Targeting the Platelet-Activating Factor Receptor (PAF-R): Antithrombotic and Anti-Atherosclerotic Nutrients

Platelet-activating factor (PAF) is a lipid mediator that interacts with its receptor (PAF-R) to carry out cell signalling. However, under certain conditions the binding of PAF to PAF-R leads to the activation of pro-inflammatory and prothrombotic pathways that have been implicated in the onset and development of atherosclerotic cardiovascular diseases (CVD) and inflammatory diseases. Over the past four decades, research has focused on the identification and development of PAF-R antagonists that target these inflammatory diseases. Research has also shown that dietary factors such as polar lipids, polyphenols, and other nutrient constituents may affect PAF metabolism and PAF-R function through various mechanisms. In this review we focus on the inhibition of PAF-R and how this may contribute to reducing cardiovascular disease risk. We conclude that further development of PAF-R inhibitors and human studies are required to investigate how modulation of the PAF-R may prevent the development of atherosclerotic cardiovascular disease and may lead to the development of novel therapeutics.     

PROTEIN AI Advisor: A Knowledge-Based Recommendation Framework Using Expert-Validated Meals for Healthy Diets

AI-based software applications for personalized nutrition have recently gained increasing attention to help users follow a healthy lifestyle. In this paper, we present a knowledge-based recommendation framework that exploits an explicit dataset of expert-validated meals to offer highly accurate diet plans spanning across ten user groups of both healthy subjects and participants with health conditions. The proposed advisor is built on a novel architecture that includes (a) a qualitative layer for verifying ingredient appropriateness, and (b) a quantitative layer for synthesizing meal plans. The first layer is implemented as an expert system for fuzzy inference relying on an ontology of rules acquired by experts in Nutrition, while the second layer as an optimization method for generating daily meal plans based on target nutrient values and ranges. The system’s effectiveness is evaluated through extensive experiments for establishing meal and meal plan appropriateness, meal variety, as well as system capacity for recommending meal plans. Evaluations involved synthetic data, including the generation of 3000 virtual user profiles and their weekly meal plans. Results reveal a high precision and recall for recommending appropriate ingredients in most user categories, while the meal plan generator achieved a total recommendation accuracy of 92% for all nutrient recommendations.     

Immunotherapy for advanced hepatocellular carcinoma: From clinical trials to real-world data and future advances

Hepatocellular carcinoma (HCC) is a leading cause of cancer-associated mortality worldwide. HCC is an inflammation-associated immunogenic cancer that frequently arises in chronically inflamed livers. Advanced HCC is managed with systemic therapies; the tyrosine kinase inhibitor (TKI) sorafenib has been used in 1^st-line setting since 2007. Immunotherapies have emerged as promising treatments across solid tumors including HCC for which immune checkpoint inhibitors (ICIs) are licensed in 1^st- and 2^nd-line treatment setting. The treatment field of advanced HCC is continuously evolving. Several clinical trials are investigating novel ICI candidates as well as new ICI regimens in combination with other therapeutic modalities including systemic agents, such as other ICIs, TKIs, and anti-angiogenics. Novel immunotherapies including adoptive cell transfer, vaccine-based approaches, and virotherapy are also being brought to the fore. Yet, despite advances, several challenges persist. Lack of real-world data on the use of immunotherapy for advanced HCC in patients outside of clinical trials constitutes a main limitation hindering the breadth of application and generalizability of data to this larger and more diverse patient cohort. Consequently, issues encountered in real-world practice include patient ineligibly for immunotherapy because of contraindications, comorbidities, or poor performance status; lack of response, efficacy, and safety data; and cost-effectiveness. Further real-world data from high-quality large prospective cohort studies of immunotherapy in patients with advanced HCC is mandated to aid evidence-based clinical decision-making. This review provides a critical and comprehensive overview of clinical trials and real-world data of immunotherapy for HCC, with a focus on ICIs, as well as novel immunotherapy strategies underway.     

Acute myeloid leukemia: negative prognostic impact of early blast persistence can be in part overcome by a later remission prior to post-induction therapy

In acute myeloid leukemia, there is an ongoing debate on the prognostic value of the early bone marrow assessment in patients receiving intensive therapy. In this retrospective study, we analyzed the prognostic impact of the early response in 1,008 patients with newly diagnosed acute myeloid leukemia, who were treated at our institution with intensive chemotherapy followed by consolidation chemotherapy and/or allogeneic hematopoietic stem cell transplantation (HSCT). We found that early blast persistence has an independent negative prognostic impact on overall survival, event-free survival and relapse-free survival. This negative prognostic impact may only be overcome in patients showing at least a partial remission at the early bone marrow assessment and who subsequently achieve blast clearance by additional induction chemotherapy prior to consolidation therapy with allogeneic HSCT. In accordance, we propose that the time slope of remission is an additional leukemia-related dynamic parameter that reflects chemosensitivity and thus may inform post-induction therapy decision-making. In addition to patient-related factors, European LeukemiaNet risk group, measurable residual disease monitoring and donor availability, this may particularly apply to European LeukemiaNet intermediate-risk patients, for whom a decision between consolidation chemotherapy and allogeneic HSCT remains challenging in many cases.     

Translating genomic insights into cardiovascular medicine: Opportunities and challenges of CRISPR-Cas9

The growing appreciation of human genetics and genomics in cardiovascular disease (CVD) accompanied by the technological breakthroughs in genome editing, particularly the CRISPR-Cas9 technologies, has presented an unprecedented opportunity to explore the application of genome editing in cardiovascular medicine. The ever-growing genome editing toolbox includes an assortment of CRISPR-Cas systems with increasing efficiency, precision, flexibility, and targeting capacity. Over the past decade, the advent of large-scale genotyping technologies and genome-wide association studies (GWAS) has provided numerous genotype-phenotype associations for diseases with complex traits. Notably, a growing number of loss-of-function mutations have been associated with favorable CVD risk-factor profiles that may confer protection. Combining the newly gained insights of human genetics with recent breakthrough technologies, such as the CRISPR-Cas9 technologies, holds great promise in elucidating novel disease mechanisms and transforming genes into medicines. Nonetheless, translating genetic insights into novel therapeuties remains challenging. Applications of “in body” genome editing for CVD treatment and engineering cardioprotection remain mostly theoretical. Here we highlight the recent advances of the CRISPR-based genome editing toolbox and discuss the potential and challenges of CRISPR-based technologies for translating GWAS findings into genomic medicines.     

COVID-19 in the endoscopy unit: How likely is transmission of infection? Results from an international,multicenter study

BACKGROUND Coronavirus disease 2019(COVID-19) significantly affected endoscopy practice,as gastrointestinal endoscopy is considered a risky procedure for transmission of infection to patients and personnel of endoscopy units(PEU).AIM To assess the impact of COVID-19 on endoscopy during the first European lockdown(March-May 2020).METHODS Patients undergoing endoscopy in nine endoscopy units across six European countries during the period of the first European lockdown for COVID-19(MarchMay 2020) were included. Prior to the endoscopy procedure, participants were stratified as low-or high-risk for potential COVID-19 infection according to the European Society of Gastrointestinal Endoscopy(ESGE) and the European Society of Gastroenterology and Endoscopy Nurses and Associates(ESGENA) joint statement, and contacted 7-14 d later to assess COVID-19 infection status. PEU were questioned regarding COVID-19 symptoms and/or infection via questionnaire, while information regarding hospitalizations, intensive care unitadmissions and COVID-19-related deaths were collected. The number of weekly endoscopies at each center during the lockdown period was also recorded.RESULTS A total of 1267 endoscopies were performed in 1222 individuals across nine European endoscopy departments in six countries. Eighty-seven(7%) were excluded because of initial positive testing. Of the 1135 pre-endoscopy low risk or polymerase chain reaction negative for COVID-19, 254(22.4%) were tested post endoscopy and 8 were eventually found positive, resulting in an infection rate of 0.7% [(95%CI: 0.2-0.12]. The majority(6 of the 8 patients, 75%) had undergone esophagogastroduodenoscopy. Of the 163 PEU, 5 [3%;(95%CI: 0.4-5.7)] tested positive during the study period. A decrease of 68.7%(95%CI: 64.8-72.7) in the number of weekly endoscopies was recorded in all centers after March 2020. All centers implemented appropriate personal protective measures(PPM) from the initial phases of the lockdown.CONCLUSION COVID-19 transmission in endoscopy units is highly unlikely in a lockdown setting, provided endoscopies are restricted to emergency cases and PPM are implemented.