A new prognostic algorithm based on stage of cirrhosis and HVPG to improve risk-stratification after variceal bleeding

Background & Aims: HVPG decrease ≥20% or ≤12mmHg (“responders”) indicates good prognosis during propranolol/nadolol treatment but requires two HVPG measurements. We aimed at simplifying risk‐stratification after variceal bleeding using clinical data and HVPG. Methods: 193 cirrhotic patients (62% with ascites and/or hepatic encephalopathy, HE) included within 7‐days of bleeding had HVPG measured before and at 1‐3 months of treatment with propranolol/nadolol plus endoscopic band ligation. End‐points: Rebleeding and rebleeding/transplantation‐free survival for 4‐years. Another cohort (n=231) served as validation set. Results: During follow‐up 45 patients had variceal bleeding and 61 died. HVPG‐responders (n=71) had lower rebleeding‐risk (10% vs 34%, p=0.001) and better survival than 122 non‐responders (61% vs 39%, p=0.001). Patients with/HE (n=120) had lower survival than patients without (40% vs 63%, p=0.005). Among patients with ascites/HE, those with baseline HVPG≤16mmHg (n=16) had low rebleeding‐risk (13%). By contrast, among patients with ascites/HE and baseline HVPG>16mmHg, only HVPG‐responders (n=32) had good prognosis, with lower rebleeding‐risk and better survival than non‐responders (n=72) (respective proportions: 7% vs 39%,p=0.018; 56% vs 30% p=0.010). These findings allowed developing a new algorithm for risk‐stratification in which HVPG‐response was only measured in patients with ascites and/or HE and baseline HVPG>16mmHg. This algorithm reduced the grey‐zone (high‐risk patients not dying on follow‐up) from 46% to 35% and decreased by 42% the HVPG measurements required. The validation cohort confirmed these results. Conclusion: Restricting HVPG measurements to patients with ascites/HE and measuring HVPG‐response only if baseline HVPG>16mmHg improves detection of high‐risk patients while markedly reducing the number of HVPG measurements required

Activation of PKR Causes Amyloid ß-Peptide Accumulation via De-Repression of BACE1 Expression

BACE1 is a key enzyme involved in the production of amyloid ß-peptide (Aß) in Alzheimer's disease (AD) brains. Normally, its expression is constitutively inhibited due to the presence of the 5′untranslated region (5′UTR) in the BACE1 promoter. BACE1 expression is activated by phosphorylation of the eukaryotic initiation factor (eIF)2-alpha, which reverses the inhibitory effect exerted by BACE1 5′UTR. There are four kinases associated with different types of stress that could phosphorylate eIF2-alpha. Here we focus on the double-stranded (ds) RNA-activated protein kinase (PKR). PKR is activated during viral infection, including that of herpes simplex virus type 1 (HSV1), a virus suggested to be implicated in the development of AD, acting when present in brains of carriers of the type 4 allele of the apolipoprotein E gene. HSV1 is a dsDNA virus but it has genes on both strands of the genome, and from these genes complementary RNA molecules are transcribed. These could activate BACE1 expression by the PKR pathway. Here we demonstrate in HSV1-infected neuroblastoma cells, and in peripheral nervous tissue from HSV1-infected mice, that HSV1 activates PKR. Cloning BACE1 5′UTR upstream of a luciferase (luc) gene confirmed its inhibitory effect, which can be prevented by salubrinal, an inhibitor of the eIF2-alpha phosphatase PP1c. Treatment with the dsRNA analog poly (I∶C) mimicked the stimulatory effect exerted by salubrinal over BACE1 translation in the 5′UTR-luc construct and increased Aß production in HEK-APPsw cells. Summarizing, our data suggest that PKR activated in brain by HSV1 could play an important role in the development of AD

The Catalan Surveillance Network of SARS-CoV-2 in Sewage: design, implementation, and performance

Wastewater-based epidemiology has shown to be an efficient tool to track the circulation of SARS-CoV-2 in communities assisted by wastewater treatment plants (WWTPs). The challenge comes when this approach is employed to help Health authorities in their decision-making. Here, we describe the roadmap for the design and deployment of SARSAIGUA, the Catalan Surveillance Network of SARS-CoV-2 in Sewage. The network monitors, weekly or biweekly, 56 WWTPs evenly distributed across the territory and serving 6 M inhabitants (80% of the Catalan population). Each week, samples from 45 WWTPs are collected, analyzed, results reported to Health authorities, and finally published within less than 72 h in an online dashboard ( https://sarsaigua.icra.cat ). After 20 months of monitoring (July 20-March 22), the standardized viral load (gene copies/day) in all the WWTPs monitored fairly matched the cumulative number of COVID-19 cases along the successive pandemic waves, showing a good fit with the diagnosed cases in the served municipalities (Spearman Rho = 0.69). Here we describe the roadmap of the design and deployment of SARSAIGUA while providing several open-access tools for the management and visualization of the surveillance data.The authors wish to thank the staff from all the WWTPs monitored for their help and technical support during the sampling campaigns. The authors acknowledge the funding received from the ACA and the ASPCAT from the Catalan Government (Generalitat de Catalunya). ICRA authors acknowledge the funding provided by the Generalitat de Catalunya through the Consolidated Research Group grants ICRA-ENV 2017 SGR 1124 and ICRA-TiA 2017 SGR 1318. ICRA researchers also thank the funding from the CERCA program of the Catalan Government.Peer reviewe

HPV-relatedness definitions for classifying HPV-related oropharyngeal cancer patient do impact on TNM classification and patients' survival

Given the different nature and better outcomes of oropharyngeal carcinoma (OPC) associated with human papillomavirus (HPV) infection, a novel clinical stage classification for HPV-related OPC has been accepted for the 8 edition AJCC TNM (ICON-S model). However, it is still unclear the HPV-relatedness definition with best diagnostic accuracy and prognostic value. The aim of this study was to compare different staging system models proposed for HPV-related OPC patients: 7 edition AJCC TNM, RPA stage with non-anatomic factors (Princess Margaret), RPA with N categories for nasopharyngeal cancer (MD-Anderson) and AHR-new (ICON-S), according to different HPV-relatedness definitions: HPV-DNA detection plus an additional positive marker (p16 or HPV-mRNA), p16 positivity alone or the combination of HPV-DNA/p16 positivity as diagnostic tests. A total of 788 consecutive OPC cases diagnosed from 1991 to 2013 were considered eligible for the analysis. Of these samples, 66 (8.4%) were positive for HPV-DNA and (p16 or HPV-mRNA), 83 (10.5%) were p16 positive and 58 (7.4%) were double positive for HPV-DNA/p16. ICON-S model was the staging system, which performed better in our series when using at least two biomarkers to define HPV-causality. When the same analysis was performed considering only p16-positivity, RPA stage with non-anatomic factors (Princess Margaret) has the best classification based on AIC criteria. HPV-relatedness definition for classifying HPV-related OPC patient do impact on TNM classification and patients' survival. Further studies assessing HPV-relatedness definitions are warranted to better classify HPV-related OPC patients in the era of de-escalation clinical trials

The use of HPV16-E5, EGFR, and PEGFR as prognostic biomarkers for oropharyngeal cancer patients

Anti-epidermal-growth-factor-receptor (EGFR) therapies in combination with radiotherapy are being studied on deescalation clinical trials for HPV-related oropharyngeal cancer (OPC) patients. The HPV16-E5 oncoprotein increases recycling of activated EGFR to the cell surface, enhancing factor signal transduction. Our aim was to evaluate viral HPV16-E5 oncogene expression as well as EGFR and phosphorylated-EGFR (pEGFR), protein levels as biomarkers for clinical outcome in a retrospective cohort of OPC patients. Formalin-fixed-paraffin-embedded OPCs were collected from 1990 to 2013. OPC samples containing HPV-DNA were subject to viral E6*I mRNA detection and p16INK4a immunohistochemistry (IHC). HPV16-positive cases were evaluated for HPV16-E5 (RT-PCR) and EGFR/pEGFR (IHC). A stratified and matched random sample of HPV-negative samples was used as control and evaluated for EGFR/pEGFR. Overall survival (OS) and disease free survival (DFS) estimates were assessed for locally advanced OPC patients (stage III, IVa,b 7th edition). Among 788 OPC patient samples, 53 were double positive for HPV16-DNA/p16. HPV16-E5 expression was found in 41 of 53 samples (77.4%). EGFR expression was observed in 37.7 vs 70.8% of HPV16-positive vs HPV-negative samples, respectively; (adjusted OR = 0.15) 5% CI = 0.04-0.56]). Expression of pEGFR followed an inverse pattern with 39.6 and 24.9% detection in HPV16-positive and HPV-negative samples; (adjusted OR = 1.58 [95% CI = 0.48-5.17]). Within HPV16-positive cases, no association between HPV16-E5/EGFR nor pEGFR was observed. With a median follow-up of 39.36 months (min = 0.03 - max = 272.07), the combination of HPV status and EGFR or pEGFR expression were predictors of better OS (p < 0.001, for both) and DFS (p < 0.001 for EGFR and p = 0.003 for pEGFR). HPV16-E5 is highly expressed on HPV16-positive OPCs. Interestingly, HPV16-positive cases expressed significantly more pEGFR while HPV-negative cases expressed more EGFR. The combinations of HPV status and EGFR or pEGFR may be useful biomarkers for evaluating prognosis outcome in OPC patients

Hpv-relatedness Definitions For Classifying Hpv-related Oropharyngeal Cancer Patient Do Impact On Tnm Classification And Patients' Survival

Background Given the different nature and better outcomes of oropharyngeal carcinoma (OPC) associated with human papillomavirus (HPV) infection, a novel clinical stage classification for HPV-related OPC has been accepted for the 8 th edition AJCC TNM (ICON-S model). However, it is still unclear the HPV-relatedness definition with best diagnostic accuracy and prognostic value. Material and methods The aim of this study was to compare different staging system models proposed for HPV-related OPC patients: 7 th edition AJCC TNM, RPA stage with non-anatomic factors (Princess Margaret), RPA with N categories for nasopharyngeal cancer (MD-Anderson) and AHR-new (ICON-S), according to different HPV-relatedness definitions: HPV-DNA detection plus an additional positive marker (p16(INK4a) or HPV-mRNA), p16(INK4a) positivity alone or the combination of HPV-DNA/p16(INK4a) positivity as diagnostic tests. Results A total of 788 consecutive OPC cases diagnosed from 1991 to 2013 were considered eligible for the analysis. Of these samples, 66 (8.4%) were positive for HPV-DNA and (p16(INK4a) or HPV-mRNA), 83 (10.5%) were p16(INK4a) positive and 58 (7.4%) were double positive for HPV-DNA/p16(INK4a). ICON-S model was the staging system, which performed better in our series when using at least two biomarkers to define HPV-causality. When the same analysis was performed considering only p16(INK4a)-positivity, RPA stage with non-anatomic factors (Princess Margaret) has the best classification based on AIC criteria. Conclusion HPV-relatedness definition for classifying HPV-related OPC patient do impact on TNM classification and patients' survival. Further studies assessing HPV-relatedness definitions are warranted to better classify HPV-related OPC patients in the era of de-escalation clinical trials

Kaplan-Maier estimates of Overall Survival among the 66 HPV-related OPSCC patients, according to each staging system.

<p>Data on 5-years Overall Survival and Trend test are shown according to each staging system for HPV-related OPSCC patient. Panel A showed Kaplan-Meier curve for the 7^th edition AJCC TNM classification with a non-statistically significant Trend test P-value. Panel B showed Kaplan-Meier curve for RPA stage with non-anatomic factors (Princess Margaret). Panel C showed Kaplan-Meier curve for RPA with N categories for nasopharyngeal cancer (MD-Anderson). Panel D showed Kaplan-Meier curve for AHR-new (ICON-S). For Panel B, C and D Trend tests were statistically significant, indicating that the trend of the survival function across the three or more stages classifies them in a linear tendency. Panel D, AHR-new (ICON-S), has the best classification based on AIC criteria.</p

Main differences among 7^th and 8^th TNM editions including HPV-related oropharyngeal cancer patients.

<p>Modified from Taberna et al. Annals of Oncology 2017 [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0194107#pone.0194107.ref001" target="_blank">1</a>].</p