herniated lumbar disc fragment: a literature review

Elsharkawy AE, Hagemann A, Klassen PD. Posterior epidural migration of herniated lumbar disc fragment: a literature review. Neurosurgical review. 2019;42(4):811-823