Prevalence and clinical and psychological correlates of high fear of cancer recurrence in patients newly diagnosed with head and neck cancer

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A nationwide study on cancer recurrences, second primary tumours, distant metastases and survival after treatment for primary head and neck cancer in the Netherlands

Introduction: There is no consensus on the optimal duration of post-treatment follow-up after head and neck cancer (HNC). To generate site-specific input for follow-up guidelines, this study describes the incidence and timing of manifestations of disease during five years of follow-up. Methods: All patients diagnosed with HNC in the Netherlands in 2015 were selected from the Netherlands Cancer Registry. The follow-up events local recurrence (LR), regional recurrence (RR), second primary tumour (SPT), distant metastasis (DM) and death were studied per follow-up-year. The cumulative incidence of these events was calculated using competing risk analyses, with LR, RR and SPT of the head and neck (SPHNC) as events and SPT outside the head-neck (SPOHN), DM and death as competing events. Analyses were performed for oral cavity-, oropharynx-, larynx- and hypopharynx squamous cell carcinoma (SCC), and all HNC patients. Results: The 1-, 1.5-, and 2-year cumulative incidence of an event (LR, RR, SPHNC) were 10% (95%CI 8–13), 12% (95%CI 10–15), and 13% (95%CI 10–16) for oral cavity SCC; 6% (95%CI 4–9), 10% (95%CI 7–14), and 11% (95%CI 8–15) for oropharynx SCC; 7% (95%CI 5–10), 11% (95%CI 9–15), and 13% (95%CI 10–16) for larynx SCC and 11% (95%CI 6–19), 19% (95%CI 12–27), and 19% (95%CI 12–27) for hypopharynx SCC. Conclusions: One year of follow-up for oral cavity SCC, and 1.5 years for oropharynx-, larynx-, and hypopharynx SCC suffices for the goal of detecting disease manifestations after treatment. More research into other aspects of follow-up care should be performed to determine the optimal follow-up regimen.</p

Macrocyclization of enzyme-based supramolecular polymers

AB type monomers for supramolecular polymers have been developed based on the strong and reversible noncovalent interaction between ribonuclease S-peptide (A) and S-protein (B), resulting in an active enzyme complex as the linking unit. Two AB-type protein constructs are synthesized differing in the length of the flexible oligo(ethylene glycol) spacer separating the two end groups. Using an experimental setup where size exclusion chromatography is directly coupled to Q-TOF mass spectrometry, we have analyzed the self-assembled architectures as a function of concentration. The theory of macrocyclization under thermodynamic control is used to quantitatively analyze the experimental data. Using this theory, we show that AB-type monomers linked by flexible linkers grow reversibly via ring-chain competition. Inherently the formation of linear polymeric assemblies is beyond the capability of these types of building blocks due to concentration limits of proteins. The results therefore contribute to the general understanding of supramolecular polymerization with biological building blocks and demonstrate design requirements for monomers if linear polymerization is desired

Integrated Bioluminescent Immunoassays for High-Throughput Sampling and Continuous Monitoring of Cytokines

Immunoassays show great potential for the detection of low levels of cytokines, due to their high sensitivity and excellent specificity. There is a particular demand for biosensors that enable both high-throughput screening and continuous monitoring of clinically relevant cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNFα). To this end, we here introduce a novel bioluminescent immunoassay based on the ratiometric plug-and-play immunodiagnostics (RAPPID) platform, with an improved intrinsic signal-to-background and an &gt;80-fold increase in the luminescent signal. The new dRAPPID assay, comprising a dimeric protein G adapter connected via a semiflexible linker, was applied to detect the secretion of IL-6 by breast carcinoma cells upon TNFα stimulation and the production of low concentrations of IL-6 (∼18 pM) in an endotoxin-stimulated human 3D muscle tissue model. Moreover, we integrated the dRAPPID assay in a newly developed microfluidic device for the simultaneous and continuous monitoring of changes in IL-6 and TNFα in the low-nanomolar range. The luminescence-based read-out and the homogeneous nature of the dRAPPID platform allowed for detection with a simple measurement setup, consisting of a digital camera and a light-sealed box. This permits the usage of the continuous dRAPPID monitoring chip at the point of need, without the requirement for complex or expensive detection techniques.</p

Ultrathin superconducting TaCxN1−x films prepared by plasma-enhanced atomic layer deposition with ion-energy control

This work demonstrates that plasma-enhanced atomic layer deposition (PEALD) with substrate biasing enables the preparation of ultrathin superconducting TaCxN1−x films. By comparing with films grown without substrate biasing, the enhanced ion energies yield a hundredfold reduction in room-temperature resistivity: a comparably low value of 217 μΩ cm is obtained for a 40 nm film. The ion-energy control enables tuning of the composition, counteracts oxygen impurity incorporation, and promotes a larger grain size. Correspondingly, the critical temperature of superconductivity (Tc) displays clear ion-energy dependence. With optimized ion energies, a consistently high Tc around 7 K is measured down to 11 nm film thickness. These results demonstrate the high ultrathin-film quality achievable through PEALD combined with substrate biasing. This process is particularly promising for the fabrication of low-loss superconducting quantum devices

A New Heterobinuclear FeIIICuII Complex with a Single Terminal FeIII–O(phenolate) Bond. Relevance to Purple Acid Phosphatases and Nucleases

A novel heterobinuclear mixed valence complex [Fe^IIICu^II(BPBPMP)(OAc)_2]ClO_4, 1, with the unsymmetrical N_5O_2 donor ligand 2-bis[{(2-pyridylmethyl)aminomethyl}-6-{(2-hydroxybenzyl)(2-pyridylmethyl)} aminomethyl]-4-methylphenol (H_2BPBPMP) has been synthesized and characterized. A combination of data from mass spectrometry, potentiometric titrations, X-ray absorption and electron paramagnetic resonance spectroscopy, as well as kinetics measurements indicates that in ethanol/water solutions an [Fe^III-(nu)OH-Cu^IIOH_2]+ species is generated which is the likely catalyst for 2,4-bis(dinitrophenyl)phosphate and DNA hydrolysis. Insofar as the data are consistent with the presence of an Fe_III-bound hydroxide acting as a nucleophile during catalysis, 1 presents a suitable mimic for the hydrolytic enzyme purple acid phosphatase. Notably, 1 is significantly more reactive than its isostructural homologues with different metal composition (Fe^IIIM^II, where M^II is Zn^II, Mn^II, Ni^II,or Fe^II). Of particular interest is the observation that cleavage of double-stranded plasmid DNA occurs even at very low concentrations of 1 (2.5 nuM), under physiological conditions (optimum pH of 7.0), with a rate enhancement of 2.7 x 10^7 over the uncatalyzed reaction. Thus, 1 is one of the most effective model complexes to date, mimicking the function of nucleases

Resolving sepsis-induced immunoparalysis via trained immunity by targeting interleukin-4 to myeloid cells.

Immunoparalysis is a compensatory and persistent anti-inflammatory response to trauma, sepsis or another serious insult, which increases the risk of opportunistic infections, morbidity and mortality. Here, we show that in cultured primary human monocytes, interleukin-4 (IL4) inhibits acute inflammation, while simultaneously inducing a long-lasting innate immune memory named trained immunity. To take advantage of this paradoxical IL4 feature in vivo, we developed a fusion protein of apolipoprotein A1 (apoA1) and IL4, which integrates into a lipid nanoparticle. In mice and non-human primates, an intravenously injected apoA1-IL4-embedding nanoparticle targets myeloid-cell-rich haematopoietic organs, in particular, the spleen and bone marrow. We subsequently demonstrate that IL4 nanotherapy resolved immunoparalysis in mice with lipopolysaccharide-induced hyperinflammation, as well as in ex vivo human sepsis models and in experimental endotoxemia. Our findings support the translational development of nanoparticle formulations of apoA1-IL4 for the treatment of patients with sepsis at risk of immunoparalysis-induced complications.We thank M. Jaeger (Radboudumc) for kindly providing flourescein isothiocyanate-labelled Candida albicans. D. Williams (East Tennessee State University) provided the β-glucan we used in our initial experiments. H. Lemmers (Radboudumc) kindly prepared the purified lipopolysaccharide used for stimulation of primary human monocytes and macrophages. Part of the figures were prepared using (among other software) Biorender.com. B.N. is supported by a National Health and Medical Research Council (Australia) Investigator Grant (APP1173314). This work was supported by National Institutes of Health grants R01 HL144072, R01 CA220234 and P01 HL131478, as well as a Vici grant from the Dutch Research Council NWO and an ERC Advanced Grant (all to W.J.M.M.). M.G.N. was supported by a Spinoza grant from Dutch Research Council NWO and an ERC Advanced Grant (#833247).S