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The efficacy of ferroptosis-inducing compounds IKE and RSL3 correlates with the expression of ferroptotic pathway regulators CD71 and SLC7A11 in biliary tract cancer cells

by Dino Bekric, Tobias Kiesslich, Matthias Ocker, Martina Winklmayr, Markus Ritter, Heidemarie Dobias, Marlena Beyreis, Daniel Neureiter, Christian Mayr

Introduction

Biliary tract cancer (BTC) is a lethal disease with a bad overall survivability, partly arising from inadequate therapeutic alternatives, detection at a belated stage, and a resistance to common therapeutic approaches. Ferroptosis is a form of programmed cell death that depends on reactive oxygen species (ROS) and iron, causing excessive peroxidation of polyunsaturated fatty acids (PUFAs). Therefore, the objective of this investigation is, whether ferroptosis can be induced in BTC in vitro and whether this induction is dependent on specific molecular markers.

Methods

The study conducted resazurin assay and IC25/50 calculation to explore the possible cytotoxic outcomes of different classes of ferroptosis-inducing substances (FINs) on a comprehensive in vitro model of 11 BTC cell lines. Combinatory treatments with different cell death inhibitors were performed to evaluate the magnitude of ferroptosis induction. To ascertain whether ferroptotic cell death occurred, liperfluo and iron assay kits were employed to evaluate lipid ROS and intracellular iron abundance. Potential biomarkers of ferroptosis sensitivity were then assessed via western blot analysis, a rtPCR panel and functional assay kits.

Results

The study found that different FINs reduced cell viability in a cell line-dependent manner. In addition, we measured increased lipid ROS and intracellular Fe2+ levels upon exposure to FINs in BTC cells. Combining FINs with inhibitors of ferroptosis, necroptosis or apoptosis suggests the occurrence of ferroptotic events in BTC cell lines CCC-5, HuH-28 and KKU-055. Furthermore, we found that BTC cells display a heterogeneous profile regarding different molecular genes/markers of ferroptosis. Subsequent analysis revealed that sensitivity of BTC cells towards IKE and RSL3 positively correlated with CD71 and SLC7A11 protein expression.

Conclusion

Our results demonstrate that induction of ferroptosis is a promising approach to inhibit BTC cell growth and that the sensitivity of BTC cells towards ferroptosis induction might be dependent on molecular markers such as CD71 and SLC7A11.

'Ive never been so stressed in my life: a qualitative analysis of young adults lived experience amidst pandemic restrictions in Prince Edward Island, Canada

Por: Postill · G. · Halpin · M. · Zanin · C. · Ritter · C.
Objectives

This qualitative study aimed to explore how young adults experienced the COVID-19 pandemic in relation to extensive lockdowns, social isolation and psychosocial distress. Specifically, this research focused on how the pandemic impacted those who did not contract COVID-19 and lived in a low-risk geographical location. The focus was young adults given they have large social circles (high risk for disease transmission) and have an increased propensity to mental health conditions. These insights can inform planning for future pandemics.

Design

This paper draws on 30 in-depth semistructured interviews. Data were analysed inductively following the principles of a constructivist grounded theory approach.

Setting and participants

30 young adults living in Prince Edward Island during the COVID-19 pandemic, a Canadian province with a low number of COVID-19 cases at the time of data collection.

Results

We developed four themes that describe the experience of young adults during the COVID-19 pandemic: (1) life course disruption, (2) fear and anxiety about the COVID-19 virus, (3) isolation and loss of hope and (4) strategies for managing adversity. Our findings highlight the areas of young adults’ lives that were affected by extensive social changes related to the COVID-19 pandemic. We demonstrate that even individuals who had not contracted the virus were considerably impacted.

Conclusion

We provide a detailed description of the comprehensive impact of COVID-19 on low-risk young adults not previously infected with the COVID-19 virus. By reflecting on the biographical disruption experienced by young adults, we highlight the need and opportunity to direct healthcare resources towards identifying and addressing the secondary impacts of pandemics. Consequently, these findings can guide decisions relating to future pandemic restrictions to better account for the experiences of individuals living through them.

Does atrial fibrillation affect prognosis in hospitalised COVID-19 patients? A multicentre historical cohort study in the Netherlands

Por: Spruit · J. R. · Jansen · R. W. M. M. · de Groot · J. R. · de Vries · T. A. C. · Hemels · M. E. W. · Douma · R. A. · de Haan · L. R. · Brinkman · K. · Moeniralam · H. S. · de Kruif · M. · Dormans · T. · Appelman · B. · Reidinga · A. C. · Rusch · D. · Gritters van den Oever · N. C.
Objectives

The aim of this multicentre COVID-PREDICT study (a nationwide observational cohort study that aims to better understand clinical course of COVID-19 and to predict which COVID-19 patients should receive which treatment and which type of care) was to determine the association between atrial fibrillation (AF) and mortality, intensive care unit (ICU) admission, complications and discharge destination in hospitalised COVID-19 patients.

Setting

Data from a historical cohort study in eight hospitals (both academic and non-academic) in the Netherlands between January 2020 and July 2021 were used in this study.

Participants

3064 hospitalised COVID-19 patients >18 years old.

Primary and secondary outcome measures

The primary outcome was the incidence of new-onset AF during hospitalisation. Secondary outcomes were the association between new-onset AF (vs prevalent or non-AF) and mortality, ICU admissions, complications and discharge destination, performed by univariable and multivariable logistic regression analyses.

Results

Of the 3064 included patients (60.6% men, median age: 65 years, IQR 55–75 years), 72 (2.3%) patients had prevalent AF and 164 (5.4%) patients developed new-onset AF during hospitalisation. Compared with patients without AF, patients with new-onset AF had a higher incidence of death (adjusted OR (aOR) 1.71, 95% CI 1.17 to 2.59) an ICU admission (aOR 5.45, 95% CI 3.90 to 7.61). Mortality was non-significantly different between patients with prevalent AF and those with new-onset AF (aOR 0.97, 95% CI 0.53 to 1.76). However, new-onset AF was associated with a higher incidence of ICU admission and complications compared with prevalent AF (OR 6.34, 95% CI 2.95 to 13.63, OR 3.04, 95% CI 1.67 to 5.55, respectively).

Conclusion

New-onset AF was associated with an increased incidence of death, ICU admission, complications and a lower chance to be discharged home. These effects were far less pronounced in patients with prevalent AF. Therefore, new-onset AF seems to represent a marker of disease severity, rather than a cause of adverse outcomes.

Recommendations for the primary prevention of atherosclerotic cardiovascular disease in primary care: study protocol for a systematic guideline review

Por: Schürmann · L. · Bredehorst · M. · Gonzalez-Gonzalez · A. I. · Muth · C. · van der Wardt · V. · Puzhko · S. · Haasenritter · J.
Introduction

Atherosclerotic cardiovascular disease (ASCVD) was the main cause of death in Germany in 2021, with major risk factors (ie, hypertension, diabetes, dyslipidaemia, obesity and certain lifestyle factors) being highly prevalent. Preventing ASCVD by assessment and modification of these risk factors is an important challenge for general practitioners. This study aims to systematically review and synthesise recent recommendations of national and international guidelines regarding the primary prevention of ASCVD in adults in primary care.

Methods and analysis

We will conduct a systematic review of clinical practice guidelines (CPGs) to evaluate primary prevention strategies for ASCVD. CPGs will be retrieved from MEDLINE and the Turning Research Into Practice database, guideline-specific databases and websites of guidelines-producing societies, with searches limited to publications from 2016 onwards. We will include CPGs in English, Spanish, German or Dutch languages that provide evidence-based recommendations for ASCVD prevention. The study population will include adults without diagnosed ASCVD. Two independent reviewers will assess guideline eligibility and quality by means of the mini-checklist MiChe, and extract study characteristics and relevant recommendations for further consistency analysis. A third reviewer will resolve disagreements. Findings will be presented as a narrative synthesis and in tabular form.

Ethics and dissemination

This review does not require ethical approval. Our systematic review will inform the CPG of the German College of General Practitioners and Family Physicians on the primary prevention of ASCVD. The review results will also be disseminated through publications in peer-reviewed journals and presentations at local, national and international conferences.

PROSPERO registration number

CRD42023394605.

What is the aetiology of dysnatraemia in COVID-19 and how is this related to outcomes in patients admitted during earlier and later COVID-19 waves? A multicentre, retrospective observational study in 11 Dutch hospitals

Por: de Haan · L. · ten Wolde · M. · Beudel · M. · Olde Engberink · R. H. G. · Appelman · B. · Haspels-Hogervorst · E. K. · Rusch · D. · Gritters van den Oever · N. C. · Simsek · S. · Paternotte · N. · van den Bergh · J. P. · Wyers · C. E. · de Kruif · M. D. · Dormans · T. · Moeniralam
Objectives

To evaluate the relationship among dysnatraemia at hospital presentation and duration of admission, risk of intensive care unit (ICU) admission and all-cause mortality and to assess the underlying pathophysiological mechanism of hyponatraemia in patients with COVID-19. Our hypothesis is that both hyponatraemia and hypernatraemia at presentation are associated with adverse outcomes.

Design

Observational study.

Setting

Secondary care; 11 Dutch hospitals (2 university and 9 general hospitals).

Participants

An analysis was performed within the retrospective multicentre cohort study COVIDPredict. 7811 patients were included (60% men, 40% women) between 24 February 2020 and 9 August 2022. Patients who were ≥18 years with PCR-confirmed COVID-19 or CT with COVID-19 reporting and data system score≥4 and alternative diagnosis were included. Patients were excluded when serum sodium levels at presentation were not registered in the database or when they had been transferred from another participating hospital.

Outcome measures

We studied demographics, medical history, symptoms and outcomes. Patients were stratified according to serum sodium concentration and urinary sodium excretion.

Results

Hyponatraemia was present in 2677 (34.2%) patients and hypernatraemia in 126 (1.6%) patients. Patients with hyponatraemia presented more frequently with diarrhoea, lower blood pressure and tachycardia. Hyponatraemia was, despite a higher risk for ICU admission (OR 1.27 (1.11–1.46; p

Conclusions

Hypernatraemia at presentation was associated with adverse outcomes in patients with COVID-19. Hypovolaemic hyponatraemia was found to be the most common aetiology of hyponatraemia. Hyponatraemia of unknown aetiology was associated with a higher risk for ICU admission and intubation and longer duration of admission.

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