The impact of neural invasion severity in gastrointestinal malignancies: a clinicopathological study.

OBJECTIVES Because neural invasion (NI) is still inconsistently reported and not well characterized within gastrointestinal malignancies (GIMs), our aim was to determine the exact prevalence and severity of NI and to elucidate the true impact of NI on patient's prognosis. BACKGROUND The union internationale contre le cancer (UICC) recently added NI as a novel parameter in the current TNM classification. However, there are only a few existing studies with specific focus on NI, so that the distinct role of NI in GIMs is still uncertain. MATERIALS AND METHODS NI was characterized in approximately 16,000 hematoxylin and eosin tissue sections from 2050 patients with adenocarcinoma of the esophagogastric junction (AEG)-I-III, squamous cell carcinoma (SCC) of the esophagus, gastric cancer (GC), colon cancer (CC), rectal cancer (RC), cholangiocellular cancer (CCC), hepatocellular cancer (HCC), and pancreatic cancer (PC). NI prevalence and severity was determined and related to patient's prognosis and survival. RESULTS NI prevalence largely varied between HCC/6%, CC/28%, RC/34%, AEG-I/36% and AEG-II/36%, SCC/37%, GC/38%, CCC/58%, and AEG-III/65% to PC/100%. NI severity score was uppermost in PC (24.9±1.9) and lowest in AEG-I (0.8±0.3). Multivariable analyses including age, sex, TNM stage, and grading revealed that the prevalence of NI was significantly associated with diminished survival in AEG-II/III, GC, and RC. However, increasing NI severity impaired survival in AEG-II/III and PC only. CONCLUSIONS NI prevalence and NI severity strongly vary within GIMs. Determination of NI severity in GIMs is a more precise tool than solely recording the presence of NI and revealed dismal prognostic impact on patients with AEG-II/III and PC. Evidently, NI is not a concomitant side feature in GIMs and, therefore, deserves special attention for improved patient stratification and individualized therapy after surgery.

Impact of sepsis on risk of postoperative arterial and venous thromboses: large prospective cohort study

OBJECTIVES To evaluate the impact of preoperative sepsis on risk of postoperative arterial and venous thromboses. DESIGN Prospective cohort study using the National Surgical Quality Improvement Program database of the American College of Surgeons (ACS-NSQIP). SETTING Inpatient and outpatient procedures in 374 hospitals of all types across the United States, 2005-12. PARTICIPANTS 2,305,380 adults who underwent surgical procedures. MAIN OUTCOME MEASURES Arterial thrombosis (myocardial infarction or stroke) and venous thrombosis (deep venous thrombosis or pulmonary embolism) in the 30 days after surgery. RESULTS Among all surgical procedures, patients with preoperative systemic inflammatory response syndrome or any sepsis had three times the odds of having an arterial or venous postoperative thrombosis (odds ratio 3.1, 95% confidence interval 3.0 to 3.1). The adjusted odds ratios were 2.7 (2.5 to 2.8) for arterial thrombosis and 3.3 (3.2 to 3.4) for venous thrombosis. The adjusted odds ratios for thrombosis were 2.5 (2.4 to 2.6) in patients with systemic inflammatory response syndrome, 3.3 (3.1 to 3.4) in patients with sepsis, and 5.7 (5.4 to 6.1) in patients with severe sepsis, compared with patients without any systemic inflammation. In patients with preoperative sepsis, both emergency and elective surgical procedures had a twofold increased odds of thrombosis. CONCLUSIONS Preoperative sepsis represents an important independent risk factor for both arterial and venous thromboses. The risk of thrombosis increases with the severity of the inflammatory response and is higher in both emergent and elective surgical procedures. Suspicion of thrombosis should be higher in patients with sepsis who undergo surgery.

Injury severity and mortality of adult zebra crosswalk and non-zebra crosswalk road crossing accidents: a cross-sectional analysis

PRINCIPALS Over a million people worldwide die each year from road traffic injuries and more than 10 million sustain permanent disabilities. Many of these victims are pedestrians. The present retrospective study analyzes the severity and mortality of injuries suffered by adult pedestrians, depending on whether they used a zebra crosswalk. METHODS Our retrospective data analysis covered adult patients admitted to our emergency department (ED) between 1 January 2000 and 31 December 2012 after being hit by a vehicle while crossing the road as a pedestrian. Patients were identified by using a string term. Medical, police and ambulance records were reviewed for data extraction. RESULTS A total of 347 patients were eligible for study inclusion. Two hundred and three (203; 58.5%) patients were on a zebra crosswalk and 144 (41.5%) were not. The mean ISS (injury Severity Score) was 12.1 (SD 14.7, range 1-75). The vehicles were faster in non-zebra crosswalk accidents (47.7 km/n, versus 41.4 km/h, p<0.027). The mean ISS score was higher in patients with non-zebra crosswalk accidents; 14.4 (SD 16.5, range 1-75) versus 10.5 (SD13.14, range 1-75) (p<0.019). Zebra crosswalk accidents were associated with less risk of severe injury (OR 0.61, 95% CI 0.38-0.98, p<0.042). Accidents involving a truck were associated with increased risk of severe injury (OR 3.53, 95%CI 1.21-10.26, p<0.02). CONCLUSION Accidents on zebra crosswalks are more common than those not on zebra crosswalks. The injury severity of non-zebra crosswalk accidents is significantly higher than in patients with zebra crosswalk accidents. Accidents involving large vehicles are associated with increased risk of severe injury. Further prospective studies are needed, with detailed assessment of motor vehicle types and speed.

Retrocrural space involvement on computed tomography as a predictor of mortality and disease severity in acute pancreatitis

BACKGROUND Because computed tomography (CT) has advantages for visualizing the manifestation of necrosis and local complications, a series of scoring systems based on CT manifestations have been developed for assessing the clinical outcomes of acute pancreatitis (AP), including the CT severity index (CTSI), modified CTSI, etc. Despite the internationally accepted CTSI having been successfully used to predict the overall mortality and disease severity of AP, recent literature has revealed the limitations of the CTSI. Using the Delphi method, we establish a new scoring system based on retrocrural space involvement (RCSI), and compared its effectiveness at evaluating the mortality and severity of AP with that of the CTSI. METHODS We reviewed CT images of 257 patients with AP taken within 3-5 days of admission in 2012. The RCSI scoring system, which includes assessment of infectious conditions involving the retrocrural space and the adjacent pleural cavity, was established using the Delphi method. Two radiologists independently assessed the RCSI and CTSI scores. The predictive points of the RCSI and CTSI scoring systems in evaluating the mortality and severity of AP were estimated using receiver operating characteristic (ROC) curves. PRINCIPAL FINDINGS The RCSI score can accurately predict the mortality and disease severity. The area under the ROC curve for the RCSI versus CTSI score was 0.962±0.011 versus 0.900±0.021 for predicting the mortality, and 0.888±0.025 versus 0.904±0.020 for predicting the severity of AP. Applying ROC analysis to our data showed that a RCSI score of 4 was the best cutoff value, above which mortality could be identified. CONCLUSION The Delphi method was innovatively adopted to establish a scoring system to predict the clinical outcome of AP. The RCSI scoring system can predict the mortality of AP better than the CTSI system, and the severity of AP equally as well.

Role of IkappaB kinase beta in inflammation-mediated breast cancer development

Breast cancer is the second most common farm of cancers and the second leading cause of cancer death for American women. Clinical studies indicate inflammation is a risk factor for breast cancer development. Among the cytokines and chemokines secreted by the infiltrating inflammatory cells, tumor necrosis factor a (TNFα) is considered one of the most important inflammatory factors involved in inflammation-mediated tumorigenesis. ^ Here we found that TNFα/IKKβ signaling pathway is able to increase tumor angiogenesis through activation of mTOR pathway. While investigating which molecule in the mTOR pathway involved in TNFα/IKKβ-mediated mTOR activation, our results showed that IKKβ physically interacts with and phosphorylates TSC1 at Ser487 and Ser511 in vitro and in vivo. Phosphorylation of TSC1 by IKKβ inhibits its association with TSC2, alters TSC2 membrane localization, and thereby activates mTOR. In vitro angiogenesis assays and orthotopic breast cancer model reveals that phosphorylation of TSC1 by IKKβ enhances VEGF expression, angiogenesis and culminates in tumorigenesis. Furthermore, expression of activated IKKβ is associated with TSC1 Ser511 phosphorylation and VEGF production in multiple tumor types and correlates with poor clinical outcome of breast cancer patients. ^ Furthermore, dysregulation of tumor suppressor FOXO3a contributes to the development of breast cancer. We found that overexpression of IKKβ led to inhibition of FOXO3a-mediated transactivation activity. While investigating the underlying mechanisms of IKKβ-mediated dysregulation of FOXO3a, our results showed that IKKβ physically associated with FOXO3a and phosphorylated FOXO3a at Ser644 in vitro and in vivo. The phosphorylation of FOXO3a by IKKβ altered its subcellular localization from nucleus to cytoplasm and promoted its degradation through ubiquitin-proteasome pathway. Mutation of FOXO3a at Ser644 prevented IKKβ-induced ubiquitination and degradation. In vitro cell proliferation assay and orthotopic breast cancer model revealed that phosphorylation of FOXO3a by IKKβ overrode FOXO3a-mediated repression of tumor progression. ^ In conclusion, our findings identify IKKβ-mediated suppressions of both TSC1 and FOXO3a are critical for inflammation-mediated breast cancer development through increasing tumor angiogenesis and evading apoptosis, respectively. Understanding the role of IKKβ in both FOXO3a and TSC/mTOR signaling pathways provides a critical insight of inflammation-mediated diseases and may provide a target for clinical intervention in human breast cancer. ^

Cellular Uptake of Neutrohpil Elastase Links Inflammation to Adaptive Immunity

Many tumors arise from sites of inflammation providing evidence that innate immunity is a critical component in the development and progression of cancer. Neutrophils are primary mediators of the innate immune response. Upon activation, an important function of neutrophils is release of an assortment of proteins from their granules including the serine protease neutrophil elastase (NE). The effect of NE on cancer has been attributed primarily to its ability to degrade the extracellular matrix thereby promoting invasion and metastasis. Recently, it was shown that NE could be taken up by lung cancer cells leading to degradation of insulin receptor substrate-1 thereby promoting hyperactivity of the phosphatidylinositol-3 kinase (PI3K) pathway and tumor cell proliferation. To our knowledge, nobody has investigated uptake of NE by other tumor types. In addition, NE has broad substrate specificity suggesting that uptake of NE by tumor cells could impact processes regulating tumorigenensis other than activation of the PI3K pathway. Neutrophil elastase has been identified in breast cancer specimens where high levels of NE have prognostic significance. These studies have assessed NE levels in whole tumor lysates. Because the major source of NE is from activated neutrophils, we hypothesized that breast cancer cells do not have endogenous NE but may take up NE released by tumor associated neutrophils in the tumor microenvironment and that this could provide a link between the innate immune response to tumors and specific adaptive immune responses. In this thesis, we show that breast cancer cells lack endogenous NE expression and that they are able to take up NE resulting in increased generation of low molecular weight cyclin E (CCNE) and enhanced susceptibility to lysis by CCNE-specific cytotoxic T lymphocytes. We also show that after taking up NE and proteinase 3 (PR3), a second primary granule protease with significant homology to NE, breast cancer cells cross-present the NE- and PR3-derived peptide PR1 rendering them susceptible to PR1-targeted therapies. Taken together, our data support a role for NE uptake in modulating adaptive immune responses against breast cancer.

NF-κB activation provides the potential link between inflammation and hyperplasia in the arthritic joint

The transcription factor NF-κB is a pivotal regulator of inflammatory responses. While the activation of NF-κB in the arthritic joint has been associated with rheumatoid arthritis (RA), its significance is poorly understood. Here, we examine the role of NF-κB in animal models of RA. We demonstrate that in vitro, NF-κB controlled expression of numerous inflammatory molecules in synoviocytes and protected cells against tumor necrosis factor α (TNFα) and Fas ligand (FasL) cytotoxicity. Similar to that observed in human RA, NF-κB was found to be activated in the synovium of rats with streptococcal cell wall (SCW)-induced arthritis. In vivo suppression of NF-κB by either proteasomal inhibitors or intraarticular adenoviral gene transfer of super-repressor IκBα profoundly enhanced apoptosis in the synovium of rats with SCW- and pristane-induced arthritis. This indicated that the activation of NF-κB protected the cells in the synovium against apoptosis and thus provided the potential link between inflammation and hyperplasia. Intraarticular administration of NF-kB decoys prevented the recurrence of SCW arthritis in treated joints. Unexpectedly, the severity of arthritis also was inhibited significantly in the contralateral, untreated joints, indicating beneficial systemic effects of local suppression of NF-κB. These results establish a mechanism regulating apoptosis in the arthritic joint and indicate the feasibility of therapeutic approaches to RA based on the specific suppression of NF-κB.

Inflammation-induced recombinant protein expression in vivo using promoters from acute-phase protein genes.

We report that promoters for two murine acute-phase protein (APP) genes, complement factor 3 (C3) and serum amyloid A3 (SAA3), can increase recombinant protein expression in response to inflammatory stimuli in vivo. To deliver APP promoter-luciferase reporter gene constructs to the liver, where most endogenous APP synthesis occurs, we introduced them into a nonreplicating adenovirus vector and injected the purified viruses intravenously into mice. When compared with the low levels of basal luciferase expression observed prior to inflammatory challenge, markedly increased expression from the C3 promoter was detected in liver in response to both lipopolysaccharide (LPS) and turpentine, and lower-level inducible expression was also found in lung. In contrast, expression from the SAA3 promoter was found only in liver and was much more responsive to LPS than to turpentine. After LPS challenge, hepatic luciferase expression increased rapidly and in proportion to the LPS dose. Use of cytokine-inducible promoters in gene transfer vectors may make it possible to produce antiinflammatory proteins in vivo in direct relationship to the intensity and duration of an individual's inflammatory response. By providing endogenously controlled production of recombinant antiinflammatory proteins, this approach might limit the severity of the inflammatory response without interfering with the beneficial components of host defense and immunity.

Social determinants and health effects of low and high severity intimate partner violence

PURPOSE: We sought to analyze whether the sociodemographic profile of battered women varies according to the level of severity of intimate partner violence (IPV), and to identify possible associations between IPV and different health problems taking into account the severity of these acts. METHODS: A cross-sectional study of 8,974 women (18-70 years) attending primary healthcare centers in Spain (2006-2007) was performed. A compound index was calculated based on frequency, types (physical, psychological, or both), and duration of IPV. Descriptive and multivariate procedures using logistic regression models were fitted. RESULTS: Women affected by low severity IPV and those affected by high severity IPV were found to have a similar sociodemographic profile. However, divorced women (odds ratio [OR], 8.1; 95% confidence interval [CI], 3.2-20.3), those without tangible support (OR, 6.6; 95% CI, 3.3-13.2), and retired women (OR, 2.7; 95% CI, 1.2-6.0) were more likely to report high severity IPV. Women experiencing high severity IPV were also more likely to suffer from poor health than were those who experienced low severity IPV. CONCLUSIONS: The distribution of low and high severity IPV seems to be influenced by the social characteristics of the women involved and may be an important indicator for estimating health effects. This evidence may contribute to the design of more effective interventions.

The Effect of Fructose vs. Glucose Beverages on Low-Grade Systemic Inflammation

Thesis (Ph.D.)--University of Washington, 2016-04

Potent cyclic antagonists of the complement C5a receptor on human polymorphonulcear leukocytes. Relationships between structures and activity

Human C5a is a plasma protein with potent chemoattractant and pro-inflammatory properties, and its overexpression correlates with severity of inflammatory diseases. C5a binds to its G protein-coupled receptor (C5aR) on polymorphonuclear leukocytes (PMNLs) through a high-affinity helical bundle and a low-affinity C terminus, the latter being solely responsible for receptor activation. Potent and selective C5a antagonists are predicted to be effective anti-inflammatory drugs, but no pharmacophore for small molecule antagonists has yet been developed, and it would significantly aid drug design. We have hypothesized that a turn conformation is important for activity of the C terminus of C5a and herein report small cyclic peptides that are stable turn mimics with potent antagonism at C5aR on human PMNLs. A comparison of solution structures for the C terminus of C5a, small acyclic peptide ligands, and cyclic antagonists supports the importance of a turn for receptor binding. Competition between a cyclic antagonist and either C5a or an acyclic agonist for C5aR on PMNLs supports a common or overlapping binding site on the C5aR. Structure-activity relationships for 60 cyclic analogs were evaluated by competitive radioligand binding with C5a (affinity) and myeloperoxidase release (antagonist potency) from human PMNLs, with 20 compounds having high antagonist potencies (IC50, 20 nM(-1) muM). Computer modeling comparisons reveal that potent antagonists share a common cyclic backbone shape, with affinity-determining side chains of defined volume projecting from the cyclic scaffold. These results define a new pharmacophore for C5a antagonist development and advance our understanding of ligand recognition and receptor activation of this G protein-coupled receptor.

Differential expression of muscle damage in humans following acute fast and slow velocity eccentric exercise

We sought to determine if the velocity of an acute bout of eccentric contractions influenced the duration and severity of several common indirect markers of muscle damage. Subjects performed 36 maximal fast (FST, n=8: 3.14 rad center dot s(-1)) or slow (SLW, n=7: 0.52 rad center dot s(-1)) velocity isokinetic eccentric contractions with the elbow flexors of the non-dominant arm. Muscle soreness, limb girth, plasma creatine kinase (CK) activity, isometric torque and concentric and eccentric torque at 0.52 and 3.14 rad center dot s(-1) were assessed prior to and for several days following the eccentric bout. Peak plasma CK activity was similar in SLW (4030 +/- 1029 U center dot l(-1)) and FST (5864 +/- 2664 U center dot l(-1)) groups, (p > 0.05). Both groups experienced similar decrement in all strength variables during the 48 hr following the eccentric bout. However, recovery occurred more rapidly in the FST group during eccentric (0.52 and 3.14 rad center dot s(-1)) and concentric (3.14 rad center dot s(-1)) post-testing. The severity of muscle soreness was similar in both groups. However, the FST group experienced peak muscle soreness 48 hr later than the SLW group (24 hr vs. 72 hr). The SLW group experienced a greater increase in upper arm girth than the FST group 20 min, 24 hr and 96 hr following the eccentric exercise bout. The contraction velocity of an acute bout of eccentric exercise differentially influences the magnitude and time course of several indirect markers of muscle damage.

Multiparametric evaluation of dysphonic severity

In recent years, the multiparametric approach for evaluating perceptual rating of voice quality has been advocated. This study evaluates the accuracy of predicting perceived overall severity of voice quality with a minimal set of aerodynamic, voice range profile (phonetogram), and acoustic perturbation measures. One hundred and twelve dysphonic persons (93 women and 19 men) with laryngeal pathologies and 41 normal controls (35 women and six men) with normal voices participated in this study. Perceptual severity judgement was carried out by four listeners rating the G (overall grade) parameter of the GRBAS scale.(1) The minimal set of instrumental measures was selected based on the ability of the measure to discriminate between dysphonic and normal voices, and to attain at least a moderate correlation with perceived overall severity. Results indicated that perceived overall severity was best described by maximum phonation time of sustained /a/, peak intraoral pressure of the consonant-vowel /pi/ strings production, voice range profile area, and acoustic jitter. Direct-entry discriminant function analysis revealed that these four voice measures in combination correctly predicted 67.3% of perceived overall severity levels.

Identification and characterization of non-pathogenic Fusarium oxysporum capable of increasing and decreasing Fusarium wilt severity

Fusarium wilt of banana is a potentially devastating disease throughout the world. Options for control of the causal organism, Fusarium oxysporum f.sp. cubense (Foc) are limited. Suppressive soil sites have previously been identified where, despite the presence of Foc, Fusarium wilt does not develop. In order to understand some aspects of this disease suppression, endophytic Fusarium oxysporum isolates were obtained from banana roots. These isolates were genetically characterized and compared with an isolate of Fusarium oxysporum previously identified as being capable of suppressing Fusarium wilt of banana in glasshouse trials. Three additional isolates were selected for glasshouse trials to assess suppression of Fusarium wilt in two different cultivars of banana, Cavendish and Lady Finger. One isolate (BRIP 29089) was identified as a potential biocontrol organism, reducing the disease severity of Fusarium wilt in Lady Finger and Cavendish cultivars. Interestingly, one isolate (BRIP 45952) increased Fusarium wilt disease severity on Cavendish. The implications of an isolate of Fusarium oxysporum, non-pathogenic on banana, increasing disease severity and the potential role of non-pathogenic isolates of Fusarium oxysporum in disease complexes are discussed. (c) 2006 Published by Elsevier Ltd on behalf of The British Mycological Society.

Mediators of monocyte activity in inflammation

C-reactive protein (CRP) is the prototypic acute phase serum protein in humans. CRP is currently one of the best markers of inflammatory disease and disease activity. One of the keys cells involved in inflammation within chronic inflammatory diseases is the monocyte. Monocytes are able to modulate inflammation through cytokine expression, cytosolic peroxide formation, adhesion molecule expression and subsequent adhesion/migration to sites of inflammation. CRP has been previously shown to bind directly to monocytes through Fc receptors. However this observation is not conclusive and requires further investigation. The effects of incubation of CRP with human primary and monocytic cell lines were examined using monocytic cytokine expression, adhesion molecule expression and adhesion to endothelial cells and intracellular peroxide formation, as end points. Monocytic intracellular signalling events were investigated after interaction of CRP with specific CRP receptors on monocytes. These initial signalling events were examined for their role in modulating monocytic adhesion molecule and cytokine expression. Monocyte recruitment and retention in the vasculature is also influenced by oxidative stress. Therefore the effect of 6 weeks of antioxidant intervention in vivo was examined on monocytic adhesion molecule expression, adhesion to endothelial cells ex vivo and on serum CRP concentrations, pre- and post- supplementation with the antioxidants vitamin C and vitaInin E. In summary, CRP is able to bind FcγRIIa. CRP binding FcγR initiates an intracellular signalling cascade that phosphorylates the non-receptor tyrosine kinase, Syk, associated with intracellular tyrosine activating motifs on the cytoplasmic tail of Fcγ receptors. CRP incubations increased phosphatidyl inositol turnover and Syk phosphorylation ultimately lead to Ca2+ mobilisation in monocytes. CRP mediated Syk phosphorylation in monocytes leads to an increase in CD 11b and IL-6 expression. CRP engagement with monocytes also leads to an increase in peroxide production, which can be inhibited in vitro using the antioxidants α-tocopherol and ascorbic acid. CRP mediated CD 11b expression is not redox regulated by CRP mediated changes in cytosolic peroxides. The FcyRIla polymorphism at codon 131 effects the phenotypic driven changes described in monocytes by CRP, where R/R allotypes have a greater increase in CD11b, in response to CRP, which may be involved in promoting the monocytic inflammatory response. CRP leads to an increase in the expression of pro-inflammatory cytokines, which alters the immune phenotype of circulating monocytes. Vitamin C supplementation reduced monocytic adhesion to endothelial cells, but had no effect on serum levels of CRP. Where long-term antioxidant intervention may provide benefit from the risk of developing vascular inflammatory disease, by reducing monocytic adhesion to the vasculature. In conclusion CRP appears to be much more than just a marker of ongoing inflammation or associated inflammatory disease and disease activity. This data suggests that at pathophysiological concentrations, CRP may be able to directly modulate inflammation through interacting with monocytes and thereby alter the inflammatory response associated with vascular inflammatory diseases.