An RNA stem-loop functions in conjunction with an upstream open reading frame to direct preferential translation in the integrated stress response.

In response to environmental stresses, cells invoke translational control to conserve resources and rapidly reprogram gene expression for optimal adaptation. A central mechanism for translational control involves phosphorylation of the α subunit of eIF2 (p-eIF2α), which reduces delivery of initiator tRNA to ribosomes. Because p-eIF2α is invoked by multiple protein kinases, each responding to distinct stresses, this pathway is named the integrated stress response (ISR).

GCN2 eIF2 kinase promotes prostate cancer by maintaining amino acid homeostasis.

A stress adaptation pathway termed the integrated stress response has been suggested to be active in many cancers including prostate cancer (PCa). Here, we demonstrate that the eIF2 kinase GCN2 is required for sustained growth in androgen-sensitive and castration-resistant models of PCa both in vitro and in vivo, and is active in PCa patient samples. Using RNA-seq transcriptome analysis and a CRISPR-based phenotypic screen, GCN2 was shown to regulate expression of over 60 solute-carrier () genes, including those involved in amino acid transport and loss of GCN2 function reduces amino acid import and levels.

The eIF2 kinase GCN2 directs keratinocyte collective cell migration during wound healing via coordination of reactive oxygen species and amino acids.

Healing of cutaneous wounds requires the collective migration of epithelial keratinocytes to seal the wound bed from the environment. However, the signaling events that coordinate this collective migration are unclear. In this report, we address the role of phosphorylation of eukaryotic initiation factor 2 (eIF2) and attendant gene expression during wound healing.

TgIF2K-B Is an eIF2α Kinase in Toxoplasma gondii That Responds to Oxidative Stress and Optimizes Pathogenicity.

is an obligate intracellular parasite that persists in its vertebrate hosts in the form of dormant tissue cysts, which facilitate transmission through predation. The parasite must strike a balance that allows it to disseminate throughout its host without killing it, which requires the ability to properly counter host cell defenses. For example, oxidative stress encountered by is suggested to impair parasite replication and dissemination.

Toxoplasma gondii Co-opts the Unfolded Protein Response To Enhance Migration and Dissemination of Infected Host Cells.

is an intracellular parasite that reconfigures its host cell to promote pathogenesis. One consequence of parasitism is increased migratory activity of host cells, which facilitates dissemination. Here, we show that triggers the unfolded protein response (UPR) in host cells through calcium release from the endoplasmic reticulum (ER).

Regulation of arginine transport by GCN2 eIF2 kinase is important for replication of the intracellular parasite Toxoplasma gondii.

Toxoplasma gondii is a prevalent protozoan parasite that can infect any nucleated cell but cannot replicate outside of its host cell. Toxoplasma is auxotrophic for several nutrients including arginine, tryptophan, and purines, which it must acquire from its host cell. The demands of parasite replication rapidly deplete the host cell of these essential nutrients, yet Toxoplasma successfully manages to proliferate until it lyses the host cell.

Adducins inhibit lung cancer cell migration through mechanisms involving regulation of cell-matrix adhesion and cadherin-11 expression.

Cell migration is a critical mechanism controlling tissue morphogenesis, epithelial wound healing and tumor metastasis. Migrating cells depend on orchestrated remodeling of the plasma membrane and the underlying actin cytoskeleton, which is regulated by the spectrin-adducin-based membrane skeleton. Expression of adducins is altered during tumorigenesis, however, their involvement in metastatic dissemination of tumor cells remains poorly characterized.

Recreational Marijuana Use and Acute Myocardial Infarction: Insights from Nationwide Inpatient Sample in the United States.

Background Marijuana is a widely used recreational substance. Few cases have been reported of acute myocardial infarction following marijuana use. To our knowledge, this is the first ever study analyzing the lifetime odds of acute myocardial infarction (AMI) with marijuana use and the outcomes in AMI patients with versus without marijuana use.

Krüppel-Like Transcription Factor KLF1 Is Required for Optimal γ- and β-Globin Expression in Human Fetal Erythroblasts.

In human adult erythroid cells, lower than normal levels of Krüppel-like transcription factor 1 (KLF1) are generally associated with decreased adult β- and increased fetal γ-globin gene expression. KLF1 also regulates BCL11A, a known repressor of adult γ-globin expression. In seeming contrast to the findings in adult cells, lower amounts of KLF1 correlate with both reduced embryonic and reduced fetal β-like globin mRNA in mouse embryonic erythroid cells.

Hybrid arch debranching and endograft repair in a patient with a ruptured thoracic aortic aneurysm.

Recent advances in hybrid techniques of aortic arch debranching allow for the repair of thoracic aortic arch aneurysm without requiring cardiopulmonary bypass or hypothermic circulatory arrest. We describe the repair of a ruptured proximal descending thoracic aortic aneurysm, using off-pump aortic arch debranching and antegrade transaortic deployment of a thoracic endograft in an elderly patient.

Endovascular recanalization of total occlusions of the mesenteric and celiac arteries.

Objective: To evaluate our experience with the endovascular treatment of total occlusions of the mesenteric and celiac arteries.

Methods: We performed a retrospective review of endovascular stenting of 27 nonembolic total occlusions of the superior mesenteric artery (SMA) and celiac artery (CA) between July 2004 and July 2011 (26 patients, 16 females; mean age, 62 ± 13 years). A variety of demographic, lesion-related and procedure-related variables were evaluated for potential impact of technical success and patency.

Anatomic bifurcated reconstruction of chronic bilateral innominate-superior vena cava occlusion using the Y-stenting technique.

This article presents the case of a 42-year-old man who presented with superior vena cava (SVC) syndrome due to fibrosing mediastinitis with multiple failed attempts at recanalization. We initially treated him with unilateral sharp needle recanalization of the right innominate vein into the SVC stump followed by stenting. Although his symptoms improved immediately, they did not completely resolve.

Prophylactic antibiotic days as a predictor of sensitivity patterns in Acinetobacter pneumonia.

Background: Ventilator-associated pneumonia (VAP) secondary to Acinetobacter spp. in critically ill trauma patients has increased. More importantly, the incidence of multi-drug-resistant (MDR) Acinetobacter VAP has increased.

Secretory immunoglobulin A abrogates inflammatory responses and improves mortality after pseudomonas pneumonia.

Background: Secretory immunoglobulin A (SIgA) is the principle antibody at respiratory and other mucosal sites. Its concentration in mucosal secretions is influenced by route of nutrition and insults common to the trauma patient. SIgA has anti-inflammatory effects, which may protect against exaggerated inflammatory responses after infection.

Sequence of immunoglobulin isotype exposure modulates inflammatory response to bacteria and lipopolysaccharide in vitro.

Background: Secretory immunoglobulin A (sIgA) and immunoglobulin G (IgG) are the principal immunoglobulins in the respiratory tract. Under normal circumstances, the upper respiratory tract contains predominantly sIgA, whereas IgG is of primary importance in the lower tract. Unlike other antibody isotypes, IgA antibodies participate in host defense functions without inciting inflammatory processes that might cause collateral damage to tissues.

Benign fibroepithelial polyp arising in the bronchus: a case report and review of the literature.

Benign endobronchial polyps are rare findings that present a diagnostic dilemma not only for the clinician but also for the pathologist. We describe a man with repeated visits to emergency departments for coughing spells who ultimately underwent bronchoscopy and biopsy. The biopsy specimen was initially diagnosed as a leiomyoma, but the final pathologic diagnosis of the gross specimen was a benign fibroepithelial polyp.

Dose-dependent effects of ethanol and E. coli on gut permeability and cytokine production.

Introduction: The gut may prime inflammatory responses following shock/trauma insults. Ethanol (EtOH) use is common in trauma patients and may impair intestinal barrier function. We compared varying concentrations of EtOH on proinflammatory cytokine production of Caco2 cell monolayers and the resultant changes in barrier function.

Cleavage of SIgA by gram negative respiratory pathogens enhance neutrophil inflammatory potential.

Objective: Secretory immunoglobulin A (SIgA), the principle immune defense at respiratory and other mucosal sites in the body, is highly dependant on its molecular structure for effective antibody function. Previous studies have demonstrated that gram-negative but not gram-positive isolates from patients with nosocomial pneumonia have IgA protease activity that contributes to the development of infection. We postulate that SIgA cleavage by bacteria would also affect anti-inflammatory properties of IgA and studied this in vitro.

Conversion of intestinal bypass to Roux-en-Y gastric bypass: a case report and brief review.

Intestinal bypass procedures for the treatment of morbid obesity have been largely replaced by Roux-en-Y gastric bypass procedures. The main reason for this change over the past 40 years stems from the myriad of negative nutritional and physiologic repercussions of intestinal bypass procedures. We present a case of a patient with severely atrophied small bowel and the novel method used for the conversion of the intestinal bypass procedure to Roux-en-Y gastric bypass.

Secretory immunoglobulin a blunts gut-mediated priming of neutrophils in vitro.

Background: Gut ischemia may prime neutrophils to produce an exaggerated inflammatory response when challenged with bacterial pathogens. Secretory immunoglobulin A (sIgA) is the first line of defense against potential pathogens, but may also exert its anti-inflammatory effects on potentially destructive neutrophil functions. We hypothesized that sIgA would blunt the gut-mediated priming events that lead to neutrophil hypersensitivity to bacterial challenge.

The synergistic effect of ethanol and shock insults on Caco-2 cytokine production and apoptosis.

Gut epithelial cells are important in orchestrating immunoinflammatory responses in the gut and may impact systemic immunocompetent cells after shock and trauma. Ethanol (EtOH) intoxication is an important etiological factor in trauma and may increase the likelihood of posttraumatic septic complications. Both EtOH and gut I/R impair intestinal barrier function.

The intestinal epithelial cell modulates the effect of alcohol on neutrophil inflammatory potential.

Background: Ethanol (EtOH) intoxication increases posttraumatic infectious complications. EtOH is thought to be immunosuppressive, but the effect of the interaction with the gut and associated microflora on host defense is unknown. We studied the ability of intestinal epithelial cells and bacteria to modulate EtOH effects on polymorphonuclear (PMN) cell function in vitro.

Ethanol effects proinflammatory state of neutrophils in shock.

Introduction: Ethanol (EtOH) intoxication plays an important role in the etiology of traumatic events and has often been described as having immunosuppressive effects. EtOH has been shown to affect intestinal barrier function in prior studies. The ability of gut derived factors on neutrophil function in this setting is unknown.

T-cell cytokines affect mucosal immunoglobulin A transport.

Background: Secretory immunoglobulin A (sIgA) is the principle immune defense against bacteria and other pathogens in the gut and other mucosal surfaces. sIgA is produced locally by plasma cells and transported (transcytosis) across epithelial cells into luminal secretions. sIgA production and transcytosis are governed by multiple signals, which may be affected by T cells.