microRNAs and Esophageal Cancer - Implications for Pathogenesis and Therapy

Author version made available in accordance with the publisher's policy.There are several microRNAs that have been consistently reported to be differentially expressed in esophageal squamous cell carcinoma vs. normal squamous tissue, with prognostic associations for miR-21 (invasion, positive nodes, decreased survival), miR-143 (disease recurrence, invasion depth), and miR-375 (inversely correlated with advanced stage, distant metastasis, poor overall survival, and disease-free survival). There is also evidence that miR-375 regulates gene expression associated with resistance to chemotherapy. Hence, microRNA expression assays have the potential to provide clinically relevant information about prognosis and potential response to chemotherapy in patients with esophageal squamous cell carcinoma. Results are inconsistent, however, for microRNAs across different studies for esophageal adenocarcinoma (EAC) vs. its precursor lesion Barrett’s esophagus. These inconsistencies may partly result from pathological and/or molecular heterogeneity in both Barrett’s esophagus and EAC, but may also result from differences in study designs or different choices of comparator tissues. Despite these inconsistencies, however, several mRNA/protein targets have been identified, the cancer related biology of some of these targets is well understood, and there are clinico-pathological associations for some of these mRNA targets. MicroRNAs also have potential for use in therapy for esophageal cancers. The development of new delivery methods, such as minicells and autologous microvesicles, and molecular modifications such as the addition of aromatic benzene pyridine analogs, have facilitated the exploration of the effects of therapeutic microRNAs in vivo. These approaches are producing encouraging results, with one technology in a phase I/IIa clinical trial

COX-2 mRNA is increased in oesophageal mucosal cells by a proton pump inhibitor

Author version made available in accordance with the publisher's policy.Introduction: Barrett’s oesophagus develops in some individuals with gastro-oesophageal reflux, and is the precursor to oesophageal adenocarcinoma. Proton pump inhibitors (PPIs) suppress gastric acid production and are used to treat reflux. Clinical trials suggest that COX inhibitors might prevent oesophageal cancer, although PPIs could offset this by increasing COX-2 expression in Barrett’s oesophagus. To investigate this, we evaluated the impact of a PPI on COX expression in oesophageal mucosal cells. Methods: The effect of the PPI esomeprazole on COX-1 and COX-2 mRNA levels in oesophageal cells was determined. Oesophageal cell lines OE33 (adenocarcinoma derived) and HET-1A (immortalized squamous cells), and a control intestinal cell line - HT29 (colon carcinoma), were treated for 24 hours with increasing concentrations of the esomeprazole. Results: COX-2, but not COX-1, mRNA levels, dose dependently increased in OE33 and HET-1A cells vs. esomeprazole concentration. COX-2 mRNA levels did not increase in HT29 cells. Conclusions: Exposure to esomeprazole increases COX-2 mRNA in oesophageal cells. This might contribute to the lack of benefit for COX inhibitors for oesophageal cancer prevention in recent clinica

Molecular biomarkers and ablative therapies for Barrett’s esophagus

Author version made available in accordance with the publisher's policy.Barrett’s esophagus is the major risk factor for esophageal adenocarcinoma. Endoscopic interventions which ablate Barrett’s esophagus mucosa lead to replacement with a new squamous (neosquamous) mucosa, but it can be difficult to achieve complete ablation. Knowing whether cancer is less likely to develop in neosquamous mucosa or residual Barrett’s esophagus after ablation is critical for determining the efficacy of treatment. This issue can be informed by assessing biomarkers that are associated with an increased risk of progression to adenocarcinoma. Although there are few post-ablation biomarker studies, evidence suggests that that neosquamous mucosa may have a reduced risk of adenocarcinoma in patients who have been treated for dysplasia or cancer, but some patients who do not have complete eradication of non-dysplastic Barrett’s esophagus may still be at risk. Biomarkers could be used to optimize endoscopic surveillance strategies following ablation, but this needs to be assessed by clinical studies and economic modeling

Accuracy of identification of tissue types in endoscopic esophageal mucosal biopsies used for molecular biology studies

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Metallothionien 3 expression is frequently down-regulated in oesophageal squamous cell carcinoma by DNA methylation

BACKGROUND: Metallothionein 3 (MT3) inhibits growth in a variety of cell types. We measured MT3 gene expression by RT-PCR, and DNA methylation in the MT3 promoter by combined bisulphite restriction analysis, in four oesophageal cancer cell lines and the resected oesophagus from 64 patients with oesophageal squamous cell carcinoma (SCC). RESULTS: MT3 expression was not detected in one of the four oesophageal cell lines. The MT3 promoter was methylated in all of the oesophageal cell lines, but the degree of methylation was greater in the non-expressing cell line. After treatment with 5-aza-2'-deoxycytidine there was a reduction in the degree of methylation, and an increase in MT3 expression, in each of the cell lines (p < 0.01). Methylation was detected in 52% (33 of 64) of primary SCC and 3% (2 of 62) of histologically normal resection margins. MT3 expression was measured in 29 tumours, 17 of which had methylation of MT3. The expression of MT3 was significantly less in the methylated tumours compared to either the unmethylated tumours (p = 0.03), or the matched margin (p = 0.0005). There was not a significant difference in MT3 expression between the tumour and the margin from patients with unmethylated tumour. No correlations were observed between methylation of MT3 and survival time, patient age, gender, smoking or drinking history, tumour stage, volume, or lymph node involvement. CONCLUSION: We conclude that MT3 expression is frequently down-regulated in oesophageal SCC, by DNA methylation, but that this is not a prognostic indicator

Sentinel seroprevalence of SARS-CoV-2 in Gauteng Province, South Africa, August - October 2020

Background. Estimates of prevalence of anti-SARS-CoV-2 antibody positivity (seroprevalence) for tracking the COVID-19 epidemic are lacking for most African countries.Objectives. To determine the prevalence of antibodies against SARS-CoV-2 in a sentinel cohort of patient samples received for routine testing at tertiary laboratories in Johannesburg, South Africa.Methods. This sentinel study was conducted using remnant serum samples received at three National Health Laboratory Service laboratories in the City of Johannesburg (CoJ) district. Collection was from 1 August to 31 October 2020. We extracted accompanying laboratory results for glycated haemoglobin (HbA1c), creatinine, HIV, viral load and CD4 T-cell count. An anti-SARS-CoV-2 targeting the nucleocapsid (N) protein of the coronavirus with higher affinity for IgM and IgG antibodies was used. We reported crude as well as population-weighted and test-adjusted seroprevalence. Multivariate logistic regression analysis was used to determine whether age, sex, HIV and diabetic status were associated with increased risk for seropositivity.Results. A total of 6 477 samples were analysed, the majority (n=5 290) from the CoJ region. After excluding samples with no age or sex stated, the model population-weighted and test-adjusted seroprevalence for the CoJ (n=4 393) was 27.0% (95% confidence interval (CI) 25.4 - 28.6). Seroprevalence was highest in those aged 45 - 49 years (29.8%; 95% CI 25.5 - 35.0) and in those from the most densely populated areas of the CoJ. Risk for seropositivity was highest in those aged 18 - 49 years (adjusted odds ratio (aOR) 1.52; 95% CI 1.13 - 2.13; p=0.0005) and in samples from diabetics (aOR 1.36; 95% CI 1.13 - 1.63; p=0.001).Conclusions. Our study conducted between the first and second waves of the pandemic shows high levels of current infection among patients attending public health facilities in Gauteng Province

Circulating Serum Exosomal miRNAs As Potential Biomarkers for Esophageal Adenocarcinoma

Author version made available in accordance with publisher policy.Abstract Background The poor prognosis and rising incidence of esophageal adenocarcinoma highlight the need for improved detection methods. The potential for circulating microRNAs (miRNAs) as biomarkers in other cancers has been shown, but circulating miRNAs have not been well characterized in esophageal adenocarcinoma. We investigated whether circulating exosomal miRNAs have potential to discriminate individuals with esophageal adenocarcinoma from healthy controls and non-dysplastic Barrett’s esophagus. Methods Seven hundred fifty-eight miRNAs were profiled in serum circulating exosomes from a cohort of 19 healthy controls, 10 individuals with Barrett’s esophagus, and 18 individuals with locally advanced esophageal adenocarcinoma. MiRNA expression was assessed using all possible permutations of miRNA ratios per individual. Four hundred eight miRNA ratios were differentially expressed in individuals with cancer compared to controls and Barrett’s esophagus (Mann-Whitney U test, P<0.05). The 179/408 ratios discriminated esophageal adenocarcinoma from healthy controls and Barrett’s esophagus (linear regression, P0.7, P<0.05). A multi-biomarker panel (RNU6-1/miR- 16-5p, miR-25-3p/miR-320a, let-7e-5p/miR-15b-5p, miR- 30a-5p/miR-324-5p, miR-17-5p/miR-194-5p) demonstrated enhanced specificity and sensitivity (area under ROC=0.99, 95 % CI 0.96–1.0) over single miRNA ratios to distinguish esophageal adenocarcinoma from controls and Barrett’s esophagus. Conclusions This study highlights the potential for serum exosomal miRNAs as biomarkers for the detection of esophageal adenocarcinoma

Single hadron response measurement and calorimeter jet energy scale uncertainty with the ATLAS detector at the LHC

The uncertainty on the calorimeter energy response to jets of particles is derived for the ATLAS experiment at the Large Hadron Collider (LHC). First, the calorimeter response to single isolated charged hadrons is measured and compared to the Monte Carlo simulation using proton-proton collisions at centre-of-mass energies of sqrt(s) = 900 GeV and 7 TeV collected during 2009 and 2010. Then, using the decay of K_s and Lambda particles, the calorimeter response to specific types of particles (positively and negatively charged pions, protons, and anti-protons) is measured and compared to the Monte Carlo predictions. Finally, the jet energy scale uncertainty is determined by propagating the response uncertainty for single charged and neutral particles to jets. The response uncertainty is 2-5% for central isolated hadrons and 1-3% for the final calorimeter jet energy scale.Comment: 24 pages plus author list (36 pages total), 23 figures, 1 table, submitted to European Physical Journal

Measurements of Higgs boson production and couplings in diboson final states with the ATLAS detector at the LHC

Measurements are presented of production properties and couplings of the recently discovered Higgs boson using the decays into boson pairs, H →γ γ, H → Z Z∗ →4l and H →W W∗ →lνlν. The results are based on the complete pp collision data sample recorded by the ATLAS experiment at the CERN Large Hadron Collider at centre-of-mass energies of √s = 7 TeV and √s = 8 TeV, corresponding to an integrated luminosity of about 25 fb−1. Evidence for Higgs boson production through vector-boson fusion is reported. Results of combined fits probing Higgs boson couplings to fermions and bosons, as well as anomalous contributions to loop-induced production and decay modes, are presented. All measurements are consistent with expectations for the Standard Model Higgs boson