Mediators of Inflammation The latest articles from Hindawi Publishing Corporation © 2015 , Hindawi Publishing Corporation . All rights reserved. Lipoxin Inhibits Fungal Uptake by Macrophages and Reduces the Severity of Acute Pulmonary Infection Caused by Paracoccidioides brasiliensis Thu, 08 Oct 2015 08:14:43 +0000 Cysteinyl leukotrienes (CysLTs) and lipoxins (LXs) are lipid mediators that control inflammation, with the former inducing and the latter inhibiting this process. Because the role played by these mediators in paracoccidioidomycosis was not investigated, we aimed to characterize the role of CysLT in the pulmonary infection developed by resistant (A/J) and susceptible (B10.A) mice. 48 h after infection, elevated levels of pulmonary LTC4 and LXA4 were produced by both mouse strains, but higher levels were found in the lungs of susceptible mice. Blocking the CysLTs receptor by MTL reduced fungal loads in B10.A, but not in A/J mice. In susceptible mice, MLT treatment led to reduced influx of PMN leukocytes, increased recruitment of monocytes, predominant synthesis of anti-inflammatory cytokines, and augmented expression of 5- and 15-lipoxygenase mRNA, suggesting a prevalent LXA4 activity. In agreement, MTL-treated macrophages showed reduced fungal burdens associated with decreased ingestion of fungal cells. Furthermore, the addition of exogenous LX reduced, and the specific blockade of the LX receptor increased the fungal loads of B10.A macrophages. This study showed for the first time that inhibition of CysLTs signaling results in less severe pulmonary paracoccidioidomycosis that occurs in parallel with elevated LX activity and reduced infection of macrophages. Laura R. R. Ribeiro, Flávio V. Loures, Eliseu F. de Araújo, Cláudia Feriotti, Tânia A. Costa, Carlos Henrique Serezani, Sonia Jancar, and Vera L. G. Calich Copyright © 2015 Laura R. R. Ribeiro et al. All rights reserved. Circulating Cytokine Levels as Markers of Inflammation in Philadelphia Negative Myeloproliferative Neoplasms: Diagnostic and Prognostic Interest Wed, 07 Oct 2015 11:08:53 +0000 Cytokines are well known mediators of numerous physiological and pathological processes. They contribute to the regulation of normal hematopoiesis but increasing data suggest that they also have a clinical impact in some hematopoietic malignancies. In particular, there is evidence that cytokines are implicated in the functional symptoms of Philadelphia negative myeloproliferative neoplasms (Ph− MPNs), suggesting that evaluation of circulating levels of cytokines could be of clinical interest for the characterization of patients at the time of diagnosis and for disease prognosis. In this review, we present the current knowledge on alteration of circulating cytokine profiles in MPNs and their role in myelofibrosis pathogenesis. Phenotypic correlation, prognostic value of cytokines, and impact of JAK inhibitors are also discussed. Julie Mondet, Kais Hussein, and Pascal Mossuz Copyright © 2015 Julie Mondet et al. All rights reserved. Carbon Monoxide Inhibits Tenascin-C Mediated Inflammation via IL-10 Expression in a Septic Mouse Model Wed, 07 Oct 2015 09:50:04 +0000 Tenascin-C (TN-C), an extracellular matrix (ECM) glycoprotein, is specifically induced upon tissue injury and infection and during septic conditions. Carbon monoxide (CO) gas is known to exert various anti-inflammatory effects in various inflammatory diseases. However, the mechanisms underlying the effect of CO on TN-C-mediated inflammation are unknown. In the present study, we found that treatment with LPS significantly enhanced TN-C expression in macrophages. CO gas, or treatment with the CO-donor compound, CORM-2, dramatically reduced LPS-induced expression of TN-C and proinflammatory cytokines while significantly increased the expression of IL-10. Treatment with TN-C siRNA significantly suppressed the effects of LPS on proinflammatory cytokines production. TN-C siRNA did not affect the CORM-2-dependent increase of IL-10 expression. In cells transfected with IL-10 siRNA, CORM-2 had no effect on the LPS-induced expression of TN-C and its downstream cytokines. These data suggest that IL-10 mediates the inhibitory effect of CO on TN-C and the downstream production of proinflammatory cytokines. Additionally, administration of CORM-2 dramatically reduced LPS-induced TN-C and proinflammatory cytokines production while expression of IL-10 was significantly increased. In conclusion, CO regulated IL-10 expression and thus inhibited TN-C-mediated inflammation in vitro and in vivo. Md. Jamal Uddin, Chun-shi Li, Yeonsoo Joe, Yingqing Chen, Qinggao Zhang, Stefan W. Ryter, and Hun Taeg Chung Copyright © 2015 Md. Jamal Uddin et al. All rights reserved. Inflammation in Cachexia Wed, 07 Oct 2015 09:44:21 +0000 M. Seelaender, A. Laviano, S. Busquets, G. P. Püschel, T. Margaria, and M. L. Batista Jr. Copyright © 2015 M. Seelaender et al. All rights reserved. Nonmuscle Tissues Contribution to Cancer Cachexia Wed, 07 Oct 2015 07:05:25 +0000 Cachexia is a syndrome associated with cancer, characterized by body weight loss, muscle and adipose tissue wasting, and inflammation, being often associated with anorexia. In spite of the fact that muscle tissue represents more than 40% of body weight and seems to be the main tissue involved in the wasting that occurs during cachexia, recent developments suggest that tissues/organs such as adipose (both brown and white), brain, liver, gut, and heart are directly involved in the cachectic process and may be responsible for muscle wasting. This suggests that cachexia is indeed a multiorgan syndrome. Bearing all this in mind, the aim of the present review is to examine the impact of nonmuscle tissues in cancer cachexia. Josep M. Argilés, Britta Stemmler, Francisco J. López-Soriano, and Silvia Busquets Copyright © 2015 Josep M. Argilés et al. All rights reserved. Kinetic Profiles of Inflammatory Mediators in the Conjunctival Sac Fluid of Patients upon Photorefractive Keratectomy Wed, 07 Oct 2015 06:57:19 +0000 Photorefractive keratectomy (PRK) represents a therapeutic option to remodel corneal stroma and to compensate refractive errors, which involves inflammatory and/or regenerative processes. In this context, the modulation of cytokines/chemokines in the conjunctival sac fluid and their role in the maintenance of the corneal microenvironment during the healing process upon refractive procedures has not been deeply investigated. In this study, serial samples of conjunctival sac fluid of patients () undergoing PRK were harvested before and at different time points after surgery. The levels of 29 cytokines/chemokines/growth factors involved in inflammatory/immune processes were measured with a multiplex array system. The results have firstly highlighted the different pattern of cytokine expression between the microenvironment at the anterior surface of the eye and the systemic circulation. More importantly, the kinetic of modulation of cytokines/chemokines at the conjunctival level following PRK revealed that while the majority of cytokines/chemokines showed a significant decrease, MCP-1 emerged in light of its pronounced and significant increase soon after PRK and during the follow-up. This methodological approach has highlighted the role of MCP-1 in the healing process following PRK and has shown a potential for the identification of expression/modulation of soluble factors for biomarker profiling in ocular surface diseases. Veronica Tisato, Paolo Perri, Erika Rimondi, Elisabetta Melloni, Giuseppe Lamberti, Daniela Milani, Paola Secchiero, and Giorgio Zauli Copyright © 2015 Veronica Tisato et al. All rights reserved. Potential Biomarkers of Fat Loss as a Feature of Cancer Cachexia Mon, 05 Oct 2015 09:50:11 +0000 Fat loss is associated with shorter survival and reduced quality of life in cancer patients. Effective intervention for fat loss in cachexia requires identification of the condition using prognostic biomarkers for early detection and prevention of further depletion. No biomarkers of fat mass alterations have been defined for application to the neoplastic state. Several inflammatory cytokines have been implicated in mediating fat loss associated with cachexia; however, plasma levels may not relate to adipose atrophy. Zinc-α2-glycoprotein may be a local catabolic mediator within adipose tissue rather than serving as a plasma biomarker of fat loss. Plasma glycerol and leptin associate with adipose tissue atrophy and mass, respectively; however, no study has evaluated their potential as a prognostic biomarker of cachexia-associated fat loss. This review confirms the need for further studies to identify valid prognostic biomarkers to identify loss of fat based on changes in plasma levels of biomarkers. Maryam Ebadi and Vera C. Mazurak Copyright © 2015 Maryam Ebadi and Vera C. Mazurak. All rights reserved. Interactions between Myc and Mediators of Inflammation in Chronic Liver Diseases Mon, 05 Oct 2015 09:34:53 +0000 Most chronic liver diseases (CLDs) are characterized by inflammatory processes with aberrant expressions of various pro- and anti-inflammatory mediators in the liver. These mediators are the driving force of many inflammatory liver disorders, which often result in fibrosis, cirrhosis, and liver tumorigenesis. c-Myc is involved in many cellular events such as cell growth, proliferation, and differentiation. c-Myc upregulates IL-8, IL-10, TNF-α, and TGF-β, while IL-1, IL-2, IL-4, TNF-α, and TGF-β promote c-Myc expression. Their interactions play a central role in fibrosis, cirrhosis, and liver cancer. Molecular interference of their interactions offers possible therapeutic potential for CLDs. In this review, current knowledge of the molecular interactions between c-Myc and various well known inflammatory mediators is discussed. Ting Liu, Yu Zhou, Kwang Suk Ko, and Heping Yang Copyright © 2015 Ting Liu et al. All rights reserved. Cancer as a Proinflammatory Environment: Metastasis and Cachexia Mon, 05 Oct 2015 08:39:52 +0000 The development of the syndrome of cancer cachexia and that of metastasis are related with a poor prognostic for cancer patients. They are considered multifactorial processes associated with a proinflammatory environment, to which tumour microenvironment and other tissues from the tumour bearing individuals contribute. The aim of the present review is to address the role of ghrelin, myostatin, leptin, HIF, IL-6, TNF-α, and ANGPTL-4 in the regulation of energy balance, tumour development, and tumoural cell invasion. Hypoxia induced factor plays a prominent role in tumour macro- and microenvironment, by modulating the release of proinflammatory cytokines. Nelson Inácio Pinto, June Carnier, Lila M. Oyama, Jose Pinhata Otoch, Paulo Sergio Alcântara, Flavio Tokeshi, and Claudia M. Nascimento Copyright © 2015 Nelson Inácio Pinto et al. All rights reserved. N-Acetyl-seryl-aspartyl-lysyl-proline Alleviates Renal Fibrosis Induced by Unilateral Ureteric Obstruction in BALB/C Mice Mon, 05 Oct 2015 08:36:53 +0000 To expand the armamentarium of treatment for chronic kidney disease (CKD), we explored the utility of boosting endogenously synthesized N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), which is augmented by inhibition of the angiotensin converting enzyme. Male BALB/c mice underwent unilateral ureteral ligation (UUO) or sham operation and received exogenously administered Ac-SDKP delivered via a subcutaneous osmotic minipump or Captopril treatment by oral gavage. Seven days after UUO, there were significant reductions in the expression of both collagen 1 and collagen 3 in kidneys treated with Ac-SDKP or Captopril, and there was a trend towards reductions in collagen IV, α-SMA, and MCP-1 versus control. However, no significant attenuation of interstitial injury or macrophage infiltration was observed. These findings are in contrary to observations in other models and underscore the fact that a longer treatment time frame may be required to yield anti-inflammatory effects in BALB/c mice treated with Ac-SDKP compared to untreated mice. Finding an effective treatment regimen for CKD requires fine-tuning of pharmacologic protocols. Gary C. W. Chan, Wai Han Yiu, Hao Jia Wu, Dickson W. L. Wong, Miao Lin, Xiao Ru Huang, Hui Yao Lan, and Sydney C. W. Tang Copyright © 2015 Gary C. W. Chan et al. All rights reserved. Role of Inflammation in Muscle Homeostasis and Myogenesis Mon, 05 Oct 2015 08:36:36 +0000 Skeletal muscle mass is subject to rapid changes according to growth stimuli inducing both hypertrophy, through increased protein synthesis, and hyperplasia, activating the myogenic program. Muscle wasting, characteristic of several pathological states associated with local or systemic inflammation, has been for long considered to rely on the alteration of myofiber intracellular pathways regulated by both hormones and cytokines, eventually leading to impaired anabolism and increased protein breakdown. However, there are increasing evidences that even alterations of the myogenic/regenerative program play a role in the onset of muscle wasting, even though the precise mechanisms involved are far from being fully elucidated. The comprehension of the links potentially occurring between impaired myogenesis and increased catabolism would allow the definition of effective strategies aimed at counteracting muscle wasting. The first part of this review gives an overview of skeletal muscle intracellular pathways determining fiber size, while the second part considers the cells and the regulatory pathways involved in the myogenic program. In both parts are discussed the evidences supporting the role of inflammation in impairing muscle homeostasis and myogenesis, potentially determining muscle atrophy. Domiziana Costamagna, Paola Costelli, Maurilio Sampaolesi, and Fabio Penna Copyright © 2015 Domiziana Costamagna et al. All rights reserved. Proinflammatory Cytokines and Potassium Channels in the Kidney Mon, 05 Oct 2015 08:36:35 +0000 Proinflammatory cytokines affect several cell functions via receptor-mediated processes. In the kidney, functions of transporters and ion channels along the nephron are also affected by some cytokines. Among these, alteration of activity of potassium ion (K+) channels induces changes in transepithelial transport of solutes and water in the kidney, since K+ channels in tubule cells are indispensable for formation of membrane potential which serves as a driving force for the transepithelial transport. Altered K+ channel activity may be involved in renal cell dysfunction during inflammation. Although little information was available regarding the effects of proinflammatory cytokines on renal K+ channels, reports have emerged during the last decade. In human proximal tubule cells, interferon-γ showed a time-dependent biphasic effect on a 40 pS K+ channel, that is, delayed suppression and acute stimulation, and interleukin-1β acutely suppressed the channel activity. Transforming growth factor-β1 activated KCa3.1 K+ channel in immortalized human proximal tubule cells, which would be involved in the pathogenesis of renal fibrosis. This review discusses the effects of proinflammatory cytokines on renal K+ channels and the causal relationship between the cytokine-induced changes in K+ channel activity and renal dysfunction. Kazuyoshi Nakamura, Hikaru Hayashi, and Manabu Kubokawa Copyright © 2015 Kazuyoshi Nakamura et al. All rights reserved. Live or Die: Choice Mechanisms in Stressed Cells Mon, 05 Oct 2015 07:39:49 +0000 Francesco Cecconi, Laura Soucek, Dennis D. Taub, and Elio Ziparo Copyright © 2015 Francesco Cecconi et al. All rights reserved. Increased NHC Cells in the Peritoneal Cavity of Plasmacytoma Susceptible BALB/c Mouse Sun, 04 Oct 2015 13:57:54 +0000 BALB/c strain mice are unique in that they develop murine plasmacytoma (MPC) as a consequence of the inflammation induced by pristane oil injection in the peritoneal cavity. In this work the Treg, Th17, B1, B2, and NHC lymphocyte populations from the peritoneal environment of BALB/c, the susceptible strain, and C57BL/6 mice, which do not develop MPC after oil treatment, were studied. Both oil-treated strains showed decreased levels of Th17 lymphocytes, no significant variation in Treg lymphocytes, and a drastic decrease of all B lymphocyte populations. However, only oil-induced BALB/c showed increased levels of natural helper cells (NHC) which could be important in the myeloma induction. Berenice Sánchez-González, Francisco Javier García-Vázquez, José Eduardo Farfán-Morales, and Luis Antonio Jiménez-Zamudio Copyright © 2015 Berenice Sánchez-González et al. All rights reserved. Increased Risk of Cancer in relation to Gout: A Review of Three Prospective Cohort Studies with 50,358 Subjects Sun, 04 Oct 2015 11:41:03 +0000 Gout is a common inflammatory disease characterized by acute arthritis and hyperuricemia. A number of epidemiological studies have suggested the critical role of gout in carcinogenesis. The aim of this study was to estimate the association between gout and cancer risk by meta-analysis of all relevant studies published to date. A comprehensive literature search in PubMed and Embase databases from their inception up to July 1, 2014, was performed to identify eligible studies. The strength for relationship between gout and the risk of different cancers was evaluated by calculating pooled relative risks (RRs) with 95% confidence intervals (95% CIs). All analyses were carried out by STATA 12.0 software. Gout patients were at an increased risk of cancer, particularly urological cancers, digestive system cancers, and lung cancer. No such significant association between gout and the risk of breast or brain cancers was observed. Sensitivity analysis did not materially alter the pooled results. Gout is a risk factor of cancer, particularly that of urological cancers, digestive system cancers, and lung cancer. The pooled data further support the hypothesis of a link between gout and carcinogenesis. Weijie Wang, Donghua Xu, Bin Wang, Shushan Yan, Xiaochen Wang, Yin Yin, Xuehao Wang, Beicheng Sun, and Xiaoyang Sun Copyright © 2015 Weijie Wang et al. All rights reserved. Serum Uric Acid Increases Risk of Cancer Incidence and Mortality: A Systematic Review and Meta-Analysis Sun, 04 Oct 2015 11:27:47 +0000 SUA is a potent antioxidant and thus may play a protective role against cancer. Many epidemiological studies have investigated this hypothesis but provided inconsistent and inconclusive findings. We aimed to precisely elucidate the association between SUA levels and cancer by pooling all available publications. Totally, 5 independent studies with 456,053 subjects and 12 with 632,472 subjects were identified after a comprehensive literature screening from PubMed, Embase, and Web of Science. The pooled RRs showed that individuals with high SUA levels were at an increased risk of total cancer incidence (, 95% CI 1.01–1.05, ). Positive association between high SUA levels and total cancer incidence was observed in males but not females (for men: , 95% CI 1.02–1.08, ; for women, , 95% CI 0.98–1.04, ). Besides, high SUA levels were associated with an elevated risk of total cancer mortality (, 95% CI 1.04–1.32, ), particularly in females (, 95% CI 1.07–1.45, ). The study suggests that high SUA levels increase the risk of total cancer incidence and mortality. The data do not support the hypothesis of a protective role of SUA in cancer. Shushan Yan, Pengjun Zhang, Wei Xu, Yuqing Liu, Bin Wang, Tao Jiang, Changjiang Hua, Xuan Wang, Donghua Xu, and Beicheng Sun Copyright © 2015 Shushan Yan et al. All rights reserved. Cancer Cachexia and MicroRNAs Sun, 04 Oct 2015 11:22:29 +0000 Cancer cachexia is a paraneoplastic syndrome compromising quality of life and survival, mainly characterized by involuntary weight loss, fatigue, and systemic inflammation. The syndrome is described as a result of tumor-host interactions characterized by an inflammatory response by the host to the presence of the tumor. Indeed, systemic inflammation is considered a pivotal feature in cachexia progression and maintenance. Cytokines are intimately related to chronic systemic inflammation and the mechanisms underlying the release of these factors are not totally elucidated, the etiology of cachexia being still not fully understood. Therefore, the understanding of cachexia-related mechanisms, as well as the establishment of markers for the syndrome, is very relevant. MicroRNAs (miRNAs) are a class of noncoding RNAs interfering with gene regulation. Different miRNA expression profiles are associated with different diseases and inflammatory processes. miRNAs modulate adipose and skeletal muscle tissue metabolism in cancer cachexia and also tumor and tissue derived inflammation. Therefore, we propose a possible role for miRNAs in the modulation of the host inflammatory response during cachexia. Moreover, the establishment of a robust body of evidence in regard to miRNAs and the mechanisms underlying cachexia is mandatory, and shall contribute to the improvement of its diagnosis and treatment. Rodolfo Gonzalez Camargo, Henrique Quintas Teixeira Ribeiro, Murilo Vieira Geraldo, Emídio Matos-Neto, Rodrigo Xavier Neves, Luiz Carlos Carnevali Jr., Felipe Fedrizzi Donatto, Paulo S. M. Alcântara, José P. Ottoch, and Marília Seelaender Copyright © 2015 Rodolfo Gonzalez Camargo et al. All rights reserved. 25-OH Vitamin D and Interleukin-8: Emerging Biomarkers in Cutaneous Melanoma Development and Progression Sun, 04 Oct 2015 11:22:12 +0000 Background. There are several circulatory biomarkers that are involved in forecasting the clinical outcome of cutaneous melanoma. Serum/plasma vitamin D status is one of the markers intensively studied in this type of cutaneous cancer. The combination of validated serum biomarkers (like LDH) with new biomarkers such as IL-8, angiogenic factor, and vitamin D is still at the dawn of research. Hence, we are aiming to establish the predictive power of inflammatory biomarkers, such as IL-8, and metabolic ones, such as vitamin D. These candidate biomarkers are intended to aid classical biomarkers, such as LDH, in the prognosis of cutaneous melanoma. Methods. Serum vitamin D and IL-8 were quantified in melanoma patients and in matching healthy controls. Results. Median serum vitamin D concentrations were significantly lower () in melanoma patients as compared to healthy control subjects, while around 65% of the investigated patients have proven a severe circulatory deficiency of this vitamin. IL-8 was found increased () in melanoma patients as compared to controls. Conclusion. Upregulation of proangiogenic factors associated with vitamin D deficiency can prove to be potent future biomarkers candidates, enhancing the predictive power of classical LDH. Corina-Daniela Ene, Amalia-Elena Anghel, Monica Neagu, and Ilinca Nicolae Copyright © 2015 Corina-Daniela Ene et al. All rights reserved. Contribution of Neuroinflammation to the Pathogenesis of Cancer Cachexia Sun, 04 Oct 2015 09:42:13 +0000 Inflammation characterizes the course of acute and chronic diseases and is largely responsible for the metabolic and behavioral changes occurring during the clinical journey of patients. Robust data indicate that, during cancer, functional modifications within brain areas regulating energy homeostasis contribute to the onset of anorexia, reduced food intake, and increased catabolism of muscle mass and adipose tissue. In particular, functional changes are associated with increased hypothalamic concentration of proinflammatory cytokines, which suggests that neuroinflammation may represent the adaptive response of the brain to peripheral challenges, including tumor growth. Within this conceptual framework, the vagus nerve appears to be involved in conveying alert signals to the hypothalamus, whereas hypothalamic serotonin appears to contribute to triggering catabolic signals. Alessio Molfino, Gianfranco Gioia, Filippo Rossi Fanelli, and Alessandro Laviano Copyright © 2015 Alessio Molfino et al. All rights reserved. Modulation of Voltage-Gated Sodium Channels by Activation of Tumor Necrosis Factor Receptor-1 and Receptor-2 in Small DRG Neurons of Rats Sun, 04 Oct 2015 09:21:18 +0000 Tumor necrosis factor- (TNF-) α is a proinflammatory cytokine involved in the development and maintenance of inflammatory and neuropathic pain. Its effects are mediated by two receptors, TNF receptor-1 (TNFR-1) and TNF receptor-2 (TNFR-2). These receptors play a crucial role in the sensitization of voltage-gated sodium channels (VGSCs), a key mechanism in the pathogenesis of chronic pain. Using the whole-cell patch-clamp technique, we examined the influence of TNFR-1 and TNFR-2 on VGSCs and TTX-resistant NaV1.8 channels in isolated rat dorsal root ganglion neurons by using selective TNFR agonists. The TNFR-1 agonist R32W (10 pg/mL) caused an increase in the VGSC current (INa(V)) by 27.2 ± 5.1%, while the TNFR-2 agonist D145 (10 pg/mL) increased the current by 44.9 ± 2.6%. This effect was dose dependent. Treating isolated NaV1.8 with R32W (100 pg/mL) resulted in an increase in INaV(1.8) by 18.9 ± 1.6%, while treatment with D145 (100 pg/mL) increased the current by 14.5 ± 3.7%. Based on the current-voltage relationship, 10 pg of R32W or D145 led to an increase in INa(V) in a bell-shaped, voltage-dependent manner with a maximum effect at −30 mV. The effects of TNFR activation on VGSCs promote excitation in primary afferent neurons and this might explain the sensitization mechanisms associated with neuropathic and inflammatory pain. M. Leo, S. Argalski, M. Schäfers, and T. Hagenacker Copyright © 2015 M. Leo et al. All rights reserved. Polymorphisms of Tumor Necrosis Factor Alpha in Moroccan Patients with Gastric Pathology: New Single-Nucleotide Polymorphisms in TNF-α−193 (G/A) Sun, 04 Oct 2015 09:16:12 +0000 Polymorphisms in tumor necrosis factor alpha (TNF-α) gene are emerging as key determinants of gastric diseases. The TNF-α−308 (G/A) and TNF-α−238 (G/A) single-nucleotide polymorphisms SNPs are the most extensively studied. However, all these studies are conducted in Caucasian and Asian populations. Thus, for the first time in Africa, we sought to investigate whether polymorphisms in TNF-α gene were associated with the development of gastric pathology in Morocco. Two SNPs located in the promoter region (positions −308 and −238) in TNF-α gene were genotyped in 244 individuals (170 patients and 74 healthy controls). Odds ratios (ORs) and 95% confidence intervals (CI) were estimated using logistic regression analysis. The TNF-α−238 (G/A) genotype was significantly associated with a high risk of gastritis and gastric cancer (GC) ( and , resp.). Furthermore, a new polymorphism located in the promoter region at position −193 in TNF-α gene was identified. The distribution of this SNP was markedly different in patients suffering from ulcers. The association between TNF-α−193 (G/A) genotype and high risk of ulcer was significant (). These results suggest that the TNF-α−193 (G/A) allele has a protective function against gastric cancer by developing ulcer. A. Essadik, H. Jouhadi, T. Rhouda, S. Nadifiyine, A. Kettani, and F. Maachi Copyright © 2015 A. Essadik et al. All rights reserved. A Survey of Attitudes towards the Clinical Application of Systemic Inflammation Based Prognostic Scores in Cancer Sun, 04 Oct 2015 08:56:59 +0000 Introduction. The systemic inflammatory response (SIR) plays a key role in determining nutritional status and survival of patients with cancer. A number of objective scoring systems have been shown to have prognostic value; however, their application in routine clinical practice is not clear. The aim of the present survey was to examine the range of opinions internationally on the routine use of these scoring systems. Methods. An online survey was distributed to a target group consisting of individuals worldwide who have reported an interest in systemic inflammation in patients with cancer. Results. Of those invited by the survey (), 65% routinely measured the SIR, mainly for research and prognostication purposes and clinically for allocation of adjuvant therapy or palliative chemotherapy. 40% reported that they currently used the Glasgow Prognostic Score/modified Glasgow Prognostic Score (GPS/mGPS) and 81% reported that a measure of systemic inflammation should be incorporated into clinical guidelines, such as the definition of cachexia. Conclusions. The majority of respondents routinely measured the SIR in patients with cancer, mainly using the GPS/mGPS for research and prognostication purposes. The majority reported that a measure of the SIR should be adopted into clinical guidelines. David G. Watt, Campbell S. Roxburgh, Mark White, Juen Zhik Chan, Paul G. Horgan, and Donald C. McMillan Copyright © 2015 David G. Watt et al. All rights reserved. Lung Epithelial TRPA1 Transduces the Extracellular ROS into Transcriptional Regulation of Lung Inflammation Induced by Cigarette Smoke: The Role of Influxed Ca2+ Sun, 04 Oct 2015 07:45:00 +0000 The mechanism underlying the inflammatory role of TRPA1 in lung epithelial cells (LECs) remains unclear. Here, we show that cigarette smoke extract (CSE) sequentially induced several events in LECs. The Ca2+ influx was prevented by decreasing extracellular reactive oxygen species (ROS) with the scavenger N-acetyl-cysteine, removing extracellular Ca2+ with the chelator EGTA, or treating with the TRPA1 antagonist HC030031. NADPH oxidase activation was abolished by its inhibitor apocynin, EGTA, or HC030031. The increased intracellular ROS was halted by apocynin, N-acetyl-cysteine, or HC030031. The activation of the MAPKs/NF-κB signaling was suppressed by EGTA, N-acetyl-cysteine, or HC030031. IL-8 induction was inhibited by HC030031 or TRPA1 siRNA. Additionally, chronic cigarette smoke (CS) exposure in wild-type mice induced TRPA1 expression in LECs and lung tissues. In CS-exposure trpa1−/− mice, the increased BALF level of ROS was similar to that of CS-exposure wild-type mice; yet lung inflammation was lessened. Thus, in LECs, CSE may initially increase extracellular ROS, which activate TRPA1 leading to an increase in Ca2+ influx. The increased intracellular Ca2+ contributes to activation of NADPH oxidase, resulting in increased intracellular ROS, which activate the MAPKs/NF-κB signaling leading to IL-8 induction. This mechanism may possibly be at work in mice chronically exposed to CS. An-Hsuan Lin, Meng-Han Liu, Hsin-Kuo Ko, Diahn-Warng Perng, Tzong-Shyuan Lee, and Yu Ru Kou Copyright © 2015 An-Hsuan Lin et al. All rights reserved. Comprehensive Screening of Gene Function and Networks by DNA Microarray Analysis in Japanese Patients with Idiopathic Portal Hypertension Sun, 04 Oct 2015 07:03:50 +0000 The functions of genes involved in idiopathic portal hypertension (IPH) remain unidentified. The present study was undertaken to identify the functions of genes expressed in blood samples from patients with IPH through comprehensive analysis of gene expression using DNA microarrays. The data were compared with data from healthy individuals to explore the functions of genes showing increased or decreased expression in patients with IPH. In cluster analysis, no dominant probe group was shown to differ between patients with IPH and healthy controls. In functional annotation analysis using the Database for Annotation Visualization and Integrated Discovery tool, clusters showing dysfunction in patients with IPH involved gene terms related to the immune system. Analysis using network-based pathways revealed decreased expression of adenosine deaminase, ectonucleoside triphosphate diphosphohydrolase 4, ATP-binding cassette, subfamily C, member 1, transforming growth factor-β, and prostaglandin E receptor 2; increased expression of cytochrome P450, family 4, subfamily F, polypeptide 3, and glutathione peroxidase 3; and abnormalities in the immune system, nucleic acid metabolism, arachidonic acid/leukotriene pathways, and biological processes. These results suggested that IPH involved compromised function of immunocompetent cells and that such dysfunction may be associated with abnormalities in nucleic acid metabolism and arachidonic acid/leukotriene-related synthesis/metabolism. Kohei Kotani, Joji Kawabe, Hiroyasu Morikawa, Tomohiko Akahoshi, Makoto Hashizume, and Susumu Shiomi Copyright © 2015 Kohei Kotani et al. All rights reserved. CXCR6 Expression Is Important for Retention and Circulation of ILC Precursors Thu, 01 Oct 2015 13:43:12 +0000 Innate lymphoid cells are present at mucosal sites and represent the first immune barrier against infections, but what contributes to their circulation and homing is still unclear. Using Rag2−/−Cxcr6Gfp/+ reporter mice, we assessed the expression and role of CXCR6 in the circulation of ILC precursors and their progeny. We identify CXCR6 expressing ILC precursors in the bone marrow and characterize their significant increase in CXCR6-deficient mice at steady state, indicating their partial retention in the bone marrow after CXCR6 ablation. Circulation was also impaired during embryonic life as fetal liver from CXCR6-deficient embryos displayed decreased numbers of ILC3 precursors. When injected, fetal CXCR6-deficient ILC3 precursors also fail to home and reconstitute ILC compartments in vivo. We show that adult intestinal ILC subsets have heterogeneous expression pattern of CXCR6, integrin α4β7, CD62L, CD69, and CD44, with ILC1 and ILC3 being more likely tissue resident lymphocytes. Intestinal ILC subsets were unchanged in percentages and numbers in both mice. We demonstrate that the ILC frequency is maintained due to a significant increase of ILC peripheral proliferation, as well as an increased proliferation of the in situ ILC precursors to compensate their retention in the bone marrow. Sylvestre Chea, Cécilie Possot, Thibaut Perchet, Maxime Petit, Ana Cumano, and Rachel Golub Copyright © 2015 Sylvestre Chea et al. All rights reserved. Virological Mechanisms in the Coinfection between HIV and HCV Thu, 01 Oct 2015 08:32:50 +0000 Due to shared transmission routes, coinfection with Hepatitis C Virus (HCV) is common in patients infected by Human Immunodeficiency Virus (HIV). The immune-pathogenesis of liver disease in HIV/HCV coinfected patients is a multifactorial process. Several studies demonstrated that HIV worsens the course of HCV infection, increasing the risk of cirrhosis and hepatocellular carcinoma. Also, HCV might increase immunological defects due to HIV and risk of comorbidities. A specific cross-talk among HIV and HCV proteins in coinfected patients modulates the natural history, the immune responses, and the life cycle of both viruses. These effects are mediated by immune mechanisms and by a cross-talk between the two viruses which could interfere with host defense mechanisms. In this review, we focus on some virological/immunological mechanisms of the pathogenetic interactions between HIV and HCV in the human host. Maria Carla Liberto, Emilia Zicca, Grazia Pavia, Angela Quirino, Nadia Marascio, Carlo Torti, and Alfredo Focà Copyright © 2015 Maria Carla Liberto et al. All rights reserved. Semiannual Imaging Surveillance Is Associated with Better Survival in Patients with Non-B, Non-C Hepatocellular Carcinoma Thu, 01 Oct 2015 07:39:05 +0000 Since it remains elusive whether and how the imaging surveillance affects the survival in patients with non-B, non-C hepatocellular carcinoma (NBNC-HCC), we conducted this retrospective study which investigated the association between the semiannual surveillance prior to HCC diagnosis and the survival in patients with the initial diagnosis of HCC induced by hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infections () and non-B, non-C etiology (). It was demonstrated that surveillance was less frequently performed in the NBNC-HCC patients compared to that in HCC patients with HBV and/or HCV infections (B/C-HCC patients), and the survival was unfavorable in NBNC-HCC patients. On the other hand, the survival of NBNC-HCC patients with semiannual surveillance was significantly favorable than those patients without semiannual surveillance, and the survival was similar between B/C-HCCs and NBNC-HCCs with semiannual surveillance. In conclusion, though NBNC-HCC patients compared to B/C-HCC patients had poorer prognosis overall, these NBNC-HCC patients with semiannual surveillance had a better survival almost equivalent to the survival of B/C-HCC patients with semiannual surveillance, demonstrating the clinical utility of the semiannual imaging surveillance program for NBNC-HCCs. Kuniaki Shindo, Shinya Maekawa, Nobutoshi Komatsu, Akihisa Tatsumi, Mika Miura, Mitsuaki Sato, Yuichiro Suzuki, Shuya Matsuda, Masaru Muraoka, Fumitake Amemiya, Mitsuharu Fukasawa, Tatsuya Yamaguchi, Yasuhiro Nakayama, Tomoyoshi Uetake, Taisuke Inoue, Minoru Sakamoto, Tadashi Sato, and Nobuyuki Enomoto Copyright © 2015 Kuniaki Shindo et al. All rights reserved. Liver Cirrhosis: Evaluation, Nutritional Status, and Prognosis Thu, 01 Oct 2015 06:28:35 +0000 The liver is the major organ for the metabolism of three major nutrients: protein, fat, and carbohydrate. Chronic hepatitis C virus infection is the major cause of chronic liver disease. Liver cirrhosis (LC) results from different mechanisms of liver injury that lead to necroinflammation and fibrosis. LC has been seen to be not a single disease entity but one that can be graded into distinct clinical stages related to clinical outcome. Several noninvasive methods have been developed for assessing liver fibrosis and these methods have been used for predicting prognosis in patients with LC. On the other hand, subjects with LC often have protein-energy malnutrition (PEM) and poor physical activity. These conditions often result in sarcopenia, which is the loss of skeletal muscle volume and increased muscle weakness. Recent studies have demonstrated that PEM and sarcopenia are predictive factors for poorer survival in patients with LC. Based on these backgrounds, several methods for evaluating nutritional status in patients with chronic liver disease have been developed and they have been preferably used in the clinical field practice. In this review, we will summarize the current knowledge in the field of LC from the viewpoints of diagnostic method, nutritional status, and clinical outcomes. Hiroki Nishikawa and Yukio Osaki Copyright © 2015 Hiroki Nishikawa and Yukio Osaki. All rights reserved. Endothelial-Leukocyte Interaction in Severe Malaria: Beyond the Brain Wed, 30 Sep 2015 13:06:04 +0000 Malaria is the most important parasitic disease worldwide, accounting for 1 million deaths each year. Severe malaria is a systemic illness characterized by dysfunction of brain tissue and of one or more peripheral organs as lungs and kidney. The most severe and most studied form of malaria is associated with cerebral complications due to capillary congestion and the adhesion of infected erythrocytes, platelets, and leukocytes to brain vasculature. Thus, leukocyte rolling and adhesion in the brain vascular bed during severe malaria is singular and distinct from other models of inflammation. The leukocyte/endothelium interaction and neutrophil accumulation are also observed in the lungs. However, lung interactions differ from brain interactions, likely due to differences in the blood-brain barrier and blood-air barrier tight junction composition of the brain and lung endothelium. Here, we review the importance of endothelial dysfunction and the mechanism of leukocyte/endothelium interaction during severe malaria. Furthermore, we hypothesize a possible use of adjunctive therapies to antimalarial drugs that target the interaction between the leukocytes and the endothelium. Mariana C. Souza, Tatiana A. Padua, and Maria G. Henriques Copyright © 2015 Mariana C. Souza et al. All rights reserved. Cardiac-Restricted IGF-1Ea Overexpression Reduces the Early Accumulation of Inflammatory Myeloid Cells and Mediates Expression of Extracellular Matrix Remodelling Genes after Myocardial Infarction Wed, 30 Sep 2015 09:05:07 +0000 Strategies to limit damage and improve repair after myocardial infarct remain a major therapeutic goal in cardiology. Our previous studies have shown that constitutive expression of a locally acting insulin-like growth factor-1 Ea (IGF-1Ea) propeptide promotes functional restoration after cardiac injury associated with decreased scar formation. In the current study, we investigated the underlying molecular and cellular mechanisms behind the enhanced functional recovery. We observed improved cardiac function in mice overexpressing cardiac-specific IGF-1Ea as early as day 7 after myocardial infarction. Analysis of gene transcription revealed that supplemental IGF-1Ea regulated expression of key metalloproteinases (MMP-2 and MMP-9), their inhibitors (TIMP-1 and TIMP-2), and collagen types (Col 1α1 and Col 1α3) in the first week after injury. Infiltration of inflammatory cells, which direct the remodelling process, was also altered; in particular there was a notable reduction in inflammatory Ly6C+ monocytes at day 3 and an increase in anti-inflammatory CD206+ macrophages at day 7. Taken together, these results indicate that the IGF-1Ea transgene shifts the balance of innate immune cell populations early after infarction, favouring a reduction in inflammatory myeloid cells. This correlates with reduced extracellular matrix remodelling and changes in collagen composition that may confer enhanced scar elasticity and improved cardiac function. Enrique Gallego-Colon, Robert D. Sampson, Susanne Sattler, Michael D. Schneider, Nadia Rosenthal, and Joanne Tonkin Copyright © 2015 Enrique Gallego-Colon et al. All rights reserved.