Receptor for Advanced Glycation End Products Acts as a Fuel to Colorectal Cancer Development.

Receptor for advanced glycation end-products (RAGE) is a multiligand binding and single-pass transmembrane protein taken in diverse chronic inflammatory conditions. RAGE behaves as a pattern recognition receptor, which binds and is engaged in the cellular response to a variety of damage-associated molecular pattern molecules, as well as HMGB1, S100 proteins, and AGEs (advanced glycation end-products). The RAGE activation turns out to a formation of numerous intracellular signaling mechanisms, resulting in the progression and prolongation of colorectal carcinoma (CRC). The RAGE expression correlates well with the survival of colon cancer cells. RAGE is involved in the tumorigenesis, which increases and develops well in the stressed tumor microenvironment. In this review, we summarized downstream signaling cascade activated by the multiligand activation of RAGE, as well as RAGE ligands and their sources, clinical studies, and tumor markers related to RAGE particularly in the inflammatory tumor microenvironment in CRC. Furthermore, the role of RAGE signaling pathway in CRC patients with diabetic mellitus is investigated. RAGE has been reported to drive assorted signaling pathways, including activator protein 1, nuclear factor-κB, signal transducer and activator of transcription 3, SMAD family member 4 (Smad4), mitogen-activated protein kinases, mammalian target of rapamycin, phosphoinositide 3-kinases, reticular activating system, Wnt/ß-catenin pathway, and Glycogen synthase kinase 3ß, and even microRNAs.

Targeting High Mobility Group Box 1 in Subarachnoid Hemorrhage: A Systematic Review.

Aneurysmal subarachnoid hemorrhage (aSAH) is a complex and potentially deadly disease. Neurosurgical clipping or endovascular coiling can successfully obliterate ruptured aneurysms in almost every case. However, despite successful interventions, the clinical outcomes of aSAH patients are often poor. The reasons for poor outcomes are numerous, including cerebral vasospasm (CVS), post-hemorrhagic hydrocephalus, systemic infections and delayed cerebral ischemia. Although CVS with subsequent cerebral ischemia is one of the main contributors to brain damage after aSAH, little is known about the underlying molecular mechanisms of brain damage. This review emphasizes the importance of pharmacological interventions targeting high mobility group box 1 (HMGB1)-mediated brain damage after subarachnoid hemorrhage (SAH) and CVS. We searched Pubmed, Ovid medline and Scopus for "subarachnoid hemorrhage" in combination with "HMGB1". Based on these criteria, a total of 31 articles were retrieved. After excluding duplicates and selecting the relevant references from the retrieved articles, eight publications were selected for the review of the pharmacological interventions targeting HMGB1 in SAH. Damaged central nervous system cells release damage-associated molecular pattern molecules (DAMPs) that are important for initiating, driving and sustaining the inflammatory response following an aSAH. The discussed evidence suggested that HMGB1, an important DAMP, contributes to brain damage during early brain injury and also to the development of CVS during the late phase. Different pharmacological interventions employing natural compounds with HMGB1-antagonizing activity, antibody targeting of HMGB1 or scavenging HMGB1 by soluble receptors for advanced glycation end products (sRAGE), have been shown to dampen the inflammation mediated brain damage and protect against CVS. The experimental data suggest that HMGB1 inhibition is a promising strategy to reduce aSAH-related brain damage and CVS. Clinical studies are needed to validate these findings that may lead to the development of potential treatment options that are much needed in aSAH.

A treatise on endothelial biology and exosomes: homage to Theresa Maria Listowska Whiteside.

Exosomes are the current primary research focus of Dr. Theresa L. Whiteside. They are key mediators of intercellular communication in the head and neck, as well as other sites. Their effects in the tumor microenvironment are manifold and include suppression of immunity, promotion of angiogenesis, enabling of metastasis, as well as reprogramming of fibroblasts and mesenchymal stromal cells. The aim of this communication is to summarize Dr. Whiteside's contribution to the field of exosome research and details the interactions of exosomes with endothelial cells leading to recent findings on how to target endothelial cells using exosomes as a therapeutic approach.

Inpatients With 'Unexplained' Leukocytosis.

BACKGROUND: Unexplained or persistent leukocytosis is an increasing common cause of consultation to infectious disease physicians. Patients appear to be in a state of continued inflammation recently described as the persistent inflammation-immunosuppression and catabolism syndrome (PICS). Hospital course of such patients is frequently prolonged and associated with extensive use of empiric broad-spectrum antibiotics. We wished to determine the associated clinical features and outcome of such patients in anticipation of future specific diagnostic and therapeutic approaches to this syndrome. METHODS: We reviewed all infectious disease consultations from July 1, 2017, to March 31, 2018, for reason for consultation. Of those whose primary reason was "leukocytosis" or "bandemia," each chart was assessed for demographics, reason for admission, hospital day of consultation, peak white blood cell count, infections and possible microbiological colonization, antibiotic use, and outcome. RESULTS: A total of 29 patients were identified, constituting 4.5% of consults during the study period. Cause of admission was sepsis in 7, major trauma 6, cerebrovascular accident 5, major elective surgery 4, ischemic leg 3, and 1 each lung mass, acute myocardial infarction, interstitial lung disease, and angioblastic lymphoma. Peak total leukocyte count (WBC) was 26.4K ± 8.8 on mean day 9.6 ± 5.5 days of hospitalization. Mean duration of leukocytosis greater than 11K was 14.5 ± 10.6 days. Peak percentage early myelocytic ("band") leukocytes was 18.4 ± 13.8 and was of higher than 5% for a duration of 4.5 ± 5.6 days. Total eosinophilia count >500 was observed in 15 patients (range 500-2800) median hospital day 12. All patients received multiple and prolonged courses of broad-spectrum combination empiric antibiotics without apparent benefit either in terms of leukocytosis, signs of sepsis if present, or change in cultures, although those 7 with confirmed sepsis at admission tended to have shorter duration of leukocytosis and hospital course, whereas patients with trauma manifested greatest "bandemia." Most patients became colonized with resistant opportunistic organisms, the most significant being Clostridium difficile enteritis in 6 patients. Hospitalization was prolonged, and most common disposition was to nursing home or rehabilitation (11 patients, mean day of discharge 21.6 ± 16.8) and home (8 patients, day 16.0 ± 9.3). Three patients died at mean hospital day 35.7 ± 29.7. CONCLUSIONS: Except for 1 person with pelvic abscess post-cystectomy, patients appeared to have extensive tissue damage rather than active infection driving the leukocytosis. Patients appeared to meet clinical criteria for PICS that was substantiated by development of eosinophilia. Future studies should include direct measurements of the CD33CD11b+ myeloid suppressor cells, and the relative contribution of damage-associated molecular patterns (DAMPS) compared with pathogen-associated molecular patterns (PAMPS) such as endotoxin and other microbial products. More prudent and effective use of antibiotics could be possible.

1-Palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol ameliorates chemoradiation-induced oral mucositis.

OBJECTIVE: This study was designed to investigate whether necroptosis is involved in the pathogenesis of chemoradiation-induced oral mucositis in a murine model and whether 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) ameliorates this disorder. MATERIALS AND METHODS: A chemoradiation-induced oral mucositis model was established by treating mice with concurrent 5-fluorouracil (100 mg/kg, i.p.) and head and neck X-irradiation (20 Gy). Phosphate-buffered saline or PLAG (100 mg/kg or 250 mg/kg, p.o.) was administered daily. Body weights were recorded daily, and mice were sacrificed on Day 9 for tongue tissue analysis. RESULTS: On Day 9, chemoradiotherapy-treated (ChemoRT) mice had tongue ulcerations and experienced significant weight loss (Day 0:26.18 ± 1.41 g; Day 9:19.44 ± 3.26 g). They also had elevated serum macrophage inhibitory protein 2 (MIP-2) (control: 5.57 ± 3.49 pg/ml; ChemoRT: 130.14 ± 114.54 pg/ml) and interleukin (IL)-6 (control: 198.25 ± 16.91 pg/ml; ChemoRT: 467.25 ± 108.12 pg/ml) levels. ChemoRT-treated mice who received PLAG exhibited no weight loss (Day 0:25.78 ± 1.04 g; Day 9:26.46 ± 1.68 g) and had lower serum MIP-2 (4.42 ± 4.04 pg/ml) and IL-6 (205.75 ± 30.41 pg/ml) levels than ChemoRT-treated mice who did not receive PLAG. Tongue tissues of mice who received PLAG also displayed lower phosphorylation levels of necroptotic signalling proteins. CONCLUSION: 1-Palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol mitigated chemoradiation-induced oral mucositis by modulating necroptosis.

DNA released from neutrophil extracellular traps (NETs) activates pancreatic stellate cells and enhances pancreatic tumor growth.

Neutrophil extracellular trap (NET) formation results in the expulsion of granulocyte proteins and DNA into the extracellular space. This process is mediated by the enzyme peptidyl arginine deiminase 4 (PADI4) and translocation of elastase to the nucleus. NET formation, marked by increased levels of extracellular DNA, promotes pancreatic cancer proliferation and metastasis. Mice deficient in Padi4 demonstrate decreased pancreatic tumor growth, associated with a reduction in circulating extracellular DNA levels, diminished pancreatic stromal activation and improved survival in murine orthotopic pancreatic adenocarcinoma. Transplantation of Padi4-/- bone marrow into genetically engineered mice with Kras driven pancreatic adenocarcinoma (Pdx1-Cre:KrasG12D/+, KC mice) limits the frequency of invasive cancers when compared with syngeneic controls. DNA from neutrophils activates pancreatic stellate cells that form dense, fibrous stroma which can promote and enable tumor proliferation. DNase treatment diminishes murine tumor growth and stromal activation to reverse the effect of NETs within the tumor microenvironment. Furthermore, deletion of the receptor for advanced glycation end products (RAGE) in pancreatic stellate cells abrogates the effects of DNA in promoting stellate cell proliferation and decreases tumor growth. Circulating neutrophil-derived DNA correlates with the stage in patients with pancreatic ductal adenocarcinoma, confirming the role of NETs in human pancreatic cancer. These findings support further investigation into targeting of NETs, PADI4 and extracellular DNA as a potential treatment strategy in patients with pancreatic cancer. Trial Registration: This study reports correlative data from a clinical trial registered with clinicaltrials.gov, NCT01978184 (November 7, 2013).

Making cold malignant pleural effusions hot: driving novel immunotherapies.

Malignant pleural effusions, arising from either primary mesotheliomas or secondary malignancies, heralds advanced disease and poor prognosis. Current treatments, including therapeutic thoracentesis and tube thoracostomy, are largely palliative. The immunosuppressive environment within the pleural cavity includes myeloid derived suppressor cells, T-regulatory cells, and dysfunctional T cells. The advent of effective immunotherapy with checkpoint inhibitors and adoptive cell therapies for lung cancer and other malignancies suggests a renewed examination of local and systemic therapies for this malady. Prior strategies reporting remarkable success, including instillation of the cytokine interleukin-2, perhaps coupled with checkpoint inhibitors, should be further evaluated in the modern era.

Viperid Envenomation Wound Exudate Contributes to Increased Vascular Permeability via a DAMPs/TLR-4 Mediated Pathway.

Viperid snakebite envenomation is characterized by inflammatory events including increase in vascular permeability. A copious exudate is generated in tissue injected with venom, whose proteomics analysis has provided insights into the mechanisms of venom-induced tissue damage. Hereby it is reported that wound exudate itself has the ability to induce increase in vascular permeability in the skin of mice. Proteomics analysis of exudate revealed the presence of cytokines and chemokines, together with abundant damage associated molecular pattern molecules (DAMPs) resulting from both proteolysis of extracellular matrix and cellular lysis. Moreover, significant differences in the amounts of cytokines/chemokines and DAMPs were detected between exudates collected 1 h and 24 h after envenomation, thus highlighting a complex temporal dynamic in the composition of exudate. Pretreatment of mice with Eritoran, an antagonist of Toll-like receptor 4 (TLR4), significantly reduced the exudate-induced increase in vascular permeability, thus suggesting that DAMPs might be acting through this receptor. It is hypothesized that an "Envenomation-induced DAMPs cycle of tissue damage" may be operating in viperid snakebite envenomation through which venom-induced tissue damage generates a variety of DAMPs which may further expand tissue alterations.