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Background and Aim: Recent observational studies have shown therapeutic benefits of acetylsalicylic acid (ASA) in several types of cancer. We examined whether ASA exerts antitumor activity in esophageal adenocarcinoma (EAC).Methods: Human EAC cells (OE33) were treated with ASA (0-5 mM) to evaluate proliferation, apoptosis, and migration. In vivo model: OE33-derived tumors were subcutaneously implanted into athymic mice which were allocated to ASA (5 or 50 mg/kg/day)/vehicle (5-6 animals/group). Tumor growth was assessed every 2-3 days, and after 40 days, mice were euthanized. Plasma drug levels were determined by high-performance liquid chromatography. Histological and immunohistochemical (Ki67, activated caspase-3) analysis of tumors were performed. The effect of ASA on tumor prostaglandin E2 (PGE2) levels was also evaluated.Results: In vitro cell proliferation and migration were significantly inhibited while apoptosis increased (p < 0.05) by ASA. Although ASA did not induce tumor remission, tumor progression was significantly lower in ASA-treated mice when compared to non-treated animals (478 % in mice treated with 5 mg/kg/day ASA vs. 2696 % control; 748 % in mice treated with 50 mg/kg/day ASA vs. 2670 % control). Maximum tumor inhibition was 92 and 85 %, respectively. This effect was associated with a significant decrease of proliferation index in tumors. ASA 5 mg/kg/day did not modify tumor PGE2 levels. Whereas tumor PGE2 content in mice treated with ASA 50 mg/kg was lower than in control mice, the difference was not significant.Conclusion: Although these results need to be confirmed in other EAC cells, our data suggest a role for ASA in the treatment of this tumor. [ABSTRACT FROM AUTHOR]

A large body of evidence from epidemiological and preclinical studies have shown that nonsteroideal anti-inflammatory drugs (NSAIDs) have a chemopreventive effect on gastrointestinal cancers and, more specifically, in colorectal cancer. This review highlights recent advances in our understanding of the role of NSAIDs in colorectal cancer prevention and adjuvant treatment. Moreover, we have focused on randomized controlled studies assessing their efficacy to prevent adenoma recurrence and reduction of colorectal cancer incidence and mortality but also their gastrointestinal and cardiovascular side effects. Among NSAIDs, almost the unique agent with potential use as chemopreventive agent is aspirin at low dose since it has both no cardiovascular and low gastrointestinal risk. Furthermore, since aspirin has shown efficacy in secondary prevention of cardiovascular diseases, this drug carries a particular attractive intervention for selected populations. Nevertheless, before it can be prescribed, further studies are necessary to define some important questions, specially the most appropriate dose and time of aspirin use and the population who may benefit from it. [ABSTRACT FROM AUTHOR]

Abstract: Background: Previous studies have reported a potential genetic predisposition to NSAID-related upper gastrointestinal (GI) bleeding. Objective: This study evaluated whether there was an association between 2 polymorphisms-the platelet glycoprotein (GP) IIIa PlA1/A2 polymorphism and the 27-bp VNTR (variable number of tandem repeats) polymorphism in intron 4 of the endothelial nitric oxide synthase (eNOS) gene-and a risk for nonvariceal upper GI bleeding in Spanish patients taking low-dose aspirin for secondary prophylaxis of vascular occlusive diseases. Methods: Genotyping for the 2 polymorphisms was performed in patients hospitalized for upper GI bleeding associated with the use of low-dose aspirin between September 1998 and October 2000, and race-, age-, and sex-matched controls who were taking low-dose aspirin but had no history of upper GI bleeding. To ascertain allele frequencies in a healthy population, genotyping was also performed in an unmatched group of blood donors. Results: The study included 88 white patients (65 men, 23 women; mean age, 67.5 years) with an episode of upper GI bleeding, 108 matched controls with no history of upper GI bleeding (79 men, 29 women; mean age, 65.9 years), and 158 blood-donor controls (109 men, 49 women; mean age, 53.4 years). No significant differences were found between cases and controls in terms of genotype, carriage, or allele frequency of the GPIIIa PlA1/A2 polymorphism. However, after adjustment for confounding variables, logistic regression analysis indicated an association between carriage of the eNOS “a” allele and a reduced risk of upper GI bleeding (odds ratio [OR] ＝ 0.39; 95％ CI, 0.18-0.85; P ＝ 0.018). In this model, treatment with ni-trovasodilators (OR ＝ 0.28; 95％ CI, 0.12-0.66; P ＝ 0.004) and use of antisecretory drugs (OR ＝ 0.15; 95％ CI, 0.05-0.47; P ＝ 0.001) were also identified as protective factors. Helicobacter pylori infection (OR ＝ 3.07; 95％ CI, 1.23-7.70; P ＝ 0.017), alcohol consumption (OR ＝ 5.04; 95％ CI, 1.86-13.70; P ＝ 0.001), and a history of peptic ulcer (OR ＝ 13.41; 95％ CI, 3.78-47.64; P ＜ 0.001) were identified as risk factors for upper GI bleeding. Conclusion: In this small, selected population of individuals taking low-dose aspirin for secondary prevention, carriage of the “a” allele of the eNOS gene was associated with a decreased risk for upper GI bleeding. [Copyright &y& Elsevier]

Abstract: Accumulating evidence suggests that COX-2-derived prostaglandin E2 (PGE2) plays an important role in esophageal adenocarcinogenesis. Recently, PGE2 receptors (EP) have been shown to be involved in colon cancer development. Since it is not known which receptors regulate PGE2 signals in esophageal adenocarcinoma, we investigated the role of EP receptors using a human Barrett''s-derived esophageal adenocarcinoma cell line (OE33). OE33 cells expressed COX-1, COX-2, EP1, EP2 and EP4 but not EP3 receptors as determined by real time RT-PCR and Western-blot. Treatment with 5-aza-dC restored expression, suggesting that hypermethylation is involved in EP3 downregulation. Endogenous PGE2 production was mainly due to COX-2, since this was significantly suppressed with COX-2 inhibitors (NS-398 and SC-58125), but not COX-1 inhibitors (SC-560). Cell proliferation (3H-thymidine uptake) was significantly inhibited by NS-398 and SC-58125, the EP1 antagonist SC-51322, AH6809 (EP1/EP2 antagonist), and the EP4 antagonist AH23848B, but was not affected by exogenous PGE2. However, treatment with the selective EP2 agonist Butaprost or 16,16-dimethylPGE2 significantly inhibited butyrate-induced apoptosis and stimulated OE33 cell migration. The effect of exogenous PGE2 on migration was attenuated when cells were first treated with EP1 and EP4 antagonists. These findings suggest a potential role for EP selective antagonists in the treatment of esophageal adenocarcinoma. [Copyright &y& Elsevier]

Background and Aims: Ulceration is a common feature of inflammatory bowel diseases, where subepithelial cell growth is frequently necessary for resolution. In order to further understand the role of colonic fibroblasts in this process, we have used an in vitro model of wound repair to study the response of human colonic fibroblasts to several growth factors expressed in colonic tissues. Methods: Proliferation was determined by [[sup 3] H]thymidine incorporation into DNA in subconfluent fibroblast cultures. In vitro wound repair was determined in confluent fibroblast monolayers after mechanical denudation. The presence of growth factors secreted by fibroblasts was studied in conditioned medium by heparin affinity chromatography and immunodetection with specific antibodies. Results: Serum and platelet-derived growth factor (PDGF-BB) induced a dramatic increase in both colonic fibroblast proliferation and closure of wounded cell monolayers. Epidermal growth factor (EGF) stimulated both fibroblast activities, but the effect was less potent. However, colonic fibroblasts did not respond to transforming growth factor-β[sub 1] . Conditioned medium stimulated fibroblast proliferation and wound repair activity, which was reverted by the addition of suramin. Furthermore, a PDGF-like factor was isolated from colonic fibroblast-conditioned medium. Conclusions: EGF and PDGF-BB promote human colonic fibroblast-dependent wound repair activities. Human colonic fibroblasts may exert an autocrine regulation via the production of growth factors.Copyright © 2000 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection is highly heterogeneous, ranging from asymptomatic to severe and fatal cases. COVID-19 has been characterized by an increase of serum pro-inflammatory cytokine levels which seems to be associated with fatal cases. By contrast, the role of pro-resolving lipid mediators (SPMs), involved in the attenuation of inflammatory responses, has been scarcely investigated, so further studies are needed to understand SPMs metabolism in COVID-19 and other infectious diseases. Our aim was to analyse the lipid mediator metabolome, quantifying pro- and anti-inflammatory serum bioactive lipids by LC–MS/MS in 7 non-infected subjects and 24 COVID-19 patients divided into mild, moderate, and severe groups according to the pulmonary involvement, to better understand the disease outcome and the severity of the pulmonary manifestations. Statistical analysis was performed with the R programming language (R Foundation for Statistical Computing, Vienna, Austria). All COVID-19 patients had increased levels of Prostaglandin E2. Severe patients showed a significant increase versus controls, mild- and moderate-affected patients, expressed as median (interquartile range), in resolvin E1 [112.6 (502.7) vs 0.0 (0.0) pg/ml in the other groups], as well as in maresin 2 [14.5 (7.0) vs 8.1 (4.2), 5.5 (4.3), and 3.0 (4.0) pg/ml, respectively]. Moreover, 14-hydroxy docosahexaenoic acid (14-HDHA) levels were also increased in severe vs control and mild-affected patients [24.7 (38.2) vs 2.4 (2.2) and 3.7 (6.4) ng/mL, respectively]. Resolvin D5 was also significantly elevated in both moderate [15.0 (22.4) pg/ml] and severe patients [24.0 (24.1) pg/ml] versus controls [0.0 (0.0) pg/ml]. These results were confirmed by sparse partial least squares discriminant analysis which highlighted the contribution of these mediators to the separation between each of the groups. In conclusion, the potent inflammatory response to SARS-CoV-2 infection involves not only pro- but also anti-inflammatory lipid mediators that can be quantified in easily accessible serum samples, suggesting the need to perform future research on their generation pathways that will help us to discover new therapeutic targets. [ABSTRACT FROM AUTHOR]

Helicobacter pylori infection constitutes a silent pandemic of global concern. In the last decades, the alarming increase in multidrug resistance evolved by this pathogen has led to a marked drop in the eradication rates of traditional therapies worldwide. By using a high-throughput screening strategy, in combination with in vitro DNA binding assays and antibacterial activity testing, we identified a battery of novel drug-like HsrA inhibitors with MIC values ranging from 0.031 to 4 mg/L against several antibiotic-resistant strains of H. pylori, and minor effects against both Gram-negative and Gram-positive species of human microbiota. The most potent anti-H. pylori candidate demonstrated a high therapeutic index, an additive effect in combination with metronidazole and clarithromycin as well as a strong antimicrobial action against Campylobacter jejuni, another clinically relevant pathogen of phylum Campylobacterota. Transcriptomic analysis suggests that the in vivo inhibition of HsrA triggers lethal global disturbances in H. pylori physiology including the arrest of protein biosynthesis, malfunction of respiratory chain, detriment in ATP generation, and oxidative stress. The novel drug-like HsrA inhibitors described here constitute valuable candidates to a new family of narrow-spectrum antibiotics that allow overcoming the current resistome, protecting from dysbiosis, and increasing therapeutic options for novel personalized treatments against H. pylori. [ABSTRACT FROM AUTHOR]

Simple Summary: Aspirin has been studied for a long time in familial adenomatous polyposis (FAP), but the data on the prevention of colorectal adenoma formation and recurrence remain controversial. We conducted a biomarker-based clinical study in eight FAP patients treated with low-dose Aspirin to clarify the drug's mechanism of action. Aspirin appropriately acetylated platelet cyclooxygenase (COX)-1 but left persistently high systemic thromboxane(TX)A2 and prostaglandin (PG)E2 biosynthesis (assessed by measuring their primary urinary metabolites, i.e., 11-dehydro-TXB2 and PGEM) associated with the incomplete acetylation of COX-1 in colorectal mucosa and adenomas. Proteomics of colorectal adenomas of FAP patients showed that the vimentin upregulation and hemoglobin subunit beta downregulation distinguished the FAP patients in two groups with high vs. low residual 11-dehydro-TXB2 levels, possibly identifying Aspirin nonresponders and responders, respectively. Novel chemotherapeutic strategies in FAP may involve drugs that affect TXA2 and PGE2 signaling in the colorectum with receptor antagonists, and clinical studies should be performed to verify the drugs' impact. Background: The results of Aspirin prevention of colorectal adenomas in patients with familial adenomatous polyposis (FAP) are controversial. Methods: We conducted a biomarker-based clinical study in eight FAP patients treated with enteric-coated low-dose Aspirin (100 mg daily for three months) to explore whether the drug targets mainly platelet cyclooxygenase (COX)-1 or affects extraplatelet cellular sources expressing COX-isozymes and/or off-target effects in colorectal adenomas. Results: In FAP patients, low-dose Aspirin-acetylated platelet COX-1 at Serine529 (>70%) was associated with an almost complete inhibition of platelet thromboxane (TX) B2 generation ex vivo (serum TXB2). However, enhanced residual urinary 11-dehydro-TXB2 and urinary PGEM, primary metabolites of TXA2 and prostaglandin (PG)E2, respectively, were detected in association with incomplete acetylation of COX-1 in normal colorectal biopsies and adenomas. Proteomics of adenomas showed that Aspirin significantly modulated only eight proteins. The upregulation of vimentin and downregulation of HBB (hemoglobin subunit beta) distinguished two groups with high vs. low residual 11-dehydro-TXB2 levels, possibly identifying the nonresponders and responders to Aspirin. Conclusions: Although low-dose Aspirin appropriately inhibited the platelet, persistently high systemic TXA2 and PGE2 biosynthesis were found, plausibly for a marginal inhibitory effect on prostanoid biosynthesis in the colorectum. Novel chemotherapeutic strategies in FAP can involve blocking the effects of TXA2 and PGE2 signaling with receptor antagonists. [ABSTRACT FROM AUTHOR]

Human glutathione S-transferases (GSTs) are phase II metabolizing enzymes that play a key role in protecting against cancer by detoxifying numerous potentially cytotoxic/genotoxic compounds. The genes encoding the human GST isoenzymes GSTM(mu)1, GSTT(theta)1 and GSTP(pi)1 harbour polymorphisms, which have been considered important modifiers of the individual risk for environmentally induced cancers such as gastric cancer (GC). However, results are inconsistent among studies from different geographic areas and ethnic groups. Our goal was to perform a nationwide, case–control study in Spain to evaluate the relevance of several functional GST gene polymorphisms and environmental factors to GC risk and phenotype. DNA from 557 GC patients and 557 sex- and age-matched healthy controls (HC) was typed for two deletions in the GSTM1 and GSTT1 genes and two SNPs in the GSTP1 gene (rs1695 and rs1138272) using polymerase chain reaction-restriction fragment length polymorphism methods. Logistic regression analysis identified Helicobacter pylori infection with CagA strains [odds ratio (OR): 2.36; 95% confidence interval (CI): 1.78–3.15], smoking habit (OR: 2.10; 95% CI: 1.48–2.97) and family history of GC (OR: 3.2; 95% CI: 2.02–5.16) as independent risk factors for GC. No differences in the frequencies of GSTM1 or GSTT1 null genotypes were observed between cases and controls (GSTM1: 50.8% vs. 48%; GSTT1: 21.5% vs. 21%). Moreover, simultaneous carriage of both, the GSTM1 and the GSTT1 null genotypes, was almost identical in both groups (10.7% in GC vs. 10.6% in HC). In addition, no significant differences in GSTP1 Ile105Val (rs1695) and GSTP1 Val114Ala (rs1138272) genotype distribution were observed between GC patients and controls. Subgroup analysis for age, gender, Helicobacter pylori status, smoking habits, family history of GC, anatomic location and histological subtype revealed no significant association between GST variants and GC risk. Our results show that the GST polymorphisms evaluated in this study are not relevant when determining the individual susceptibility to GC or phenotype in a South-European population. [ABSTRACT FROM PUBLISHER]

Background: Genetic factors influencing the prognosis of gastric adenocarcinoma (GAC) are not well known. Given the relevance of cytokines and other pro-inflammatory mediators in cancer progression and invasiveness, we aimed to assess the prognostic role of several functional cytokine and cyclooxygenase gene polymorphisms in patients with GAC. Methodology: Genomic DNA from 380 Spanish Caucasian patients with primary GAC was genotyped for 23 polymorphisms in pro-inflammatory (IL1B, TNFA, LTA, IL6, IL12p40), anti-inflammatory (IL4, IL1RN, IL10, TGFB1) cytokine, and cyclooxygenase (PTGS1 and PTGS2) genes by PCR, RFLP and TaqMan assays. Clinical and histological information was collected prospectively. Survival curves were estimated by the Kaplan-Meier method and compared using the log rank test. Outcome was determined by analysis of Cox proportional hazards, adjusting for confounding factors. Results: The median follow-up period and median overall survival (OS) time were 9.9 months (range 0.4-120.3) and 10.9 months (95% CI: 8.9-14.1), respectively. Multivariate analysis identified tumor stages III (HR, 3.23; 95% CI:2-5.22) and IV (HR, 5.5; 95% CI: 3.51-8.63) as independent factors associated with a significantly reduced OS, whereas surgical treatment (HR: 0.44; 95%CI: 0.3-0.6) was related to a better prognosis of the disease. Concerning genetic factors, none of the 23 polymorphisms evaluated in the current study did influence survival. Moreover, no gene-environment interactions on GAC prognosis were observed. Conclusions: Our results show that, in our population, the panel of selected pro- and anti-inflammatory cytokine, and cyclooxygenase gene polymorphisms are not relevant in determining the prognosis of gastric adenocarcinoma. [ABSTRACT FROM AUTHOR]

Bernal V, Pascual I, Lanas A, Esquivias P, Piazuelo E, Garcia-Gil FA, Lacambra I, Simon MA. Cardiac function and aminoterminal pro-brain natriuretic peptide levels in liver-transplanted cirrhotic patients. Clin Transplant 2012: 26: 111-116. © 2011 John Wiley & Sons A/S. Abstract: Background: Cirrhosis is associated with structural and functional abnormalities of the heart. We examined the evolution of these abnormalities after liver transplantation (LT). Methods: Sixty cirrhotic patients, without cardiovascular disease, were included. Clinical data, echocardiography, and aminoterminal pro-brain natriuretic peptide (NT-proBNP) levels were analyzed before and after transplantation. Healthy controls (n = 25) were included for reference. Results: Before transplantation, cirrhotic patients had higher left atrium diameter, left ventricular (LV) mass index, and ejection fraction than controls. After transplantation, LV mass index increased (105 ± 31 vs. 119 ± 35 g/m2; p < 0.05), diastolic cardiac function deteriorated, expressed as a reduction in E/A wave ratio (1.105 ± 0.295 vs. 0.798 ± 0.248; p < 0.001), and NT-proBNP levels decreased significantly in patients compared to pre-transplantation values (1759 ± 1154 vs. 1117 ± 600 pg/mL; p < 0.001), although they were still above levels found in controls (1117 ± 600 vs. 856 ± 123 pg/mL; p < 0.05). NT-proBNP levels above 2000 pg/mL before transplantation were significantly associated with risk for cardiovascular events after procedure (37% vs. 9%, p = 0.008). Conclusions: In cirrhotic patients, diastolic function and cardiac structure deteriorate after LT. Compared to controls, NT-proBNP levels tend to be higher before and after transplantation. The mechanisms and consequences of these results require further study. [ABSTRACT FROM AUTHOR]

Abstract: We aimed to evaluate the influence of Helicobacter pylori infection and IL-1/TNF gene polymorphisms on interleukin (IL)-1β and tumor necrosis factor (TNF)-α gastric mucosal production. IL-1β and TNF-α levels in homogenized biopsy specimens taken from the antrum and corpus of 81 patients were measured by enzyme-linked immunosorbent assay. Genomic DNA was typed for the IL1B-511, IL1B+3954, variable number of tandem repeat (VNTR) IL1RN, TNFA-308, TNFA-238, LTA NcoI, and LTA Bsi gene polymorphisms by polymerase chain reaction, restriction fragment length polymorphism, and TaqMan assays. H. pylori infection and CagA/VacA antibody status were determined by Western blot. IL-1β and TNF-α protein levels were significantly higher in the gastric antrum of patients infected with H. pylori compared with uninfected patients [9.54 (5.07–16.28) vs. 4.55 (3.69–8.28) pg IL-1β/mg protein, p = 0.004, and 1.5 (0.7–2.71) vs. 0.63 (0.3–1.26) pg TNF-α/mg protein, p = 0.001]. Among H. pylori-infected individuals, carriers of the IL1RN*2 allele had significantly higher antrum mucosal IL-1β levels than noncarriers [15.97 (9.59–26.6) vs. 10.08 (7.72–13.33), p = 0.008]. No association between gastric mucosal TNF-α levels and genotypes of the TNFA and LTA gene polymorphisms was reported. Our results indicate that the VNTR polymorphism of the IL1RN gene influences IL-1β gastric mucosal production in patients infected with H. pylori. [Copyright &y& Elsevier]

BACKGROUND AND AIMS: Recent studies have reported an association between cytokine gene polymorphisms and GC risk. However, results are inconsistent among studies from different geographic regions and ethnic groups. Our goal was to evaluate the influence of Helicobacter pylori ( H. pylori) infection and host genetic factors on GC susceptibility in a population of Spanish white GC patients. METHODS: DNA from 404 unrelated patients with GC and 404 sex- and age-matched healthy controls was typed for several functional polymorphisms in pro- ( IL-1B, TNFA, LTA, IL-12p40) and anti-inflammatory ( IL-4, IL-1RN, IL-10, TGFB1) genes by PCR, RFLP, and TaqMan assays. H. pylori infection and CagA/VacA antibody status were also determined by western blot serology. RESULTS: Logistic regression analysis identified H. pylori infection with cagA strains (OR 2.54, 95% CI 1.77–3.66), smoking habit (OR 1.91, 95% CI 1.25–2.93), and positive family history of GC (OR 3.67, 95% CI 2.01–6.71) as independent risk factors for GC. None of the cytokine gene polymorphisms analyzed in this study were associated with susceptibility to GC development, whether GC patients were analyzed as a group or categorized according to anatomic location or histological subtype. Some simultaneous combinations of proinflammatory genotypes reportedly associated with greater GC risk yielded no significant differences between patients and controls. CONCLUSIONS: Our results show that, at least in some white populations, the contribution of the cytokine gene polymorphisms evaluated in this study ( IL-1B, IL-1RN, IL-12p40, LTA, IL-10, IL-4, and TGF-B1) to GC susceptibility may be less relevant than previously reported. [ABSTRACT FROM AUTHOR]

Abstract: Colorectal cancer (CRC) is one of the most common neoplasms and a leading cause of death related to cancer worldwide. Hereditary nonpolyposis colorectal cancer (HNPCC) is the most frequent autosomal dominant predisposition to the development of CRC, accounting for approximately 2.5% of the total CRC burden in Spain. Genomic rearrangements in the MSH2 and MLH1 genes have been reported to account for an important proportion of the mutation spectrum in HNPCC, and DNA dosage techniques have been developed facilitating molecular screening of such deletions/duplications. We screened for MSH2 and MLH1 genomic rearrangements by multiplex ligation-dependent probe amplification (MLPA) in 142 Spanish patients at risk for HNPCC prior to the exon-by-exon mutation scanning and found a deletion encompassing exons 9–16 of MSH2 and a duplication encompassing exons 11–16 of MSH2, both only in one case. These results showed that MSH2/MLH1 rearrangements in Spanish patients at risk for HNPCC seem to be a less frequent mutational event than in other populations. [Copyright &y& Elsevier]