Heart Failure With Preserved Ejection Fraction: A Review of Cardiac and Noncardiac Pathophysiology

Heart failure with preserved ejection fraction (HFpEF) is one of the largest unmet clinical needs in 21st-century cardiology. It is a complex disorder resulting from the influence of several comorbidities on the endothelium. A derangement in nitric oxide bioavailability leads to an intricate web of physiological abnormalities in the heart, blood vessels, and other organs. In this review, we examine the contribution of cardiac and noncardiac factors to the development of HFpEF. We zoom in on recent insights on the role of comorbidities and microRNAs in HFpEF. Finally, we address the potential of exercise training, which is currently the only available therapy to improve aerobic capacity and quality of life in HFpEF patients. Unraveling the underlying mechanisms responsible for this improvement could lead to new biomarkers and therapeutic targets for HFpEF

Staphylococcus aureus controls interleukin-5 release in upper airway inflammation

Staphylococcus aureus is a frequent colonizer of the upper airways in chronic rhinosinusitis with nasal polyps, but also resides intramucosally, it has been shown that secreted staphylococcal proteins such as enterotoxins and serine proteases induce the release of cytokines such as IL-5. We have analyzed nasal polyp tissue freshly obtained during routine surgery, which did or did not contain cultivatable S. aureus, to study spontaneous IL-5 production by nasal polyp tissue over 24 and 72 h in tissue culture In S. aureus-positive samples we interfered by killing the bacteria using antibiotics or S. aureus specific intravenous staphylococcal phages (ISP), active or heat-inactivated. Phage-neutralizing antibodies were used to demonstrate the specificity of the phage-mediated effects We monitored S. aureus colony forming units, and identified S. aureus proteins by mass spectrometry We demonstrate that cultivatable S. aureus may be found in type-2 inflamed nasal polyps, the pathogen is replicating within 24 h and secretes proteins, including enterotoxins and serine proteases The presence of S. aureus was associated with a significantly higher release of IL-5 Killing of S. aureus by antibiotics or specific ISP significantly reduced the IL-5 release. The suppressive activity of the bacteriophage on IL-5 be abolished by heat inactivation or anti-phage antibodies. Biological significance In this study, we used high resolution mass spectrometry to identify S. aureus proteins directly in infected nasal polyp tissue and nasal polyp tissue incubated over 24 and 72 h in culture We discovered bacterial proteins including enterotoxins and serine proteases like proteins These experiments indicate a direct role of S. aureus in the regulation of IL-5 production in nasal polyps and may suggest the involvement of bacterial proteins detected in the tissues

OC-0145: Preoperative radiotherapy with an integrated boost compared to chemoradiotherapy for rectal cancer

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Epigenetics in the primary and secondary prevention of cardiovascular disease: influence of exercise and nutrition

Increasing evidence links changes in epigenetic systems, such as DNA methylation, histone modification, and non-coding RNA expression, to the occurrence of cardiovascular disease (CVD). These epigenetic modifications can change genetic function under influence of exogenous stimuli and can be transferred to next generations, providing a potential mechanism for inheritance of behavioural intervention effects. The benefits of exercise and nutritional interventions in the primary and secondary prevention of CVD are well established, but the mechanisms are not completely understood. In this review, we describe the acute and chronic epigenetic effects of physical activity and dietary changes. We propose exercise and nutrition as potential triggers of epigenetic signals, promoting the reshaping of transcriptional programmes with effects on CVD phenotypes. Finally, we highlight recent developments in epigenetic therapeutics with implications for primary and secondary CVD prevention

Melanoma addiction to the long non-coding RNA SAMMSON

Focal amplifications of chromosome 3p13-3p14 occur in about 10% of melanomas and are associated with a poor prognosis. The melanoma-specific oncogene MITF resides at the epicentre of this amplicon. However, whether other loci present in this amplicon also contribute to melanomagenesis is unknown. Here we show that the recently annotated long non-coding RNA (lncRNA) gene SAMMSON is consistently co-gained with MITF. In addition, SAMMSON is a target of the lineage-specific transcription factor SOX10 and its expression is detectable in more than 90% of human melanomas. Whereas exogenous SAMMSON increases the clonogenic potential in trans, SAMMSON knockdown drastically decreases the viability of melanoma cells irrespective of their transcriptional cell state and BRAF, NRAS or TP53 mutational status. Moreover, SAMMSON targeting sensitizes melanoma to MAPK-targeting therapeutics both in vitro and in patient-derived xenograft models. Mechanistically, SAMMSON interacts with p32, a master regulator of mitochondrial homeostasis and metabolism, to increase its mitochondrial targeting and pro-oncogenic function. Our results indicate that silencing of the lineage addiction oncogene SAMMSON disrupts vital mitochondrial functions in a cancer-cell-specific manner; this silencing is therefore expected to deliver highly effective and tissue-restricted anti-melanoma therapeutic responses

Systematic comparison of ISOLDE-SC yields with calculated in-target production rates

Recently, a series of dedicated inverse-kinematics experiments performed at GSI, Darmstadt, has brought an important progress in our understanding of proton and heavy-ion induced reactions at relativistic energies. The nuclear reaction code ABRABLA that has been developed and benchmarked against the results of these experiments has been used to calculate nuclide production cross sections at different energies and with different targets and beams. These calculations are used to estimate nuclide production rates by protons in thick targets, taking into account the energy loss and the attenuation of the proton beam in the target, as well as the low-energy fission induced by the secondary neutrons. The results are compared to the yields of isotopes of various elements obtained from different targets at CERN-ISOLDE with 600 MeV protons, and the overall extraction efficiencies are deduced. The dependence of these extraction efficiencies on the nuclide half-life is found to follow a simple pattern in many different cases. A simple function is proposed to parameterize this behavior in a way that quantifies the essential properties of the extraction efficiency for the element and the target - ion-source system in question.Comment: 46 pages, 49 figures, background information on http://www-w2k.gsi.de/charms

NatF Contributes to an Evolutionary Shift in Protein N-Terminal Acetylation and Is Important for Normal Chromosome Segregation

N-terminal acetylation (N-Ac) is a highly abundant eukaryotic protein modification. Proteomics revealed a significant increase in the occurrence of N-Ac from lower to higher eukaryotes, but evidence explaining the underlying molecular mechanism(s) is currently lacking. We first analysed protein N-termini and their acetylation degrees, suggesting that evolution of substrates is not a major cause for the evolutionary shift in N-Ac. Further, we investigated the presence of putative N-terminal acetyltransferases (NATs) in higher eukaryotes. The purified recombinant human and Drosophila homologues of a novel NAT candidate was subjected to in vitro peptide library acetylation assays. This provided evidence for its NAT activity targeting Met-Lys- and other Met-starting protein N-termini, and the enzyme was termed Naa60p and its activity NatF. Its in vivo activity was investigated by ectopically expressing human Naa60p in yeast followed by N-terminal COFRADIC analyses. hNaa60p acetylated distinct Met-starting yeast protein N-termini and increased general acetylation levels, thereby altering yeast in vivo acetylation patterns towards those of higher eukaryotes. Further, its activity in human cells was verified by overexpression and knockdown of hNAA60 followed by N-terminal COFRADIC. NatF's cellular impact was demonstrated in Drosophila cells where NAA60 knockdown induced chromosomal segregation defects. In summary, our study revealed a novel major protein modifier contributing to the evolution of N-Ac, redundancy among NATs, and an essential regulator of normal chromosome segregation. With the characterization of NatF, the co-translational N-Ac machinery appears complete since all the major substrate groups in eukaryotes are accounted for

The EUFOREA pocket guide for chronic rhinosinusitis

Chronic rhinosinusitis (CRS) is known to affect around 5 % of the total population, with major impact on the quality of life of those severely affected (1). Despite a substantial burden on individuals, society and health economies, CRS often remains underdiagnosed, under-estimated and under-treated (2). International guidelines like the European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS) (3) and the International Consensus statement on Allergy and Rhinology: Rhinosinusitis 2021 (ICAR) (4) offer physicians insight into the recommended treatment options for CRS, with an overview of effective strategies and guidance of diagnosis and care throughout the disease journey of CRS

2022 ESC Guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS)

info:eu-repo/semantics/publishe

Reactivity-Dependent PCR: Direct, Solution-Phase in Vitro Selection for Bond Formation

In vitro selection is a key component of efforts to discover functional nucleic acids and small molecules from libraries of DNA, RNA, and DNA-encoded small molecules. Such selections have been widely used to evolve RNA and DNA catalysts and, more recently, to discover new reactions from DNA-encoded libraries of potential substrates. While effective, current strategies for selections of bond-forming and bond-cleaving reactivity are generally indirect, require the synthesis of biotin-linked substrates, and involve multiple solution-phase and solid-phase manipulations. In this work we report the successful development and validation of reactivity-dependent PCR (RDPCR), a new method that more directly links bond formation or bond cleavage with the amplification of desired sequences and that obviates the need for solid-phase capture, washing, and elution steps. We show that RDPCR can be used to select for bond formation in the context of reaction discovery and for bond cleavage in the context of protease activity profiling.Chemistry and Chemical Biolog