Development of a flow process for an easy and fast access to 2-pyrone derivatives

2-Pyrones are compounds widely present in nature and they represent interesting building blocks both in medicinal and synthetic chemistry. Due to their peculiar pharmacological activity and structure, they have attracted much attention during the last decades and several protocols for their synthesis have been developed. In this work we propose the synthesis of bio-sourced 2-pyrones, exploiting continuous-flow conditions for an easy, sustainable and fast access to these important molecules

Influence of MLH1 on colon cancer sensitivity to poly(ADP-ribose) polymerase inhibitor combined with irinotecan

Poly(ADP-ribose) polymerase inhibitors (PARPi) are currently evaluated in clinical trials in combination with topoisomerase I (Top1) inhibitors against a variety of cancers, including colon carcinoma. Since the mismatch repair component MLH1 is defective in 10-15% of colorectal cancers we have investigated whether MLH1 affects response to the Top1 inhibitor irinotecan, alone or in combination with PARPi. To this end, the colon cancer cell lines HCT116, carrying MLH1 mutations on chromosome 3 and HCT116 in which the wildtype MLH1 gene was replaced via chromosomal transfer (HCT116+3) or by transfection of the corresponding MLH1 cDNA (HCT116 1-2) were used. HCT116 cells or HCT116+3 cells stably silenced for PARP-1 expression were also analysed. The results of in vitro and in vivo experiments indicated that MLH1, together with low levels of Top1, contributed to colon cancer resistance to irinotecan. In the MLH1-proficient cells SN-38, the active metabolite of irinotecan, induced lower levels of DNA damage than in MLH1-deficient cells, as shown by the weaker induction of γ-H2AX and p53 phosphorylation. The presence of MLH1 contributed to induce of prompt Chk1 phosphorylation, restoring G2/M cell cycle checkpoint and repair of DNA damage. On the contrary, in the absence of MLH1, HCT116 cells showed minor Chk1 phosphorylation and underwent apoptosis. Remarkably, inhibition of PARP function by PARPi or by PARP-1 gene silencing always increased the antitumor activity of irinotecan, even in the presence of low PARP-1 expression

Ellagic acid inhibits bladder cancer invasiveness and in vivo tumor growth

Ellagic acid (EA) is a polyphenolic compound that can be found as a naturally occurring hydrolysis product of ellagitannins in pomegranates, berries, grapes, green tea and nuts. Previous studies have reported the antitumor properties of EA mainly using in vitro models. No data are available about EA influence on bladder cancer cell invasion of the extracellular matrix triggered by vascular endothelial growth factor-A (VEGF-A), an angiogenic factor associated with disease progression and recurrence, and tumor growth in vivo. In this study, we have investigated EA activity against four different human bladder cancer cell lines (i.e., T24, UM-UC-3, 5637 and HT-1376) by in vitro proliferation tests (measuring metabolic and foci forming activity), invasion and chemotactic assays in response to VEGF-A and in vivo preclinical models in nude mice. Results indicate that EA exerts anti-proliferative effects as a single agent and enhances the antitumor activity of mitomycin C, which is commonly used for the treatment of bladder cancer. EA also inhibits tumor invasion and chemotaxis, specifically induced by VEGF-A, and reduces VEGFR-2 expression. Moreover, EA down-regulates the expression of programmed cell death ligand 1 (PD-L1), an immune checkpoint involved in immune escape. EA in vitro activity was confirmed by the results of in vivo studies showing a significant reduction of the growth rate, infiltrative behavior and tumor-associated angiogenesis of human bladder cancer xenografts. In conclusion, these results suggest that EA may have a potential role as an adjunct therapy for bladder cancer

A gemini cationic lipid with histidine residues as a novel lipid-based gene nanocarrier: a biophysical and biochemical study

This work reports the synthesis of a novel gemini cationic lipid that incorporates two histidine-type head groups (C3(C16His)2). Mixed with a helper lipid 1,2-dioleoyl-sn-glycero3-phosphatidyl ethanol amine (DOPE), it was used to transfect three different types of plasmid DNA: one encoding the green fluorescence protein (pEGFP-C3), one encoding a luciferase (pCMV-Luc), and a therapeutic anti-tumoral agent encoding interleukin-12 (pCMV-IL12). Complementary biophysical experiments (zeta potential, gel electrophoresis, small-angle X-ray scattering (SAXS), and fluorescence anisotropy) and biological studies (FACS, luminometry, and cytotoxicity) of these C3(C16His)2/DOPE-pDNA lipoplexes provided vast insight into their outcomes as gene carriers. They were found to efficiently compact and protect pDNA against DNase I degradation by forming nanoaggregates of 120–290 nm in size, which were further characterized as very fluidic lamellar structures based in a sandwich-type phase, with alternating layers of mixed lipids and an aqueous monolayer where the pDNA and counterions are located. The optimum formulations of these nanoaggregates were able to transfect the pDNAs into COS-7 and HeLa cells with high cell viability, comparable or superior to that of the standard Lipo2000*. The vast amount of information collected from the in vitro studies points to this histidine-based lipid nanocarrier as a potentially interesting candidate for future in vivo studies investigating specific gene therapies

Mortality risk in patients on hemodiafiltration versus hemodialysis : a 'real-world' comparison from the DOPPS

Background. With its convective component, hemodiafiltration (HDF) provides better middle molecule clearance compared with hemodialysis (HD) and is postulated to improve survival. A previous analysis of Dialysis Outcomes and Practice Patterns Study (DOPPS) data in 1998-2001 found lower mortality rates for high replacement fluid volume HDF versus HD. Randomized controlled trials have not shown uniform survival advantage for HDF; in secondary (non-randomized) analyses, better outcomes were observed in patients receiving the highest convection volumes. Methods. In a 'real-world' setting, we analyzed patients on dialysis >90 days from seven European countries in DOPPS Phases 4 and 5 (2009-15). Adjusted Cox regression was used to study HDF (versus HD) and mortality, overall and by replacement fluid volume. Results. Among 8567 eligible patients, 2012 (23%) were on HDF, ranging from 42% in Sweden to 12% in Germany. Median follow-up was 1.5 years during which 1988 patients died. The adjusted mortality hazard ratio (95% confidence interval) was 1.14 (1.00-1.29) for any HDF versus HD and 1.08 (0.92-1.28) for HDF > 20 L replacement fluid volume versus HD. Similar results were found for cardiovascular and infection-related mortality. In an additional analysis aiming to avoid treatment-by-indication bias, we did not observe lower mortality rates in facilities usingmore HDF (versus HD). Conclusions. Our results do not support the notion that HDF provides superior patient survival. Further trials designed to test the effect of high-volume HDF (versus lower volume HDF versus HD) on clinical outcomes are needed to adequately inform clinical practices

Ambient-aware continuous care through semantic context dissemination

Background: The ultimate ambient-intelligent care room contains numerous sensors and devices to monitor the patient, sense and adjust the environment and support the staff. This sensor-based approach results in a large amount of data, which can be processed by current and future applications, e. g., task management and alerting systems. Today, nurses are responsible for coordinating all these applications and supplied information, which reduces the added value and slows down the adoption rate. The aim of the presented research is the design of a pervasive and scalable framework that is able to optimize continuous care processes by intelligently reasoning on the large amount of heterogeneous care data. Methods: The developed Ontology-based Care Platform (OCarePlatform) consists of modular components that perform a specific reasoning task. Consequently, they can easily be replicated and distributed. Complex reasoning is achieved by combining the results of different components. To ensure that the components only receive information, which is of interest to them at that time, they are able to dynamically generate and register filter rules with a Semantic Communication Bus (SCB). This SCB semantically filters all the heterogeneous care data according to the registered rules by using a continuous care ontology. The SCB can be distributed and a cache can be employed to ensure scalability. Results: A prototype implementation is presented consisting of a new-generation nurse call system supported by a localization and a home automation component. The amount of data that is filtered and the performance of the SCB are evaluated by testing the prototype in a living lab. The delay introduced by processing the filter rules is negligible when 10 or fewer rules are registered. Conclusions: The OCarePlatform allows disseminating relevant care data for the different applications and additionally supports composing complex applications from a set of smaller independent components. This way, the platform significantly reduces the amount of information that needs to be processed by the nurses. The delay resulting from processing the filter rules is linear in the amount of rules. Distributed deployment of the SCB and using a cache allows further improvement of these performance results

Serum iPTH, calcium and phosphate, and the risk of mortality in a European haemodialysis population

Background. A number of US observational studies reported an increased mortality risk with higher intact parathyroid hormone (iPTH), calcium and/or phosphate. The existence of such a link in a European haemodialysis population was explored as part of the Analysing Data, Recognising Excellence and Optimising Outcomes (ARO) Chronic Kidney Disease (CKD) Research Initiative

Developing a Set of Core Outcomes for Trials in Haemodialysis: An International Delphi Survey

AIM: To generate a consensus-based, prioritized list of core outcomes for trials in haemodialysis. BACKGROUND: Survival and quality of life for patients on haemodialysis remain poor despite substantial research efforts. Existing trials often report surrogate outcomes that may not be relevant to patients and clinicians. A core outcome set that reflects stakeholder priorities would improve the relevance, efficiency, and comparability of haemodialysis trials. METHODS: In an online Delphi survey, participants rated the importance of outcomes using a 9-point Likert scale. In Round 2 and 3, participants reviewed the scores and comments of other respondents and re-rated the outcomes. For each outcome, we calculated the median, mean, and proportion rating 7-9 (“critically important”). RESULTS: 1,181 participants (202 [17%] patients/caregivers, 979 health professionals) from 73 countries completed Round 1 and 838 (150 [18%] patients/caregivers) completed Round 3 (71% response rate). Outcomes achieving consensus as high priorities across both groups were: vascular access complications, cardiovascular disease, mortality, dialysis adequacy and fatigue. Patients/caregivers rated four outcomes higher than health professionals: ability to travel (mean difference 0.9), dialysis-free time (0.5), dialysis adequacy (0.3), and washed out after dialysis (0.2). Health professionals rated 11 outcomes higher: mortality (1.0), hospitalization (1.0), drop in blood pressure (1.0), vascular access complications (0.9), depression (0.9), cardiovascular disease (0.8), target weight (0.7), infection (0.4), potassium (0.4), ability to work (0.3), and pain (0.3). CONCLUSIONS: The top stakeholder prioritized outcomes were vascular access problems, cardiovascular disease, mortality, dialysis adequacy and fatigue. Patients/caregivers gave higher priority to lifestyle-related outcomes than health professionals. This prioritized set of outcomes can inform the establishment of a core outcome set, to improve the value of trial evidence to support decision-making for people on haemodialysis

A multi-site study on walkability, data sharing and privacy perception using mobile sensing data gathered from the mk-sense platform

Walking is a fundamental part of a physically active lifestyle, it is one of everyday activities that positively impacts health and wellbeing. In this paper we describe the challenges and experiences of conducting a sensing campaign in the wild. We make use of mk-sense; a software platform to facilitate the deployment of collaborative sensing campaigns. We elaborate on two cross-cultural studies conducted in four different countries (Mexico, Turkey, Spain, and Switzerland) with a total of 77 participants. We present a detailed description of the data collected from one of the studies aimed at measuring walkability around three different university campuses. The analysis of the data shows that walkability can be assessed using information from the sensors in the smartphones and results from surveys answered by participants. In addition, we analyze issues about data sharing and privacy awareness