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Epidermal growth factor receptor (EGFR) signaling is a known mediator of colorectal carcinogenesis. Studies have focused on the role of EGFR signaling in epithelial cells, although the exact nature of the role of EGFR in colorectal carcinogenesis remains a topic of debate. Here, we present evidence that EGFR signaling in myeloid cells, specifically macrophages, is critical for colon tumorigenesis in the azoxymethane–dextran sodium sulfate (AOM-DSS) model of colitis-associated carcinogenesis (CAC). In a human tissue microarray, colonic macrophages demonstrated robust EGFR activation in the pre-cancerous stages of colitis and dysplasia. Utilizing the AOM-DSS model, mice with a myeloid-specific deletion of Egfr had significantly decreased tumor multiplicity and burden, protection from high-grade dysplasia and significantly reduced colitis. Intriguingly, mice with gastrointestinal epithelial cell-specific Egfr deletion demonstrated no differences in tumorigenesis in the AOM-DSS model. The alterations in tumorigenesis in myeloid-specific Egfr knockout mice were accompanied by decreased macrophage, neutrophil and T-cell infiltration. Pro-tumorigenic M2 macrophage activation was diminished in myeloid-specific Egfr -deficient mice, as marked by decreased Arg1 and Il10 mRNA expression and decreased interleukin (IL)-4, IL10 and IL-13 protein levels. Surprisingly, diminished M1 macrophage activation was also detectable, as marked by significantly reduced Nos2 and Il1b mRNA levels and decreased interferon (IFN)-γ, tumor necrosis factor (TNF)-α and IL-1β protein levels. The alterations in M1 and M2 macrophage activation were confirmed in bone marrow-derived macrophages from mice with the myeloid-specific Egfr knockout. The combined effect of restrained M1 and M2 macrophage activation resulted in decreased production of pro-angiogenic factors, CXCL1 and vascular endothelial growth factor (VEGF), and reduced CD31 + blood vessels, which likely contributed to protection from tumorigenesis. These data reveal that EGFR signaling in macrophages, but not in colonic epithelial cells, has a significant role in CAC. EGFR signaling in macrophages may prove to be an effective biomarker of CAC or target for chemoprevention in patients with inflammatory bowel disease.

. Neutron capture yields of dysprosium isotopes ( 161 Dy, 162 Dy, 163 Dy, and 164 Dy were measured using the time-of-flight method with a 16 segment sodium iodide multiplicity detector. The measurements were made at the 25m flight station at the Gaerttner LINAC Center at Rensselaer Polytechnic Institute. Resonance parameters were obtained using the multilevel R-matrix Bayesian code SAMMY. The neutron capture data for four enriched dysprosium isotopes and one natural dysprosium sample were sequentially fitted. New resonances not listed in ENDF/B-VII.1 were observed. There were 29 and 17 new resonances from 161 Dy and 163 Dy isotopes, respectively. Six resonances from 161 Dy isotope, two resonances from 163 Dy, and four resonances from 164 Dy were not observed. The capture resonance integrals of each isotope were calculated with the resulting resonance parameters and those of ENDF/B-VII.1 in the energy region from 0.5eV to 20MeV and were compared to the capture resonance integrals with the resonance parameters from ENDF/B-VII.1. A resonance integral value of the natural dysprosium calculated with present resonance parameters was 1405 ± 3 . 5 barn. The value is ∼ 0 . 3 % higher than that obtained with the ENDF/B-VII.1 parameters. The distributions of the present and ENDF/B-VII.1 neutron widths were compared to a Porter-Thomas distribution. Neutron strength functions for 161 Dy and 163 Dy were calculated with the present resonance parameters and both values were in between the values of “Atlas of Neutron Resonances” and ENDF/B-VII.1. The present radiation width distributions of 161 Dy and 163 Dy were fitted with the χ 2 distribution by varying the degrees of freedom.

. After publication of the paper, the authors realized that the acknowledgements were not correct. Their correct version appears in this erratum.

Helicobacter pylori infection causes gastric cancer, the third leading cause of cancer death worldwide. More than half of the world’s population is infected, making universal eradication impractical. Clinical trials suggest that antibiotic treatment only reduces gastric cancer risk in patients with non-atrophic gastritis (NAG), and is ineffective once preneoplastic lesions of multifocal atrophic gastritis (MAG) and intestinal metaplasia (IM) have occurred. Therefore, additional strategies for risk stratification and chemoprevention of gastric cancer are needed. We have implicated polyamines, generated by the rate-limiting enzyme ornithine decarboxylase (ODC), in gastric carcinogenesis. During H. pylori infection, the enzyme spermine oxidase (SMOX) is induced, which generates hydrogen peroxide from the catabolism of the polyamine spermine. Herein, we assessed the role of SMOX in the increased gastric cancer risk in Colombia associated with the Andean mountain region when compared with the low-risk region on the Pacific coast. When cocultured with gastric epithelial cells, clinical strains of H. pylori from the high-risk region induced more SMOX expression and oxidative DNA damage, and less apoptosis than low-risk strains. These findings were not attributable to differences in the cytotoxin-associated gene A oncoprotein. Gastric tissues from subjects from the high-risk region exhibited greater levels of SMOX and oxidative DNA damage by immunohistochemistry and flow cytometry, and this occurred in NAG, MAG and IM. In Mongolian gerbils, a prototype colonizing strain from the high-risk region induced more SMOX, DNA damage, dysplasia and adenocarcinoma than a colonizing strain from the low-risk region. Treatment of gerbils with either α-difluoromethylornithine, an inhibitor of ODC, or MDL 72527 ( N 1 , N 4 -Di(buta-2,3-dien-1-yl)butane-1,4-diamine dihydrochloride), an inhibitor of SMOX, reduced gastric dysplasia and carcinoma, as well as apoptosis-resistant cells with DNA damage. These data indicate that aberrant activation of polyamine-driven oxidative stress is a marker of gastric cancer risk and a target for chemoprevention.

The gastric pathogen Helicobacter pylori causes peptic ulcer disease and gastric cancer. We have reported that in H. pylori-activated macrophages, nitric oxide (NO) derived from inducible NO synthase (iNOS) can kill the bacterium, iNOS protein expression is dependent on uptake of its substrate L-arginine (L-Arg), the polyamine spermine can inhibit iNOS translation by inhibiting L-Arg uptake, and inhibition of polyamine synthesis enhances NO-mediated bacterial killing. Because spermine oxidase (SMO), which back-converts spermine to spermidine, is induced in macrophages by H. pylori, we determined its role in iNOS-dependent host defense. SMO shRNA knockdown in RAW 264.7 murine macrophages resulted in a marked decrease in H. pylori-stimulated iNOS protein, but not mRNA expression, and a 90 % reduction in NO levels; NO production was also inhibited in primary murine peritoneal macrophages with SMO knockdown. There was an increase in spermine levels after H. pylori stimulation that rapidly decreased, while SMO knockdown caused a greater increase in spermine that was sustained. With SMO knockdown, L-Arg uptake and killing of H. pylori by macrophages was prevented. The overexpression of SMO by transfection of an expression plasmid prevented the H. pylori-stimulated increase in spermine levels, and led to increased L-Arg uptake, iNOS protein expression and NO production, and H. pylori killing. In two human monocytic cell lines, U937 and THP-1, overexpression of SMO caused a significant enhancement of NO production with H. pylori stimulation. By depleting spermine, SMO can abrogate the inhibitory effect of polyamines on innate immune responses to H. pylori by enhancing antimicrobial NO production.

Apoptosis, or programmed cell death, is normally responsible for the orderly elimination of aged or damaged cells, and is a necessary part of the homeostasis and development of multicellular organisms. Some pathogenic bacteria can disrupt this process by triggering excess apoptosis or by preventing it when appropriate. Either event can lead to disease. There has been extensive research into the modulation of host cell death by microorganisms, and several reviews have been published on the phenomenon. Rather than covering the entire field, this review focuses on the dysregulation of host cell apoptosis by members of the order Actinomycetales, containing the genera Corynebacterium, Mycobacterium, Rhodococcus, and Nocardia.

Background: Football has the highest number of nontraumatic fatalities of any sport in the United States. Purpose: To compare the incidence of nontraumatic fatalities with that of traumatic fatalities, describe the epidemiology of nontraumatic fatalities in high school (HS) and college football players, and determine the effectiveness of National Collegiate Athletic Association (NCAA) policies to reduce exertional heat stroke (EHS) and exertional sickling (ES) with sickle cell trait (SCT) fatalities in athletes. Study Design: Descriptive epidemiology study. Methods: We retrospectively reviewed 20 academic years (1998-2018) of HS and college nontraumatic fatalities in football players using the National Registry of Catastrophic Sports Injuries (NRCSI). EHS and ES with SCT fatality rates were compared before and after the implementation of the NCAA football out-of-season model (bylaw 17.10.2.4 [2003]) and NCAA Division I SCT screening (bylaw 17.1.5.1 [2010]), respectively. Additionally, we compiled incidence trends for HS and college traumatic and nontraumatic fatalities in football players for the years 1960 through 2018 based on NRCSI data and previously published reports. Results: The risk (odds ratio) of traumatic fatalities in football players in the 2010s was 0.19 (95% CI, 0.13-0.26; P < .0001) lower in HS and 0.29 (95% CI, 0.29-0.72; P = .0078) lower in college compared with that in the 1960s. In contrast, the risk of nontraumatic fatalities in football players in the 2010s was 0.7 (95% CI, 0.50-0.98; P = .0353) in HS and 0.9 (95% CI, 0.46-1.72; P = .7413) in college compared with that in the 1960s. Since 2000, the risk of nontraumatic fatalities has been 1.89 (95% CI, 1.42-2.51; P < .001) and 4.22 (95% CI, 2.04-8.73; P < .001) higher than the risk of traumatic fatalities at the HS and college levels, respectively. During the 20 years studied, there were 187 nontraumatic fatalities (average, 9.4 per year). The causes of death were sudden cardiac arrest (57.7%), EHS (23.6%), ES with SCT (12.1%), asthma (4.9%), and hyponatremia (1.6%). The risk of a nontraumatic fatality was 4.1 (95% CI, 2.8-5.9; P < .0001) higher in NCAA compared with HS athletes. There was no difference in the risk of an EHS fatality in NCAA athletes (0.86 [95% CI, 0.17-4.25]; P = .85) after implementation in 2003 of the NCAA football out-of-season model. The risk of an ES with SCT fatality in Division I athletes was significantly lower after the 2010 NCAA SCT screening bylaw was implemented (0.12 [95% CI, 0.02-0.95]; P = .04). Conclusion: Since the 1960s, the risk of nontraumatic fatalities has declined minimally compared with the reduction in the risk of traumatic fatalities. Current HS and college nontraumatic fatality rates are significantly higher than rates of traumatic fatalities. The 2003 NCAA out-of-season model has failed to significantly reduce EHS fatalities. The 2010 NCAA SCT screening bylaw has effectively prevented ES with SCT fatalities in NCAA Division I football.

Background: The incidence of nontraumatic fatalities in high school (HS) and National Collegiate Athletic Association (NCAA) football players has continued at a constant rate since the 1960s. Purpose: To describe the causes of nontraumatic fatalities in HS and NCAA football players and provide prevention strategies. Study Design: Descriptive epidemiology study. Methods: We reviewed 187 fatalities in HS and NCAA nontraumatic football players catalogued by the National Registry of Catastrophic Sports Injuries during a 20-year period between July 1998 and June 2018. Results: The majority (n = 162; 86.6%) of fatalities occurred during a practice or conditioning session. Most fatalities, when timing was known, (n = 126; 70.6%) occurred outside of the regular playing season, with the highest incidence in the August preseason (n = 64; 34.2%). All documented conditioning sessions were supervised by a coach (n = 92) or strength and conditioning coach (n = 40). The exercise regimen at the time of the fatality involved high-intensity aerobic training in 94.7%. Punishment was identified as the intent in 36 fatalities. The average body mass index of the athletes was 32.6 kg/m2. For athletes who died due to exertional heat stroke, the average body mass index was 36.4 kg/m2, and 97.1% were linemen. Conclusion: Most nontraumatic fatalities in HS and NCAA football players occurred during coach-supervised conditioning sessions. The primary cause of exertion-related fatalities was high-intensity aerobic workouts that might have been intended as punishment and/or excess repetitions. Exertion-related fatalities are potentially preventable by applying standards in workout design, holding coaches accountable, and ensuring compliance with the athlete’s health and current welfare policies.