Changes in anticancer treatment plans in patients with solid cancer hospitalized with COVID-19: analysis of the nationwide BSMO-COVID registry providing lessons for the future.

BACKGROUND: Solid cancer is an independent prognostic factor for poor outcome with COVID-19. As guidelines for patient management in that setting depend on retrospective efforts, we here present the first analyses of a nationwide database of patients with cancer hospitalized with COVID-19 in Belgium, with a focus on changes in anticancer treatment plans at the time of SARS-CoV-2 infection. METHODS: Nineteen Belgian hospitals identified all patients with a history of solid cancer hospitalized with COVID-19 between March 2020 and February 2021. Demographic, cancer-specific and COVID-specific data were pseudonymously entered into a central Belgian Society of Medical Oncology (BSMO)-COVID database. The association between survival and primary cancer type was analyzed through multivariate multinomial logistic regression. Group comparisons for categorical variables were carried out through a Chi-square test. RESULTS: A total of 928 patients were registered in the database; most of them were aged ≥70 years (61.0%) and with poor performance scores [57.2% Eastern Cooperative Oncology Group (ECOG) ≥2]. Thirty-day COVID-related mortality was 19.8%. In multivariate analysis, a trend was seen for higher mortality in patients with lung cancer (27.6% versus 20.8%, P = 0.062) and lower mortality for patients with breast cancer (13.0% versus 23.3%, P = 0.052) compared with other tumour types. Non-curative treatment was associated with higher 30-day COVID-related mortality rates compared with curative or no active treatment (25.8% versus 14.3% versus 21.9%, respectively, P < 0.001). In 33% of patients under active treatment, the therapeutic plan was changed due to COVID-19 diagnosis, most frequently involving delays/interruptions in systemic treatments (18.6%). Thirty-day COVID-related mortality was not significantly different between patients with and without treatment modifications (21.4% versus 20.5%). CONCLUSION: Interruption in anticancer treatments at the time of SARS-CoV-2 infection was not associated with a reduction in COVID-related mortality in our cohort of patients with solid cancer, highlighting that treatment continuation should be strived for, especially in the curative setting.

High speed atomic force microscopy to investigate the interactions between toxic Aß1-42 peptides and model membranes in real time: impact of the membrane composition.

Due to an aging population, neurodegenerative diseases have become a major health issue, the most common being Alzheimer's disease. The mechanisms leading to neuronal loss still remain unclear but recent studies suggest that soluble Aß oligomers have deleterious effects on neuronal membranes. Here, high-speed atomic force microscopy was used to assess the effect of oligomeric species of a variant of Aß1-42 amyloid peptide on model membranes with various lipid compositions. Results showed that the peptide does not interact with membranes composed of phosphatidylcholine and sphingomyelin. Ganglioside GM1, but not cholesterol, is required for the peptide to interact with the membrane. Interestingly, when they are both present, a fast disruption of the membrane was observed. It suggests that the presence of ganglioside GM1 and cholesterol in membranes promotes the interaction of the oligomeric Aß1-42 peptide with the membrane. This interaction leads to the membrane's destruction in a few seconds. This study highlights the power of high-speed atomic force microscopy to explore lipid-protein interactions with high spatio-temporal resolution.

Postmortem fetal imaging: prospective blinded comparison of two-dimensional ultrasound with magnetic resonance imaging.

OBJECTIVE: To compare the diagnostic rate and accuracy of 3-Tesla (T) postmortem magnetic resonance imaging (PM-MRI) and postmortem ultrasound (PM-US) in an unselected fetal population. METHODS: We performed prospectively, in a blinded manner, 3-T PM-MRI and PM-US on 160 unselected fetuses at 13-41 weeks of gestation. All imaging was reported according to a prespecified template, for five anatomical regions: brain, thorax, heart, abdomen and spine. The rates of non-diagnostic results for PM-US and PM-MRI were compared and, for results that were diagnostic, we calculated sensitivity, specificity and concordance rates for each anatomical region, using conventional autopsy as the reference standard. RESULTS: 3-T PM-MRI performed significantly better than did PM-US overall and in particular for fetuses ≥ 20 weeks' gestation. Specifically, the non-diagnostic rates for PM-MRI vs PM-US were 4.4% vs 26.9% (7/160 vs 43/160; P < 0.001) for the brain, 5.2% vs 17.4% (8/155 vs 27/155; P < 0.001) for the thorax, 3.8% vs 30.6% (6/157 vs 48/157; P < 0.001) for the heart and 3.2% vs 23.6% (5/157 vs 37/157; P < 0.001) for the abdomen. For the spine, both techniques showed an equally low non-diagnostic rate. When both postmortem imaging techniques were diagnostic, they had similar accuracy, with no difference in sensitivity or specificity, and similar concordance with autopsy (PM-US, 79.5-96.5%; PM-MRI, 81.6-99.1%). CONCLUSIONS: PM-MRI performed significantly better than PM-US in this unselected population, due mainly to a lower non-diagnostic rate. PM-MRI should remain the first-line imaging investigation for perinatal autopsy, but PM-US could be considered if MRI is not available, albeit with a higher non-diagnostic rate. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Electron transfer in an acidophilic bacterium: interaction between a diheme cytochrome and a cupredoxin.

Acidithiobacillus ferrooxidans, a chemolithoautotrophic Gram-negative bacterium, has a remarkable ability to obtain energy from ferrous iron oxidation at pH 2. Several metalloproteins have been described as being involved in this respiratory chain coupling iron oxidation with oxygen reduction. However, their properties and physiological functions remain largely unknown, preventing a clear understanding of the global mechanism. In this work, we focus on two metalloproteins of this respiratory pathway, a diheme cytochrome c4 (Cyt c4) and a green copper protein (AcoP) of unknown function. We first demonstrate the formation of a complex between these two purified proteins, which allows homogeneous intermolecular electron-transfer in solution. We then mimic the physiological interaction between the two partners by replacing one at a time with electrodes displaying different chemical functionalities. From the electrochemical behavior of individual proteins, we show that, while electron transfer on AcoP requires weak electrostatic interaction, electron transfer on Cyt c4 tolerates different charge and hydrophobicity conditions, suggesting a pivotal role of this protein in the metabolic chain. The electrochemical study of the proteins incubated together demonstrates an intermolecular electron transfer involving the protein complex, in which AcoP is reduced through the high potential heme of Cyt c4. Modelling of the electrochemical signals at different scan rates allows us to estimate the rate constant of this intermolecular electron transfer in the range of a few s-1. Possible routes for electron transfer in the acidophilic bacterium are deduced.

Interaction of Aß1-42 peptide or their variant with model membrane of different composition probed by infrared nanospectroscopy.

Toxicity of Aß peptides involved in Alzheimer's disease is linked to the interaction of intermediate species with membranes. Nanoscale Infrared Spectroscopy enhances the study of the morphology and the secondary structure of the peptides as fibers or oligomers interacting with membranes of different compositions, with nanometer scale resolution. Membrane models are used to investigate the role of different lipids in their interactions with Aß peptides. This work clearly brings to light that the presence of cholesterol in membranes is favorable to the interaction with Aß peptides in oligomers or aggregates.

Broadband near-infrared astronomical spectrometer calibration and on-sky validation with an electro-optic laser frequency comb.

The quest for extrasolar planets and their characterization as well as studies of fundamental physics on cosmological scales rely on capabilities of high-resolution astronomical spectroscopy. A central requirement is a precise wavelength calibration of astronomical spectrographs allowing for extraction of subtle wavelength shifts from the spectra of stars and quasars. Here, we present an all-fiber, 400 nm wide near-infrared frequency comb based on electro-optic modulation with 14.5 GHz comb line spacing. Tests on the high-resolution, near-infrared spectrometer GIANO-B show a photon-noise limited calibration precision of < 10 cms as required for Earth-like planet detection. Moreover, the presented comb provides detailed insight into particularities of the spectrograph such as detector inhomogeneities and differential spectrograph drifts. The system is validated in on-sky observations of a radial velocity standard star (HD221354) and telluric atmospheric absorption features. The advantages of the system include simplicity, robustness and turn-key operation, features that are valuable at the observation sites.

A tensegrity driven DNA nanopore.

Control of transport across membranes, whether natural or synthetic, is fundamental in many biotechnology applications, including sensing and drug release. Mutations of naturally existing protein channels, such as hemolysin, have been explored in the past. More recently, DNA channels with conductivities in the nanosiemens range have been designed. Regulating transport across DNA channels in response to external stimuli remains an important challenge. Previous designs relied on steric hindrance to control the inner diameter of the channel, which resulted in unstable electric signatures. In this paper we introduce a new design to control electric channel conductance of a DNA nanopore. The tensegrity driven mechanism inhibits the flux of small analytes while keeping a tightly controlled ionic transport modulated by the addition of specific DNA sequences. Current signals are clearly defined, with no sign of gating, opening new perspectives in single molecule DNA sensing.

[Tamoxifen induced thromboembolic events in breast cancer. Some possible mechanisms]. / Evénements thromboemboliques induits par le tamoxifène dans le cancer du sein. Certains mécanismes potentiels.

Tamoxifen is an antagonist of the oestrogen receptor, used in the treatment of breast cancer. It is known to reduce osteoporotic bone fractures, but it increases the risk of endometrial tumors and venous thromboembolic events (VTEs). VTEs increased significantly during tamoxifen therapy within 3 months of major surgery, immobilization or fracture. Their incidence is associated with patients' risk factors, tumor and tissue induced procoagulation. The mechanisms are still not well known. There is a need for a better understanding in order to develope a prophylactic and therapeutic strategy.

Le tamoxifène est un antagoniste du récepteur de l'oestrogène, utilisé dans le traitement du cancer du sein. Le rôle du tamoxifène dans la réduction du risque de fractures osseuses ostéoporotiques est connu. Par contre il augmente le risque d'apparition de tumeurs de l'endomètre et des événements thromboemboliques veineux (ETEV). L'incidence d'ETEV augmente de manière significative au cours du traitement par le tamoxifène dans les 3 mois d'une chirurgie majeure, suite à une immobilisation ou une fracture. L'incidence est associée aux facteurs de risque des patients et à une hyper coagulabilité tumeur ou tissu induite. Les mécanismes thromboemboliques liés au tamoxifène ne sont pas encore bien connus. Il est nécessaire de mieux les connaître pour développer une stratégie prophylactique et thérapeutique.

Probing the kinetics of lipid membrane formation and the interaction of a nontoxic and a toxic amyloid with plasmon waveguide resonance.

The kinetics of formation of solid-supported lipid model membranes were investigated using a home-made plasmon waveguide resonance (PWR) sensor possessing enhanced properties relative to classic surface plasmon resonance sensors. Additionally, the kinetics of interaction of two amyloid peptides with zwitterionic and anionic membranes and their effect on lipid organization were followed.

Sub-100 attosecond timing jitter from low-noise passively mode-locked solid-state laser at telecom wavelength.

We report on the ultralow timing jitter of the 100 MHz pulse trains generated by two identical passively mode-locked diode-pumped solid-state lasers (DPSSLs) emitting at 1556 nm. Ultralow timing jitter of 83 as (integrated from 10 kHz to 50 MHz) for one laser has been measured with a balanced optical cross-correlator as timing discriminator. Extremely low intensity noise has been measured as well. Several measurement techniques have been used and show similar jitter results. Different possible noise sources have been theoretically investigated and compared to the measured jitter power spectral density. It is found that although the measured integrated jitter is quite low, it is still significantly above the quantum limit in the considered frequency span. Therefore, there is a substantial potential for technical improvements that could make passively mode-locked DPSSL outperform fiber lasers as source of microwaves with low phase noise.

Roles of heat shock factor 1 and 2 in response to proteasome inhibition: consequence on p53 stability.

A single heat shock factor (HSF), mediating the heat shock response, exists from yeast to Drosophila, whereas several related HSFs have been found in mammals. This raises the question of the specific or redundant functions of the different members of the HSF family and in particular of HSF1 and HSF2, which are both ubiquitously expressed. Using immortalized mouse embryonic fibroblasts (iMEFs) derived from wild-type, Hsf1(-/-), Hsf2(-/-) or double-mutant mice, we observed the distinctive behaviors of these mutants with respect to proteasome inhibition. This proteotoxic stress reduces to the same extent the viability of Hsf1(-/-)- and Hsf2(-/-)-deficient cells, but through different underlying mechanisms. Contrary to Hsf2(-/-) cells, Hsf1(-/-) cells are unable to induce pro-survival heat shock protein expression. Conversely, proteasome activity is lower in Hsf2(-/-) cells and the expression of some proteasome subunits, such as Psmb5 and gankyrin, is decreased. As gankyrin is an oncoprotein involved in p53 degradation, we analyzed the status of p53 in HSF-deficient iMEFs and observed that it was strongly stabilized in Hsf2(-/-) cells. This study points a new role for HSF2 in the regulation of protein degradation and suggests that pan-HSF inhibitors could be valuable tools to reduce chemoresistance to proteasome inhibition observed in cancer therapy.

Sequential interplay between BAG6 and HSP70 upon heat shock.

BAG6/Scythe/Bat3 is a cochaperone of the heat shock protein HSP70 and is involved in various developmental processes, cellular stress and viability. BAG6 interferes with the protein-refolding activity of HSP70 but its precise involvement in proteotoxic stresses remains unknown. We show that BAG6 is required for the accumulation of HSP70 upon heat shock and that conversely, once accumulated, HSP70 leads to the massive and CHIP-independent degradation of BAG6 through the ubiquitin-proteasome system. These reciprocal influences between BAG6 and HSP70 upon heat shock suggest that BAG6 is a central regulator of the cellular content of HSP70. The HSP70-driven degradation of BAG6, following the BAG6-dependent accumulation of HSP70, could allow the protein-refolding activity of HSP70 and limit the extent of its induction.

DNA compaction into new DNA vectors based on cyclodextrin polymer: surface enhanced Raman spectroscopy characterization.

The ability of DNA to bind polycation yielding polyplexes is widely used in nonviral gene delivery. The aim of the present study was to evaluate the DNA compaction with a new DNA vector using Raman spectroscopy. The polyplexes result from an association of a beta-cyclodextrin polymer (polybeta-CD), an amphiphilic cationic connector (DC-Chol or adamantane derivative Ada2), and DNA. The charge of the polymeric vector is effectively controlled by simple addition of cationic connector in the medium. We used surface enhanced Raman spectroscopy (SERS) to characterize this ternary complex, monitoring the accessibility of adenyl residues to silver colloids. The first experiments were performed using model systems based on polyA (polyadenosine monophosphate) well characterized by SERS. This model was then extended to plasmid DNA to study polybeta-CD/Ada2/DNA and polybeta-CD/DC-Chol/DNA polyplexes. The SERS spectra show a decrease of signal intensity when the vector/DNA charge ratio (Z+/-) increases. At the highest ratio (Z+/- = 10) the signal is 6-fold and 3-fold less intense than the DNA reference signal for Ada2 and DC-Chol polyplexes, respectively. Thus adenyl residues have a reduced accessibility as DNA is bound to the vector. Moreover, the SERS intensity variations are in agreement with gel electrophoresis and zeta potential experiments on the same systems. The overall study clearly demonstrates that the cationic charges neutralizing the negative charges of DNA result in the formation of stable polyplexes. In vitro transfection efficiency of those DNA vectors are also presented and compared to the classical DC-Chol lipoplexes (DC-Chol/DNA). The results show an increase of the transfection efficiency 2-fold higher with our vector based on polybeta-CD.

Compact 10-GHz Nd:GdVO4 laser with 0.5-W average output power and low timing jitter.

We demonstrate a compact, diode-pumped Nd:GdVO4 laser with a repetition rate of 9.66 GHz and 0.5-W average output power. The laser is passively mode locked with a semiconductor saturable absorber mirror (SESAM), yielding 12-ps-long sech2-shaped pulses. For synchronization of the pulse train to an external reference clock, the SESAM is mounted on a piezoelectric transducer. With an electronic feedback loop of only a few kilohertz loop bandwidth we achieved a rms timing jitter of 146 fs (integrated from 10 Hz to 10 MHz). This is an upper limit because it is mostly limited by the measurement system. The laser setup with a simple linear cavity has a footprint of only 130 mm x 30 mm.

Optical parametric oscillator with a 10-GHz repetition rate and 100-mW average output power in the spectral region near 1.5 mum.

We demonstrate a synchronously pumped optical parametric oscillator that emits picosecond pulses at an ~1.55-mum wavelength with a repetition rate as a high as 10 GHz and as much as 100 mW of average power. It is pumped with a diode-pumped passively mode-locked 10-GHz Nd:YVO(4) laser. Because of its high repetition rate and its potential for ultrabroad tunability, this kind of system is useful for telecom applications. It should be scalable to 40 GHz and higher as required for future telecom networks.

Additional hydrogen bonds and base-pair kinetics in the symmetrical AMP-DNA aptamer complex.

The solution structure of an adenosine monophosphate (AMP)-DNA aptamer complex has been determined previously [Lin, C. H., and Patel, D. J. (1997) Chem. Biol. 4:817-832]. On a symmetrical aptamer complex containing the same binding loop, but with better resolved spectra, we have identified two additional hydrogen bond-mediated associations in the binding loop. One of these involves a rapidly exchanging G imino proton. The phosphate group of the AMP ligand was identified as the acceptor by comparison with other aptamer complexes. Imino proton exchange measurements also yielded the dissociation constants of the stem and binding loop base pairs. This study shows that nuclear magnetic resonance-based imino proton exchange is a good probe for detection of weak hydrogen-bond associations.

Highly functionalized dimeric tetraethynylethenes and expanded radialenes: strong evidence for macrocyclic cross-conjugation.

A selection of dimeric tetraethynylethenes (TEEs) and perethynylated expanded radialenes, containing different donor/acceptor substitution patterns, have been prepared and fully characterized. The first X-ray crystal structure of an expanded [6]radialene, with twelve peripheral 3,5-di(tert-butyl)phenyl substituents, is presented. This macrocycle, the all-carbon core of which is isomeric with fullerene C60, adopts a non-planar, "chair-like" conformation. Also a TEE dimer, carrying N,N-dimethylaniline donor substituents, has been subjected to an X-ray crystallographic analysis. The electronic properties were studied by UV/Vis spectroscopy and electrochemistry, providing fundamental insight into mechanisms of pi-electron delocalization in the acyclic and macrocyclic chromophores. Donor or donor-acceptor-substituted dimeric TEE derivatives show very strong absorptions extending over the entire UV/Vis region; their longest wavelength absorption bands have high charge-transfer character. Macrocyclic cross-conjugation in the expanded radialenes becomes increasingly efficient with increasing donor-acceptor polarization. A dual, strongly solvent-polarity-dependent fluorescence was observed for a tetrakis(N,N-dimethylaniline)-substituted dimeric TEE; this interesting emission behavior is explained by the twisted intramolecular charge-transfer (TICT) state model. Donor-substituted expanded radialenes display huge resonance-enhanced third-order nonlinear optical coefficients.

The RNA i-motif.

Oligodeoxynucleotides with stretches of cytidine residues associate into a four-stranded structure, the i-motif, in which two head-to-tail, intercalated, parallel-stranded duplexes are held together by hemiprotonated C.C+ pairs. We have investigated the possibility of forming an i-motif structure with C-rich ribonucleic acids. The four C-rich RNAs studied, r(UC5), r(C5), r(C5U) and r(UC3), associate into multiple intercalated structures at acidic pH. r(UC5) forms two i-motif structures that differ by their intercalation topologies. We report on a structural study of the main form and we analyze the small conformational differences found by comparison with the DNA i-motif. The stacking topology of the main structure avoids one of the six 2'-OH/2'-OH repulsive contacts expected in a fully intercalated structure. The C3'-endo pucker of the RNA sugars and the orientation of the intercalated C.C+ pairs result in a modest widening of the narrow grooves at the steps where the hydroxyl groups are in close contact. The free energy of the RNA i-motif, on average -4 kJ mol(-1) per C.C+ pair, is half of the value found in DNA i-motif structures.

Structure of a C-rich strand fragment of the human centromeric satellite III: a pH-dependent intercalation topology.

Repetitive DNA sequences may adopt unusual pairing arrangements. At acid to neutral pH, cytidine-rich DNA oligodeoxynucleotides can form the i-motif structure in which two parallel-stranded duplexes with C.C(+) pairs are intercalated head-to-tail. The i-motif may be formed by multimeric associations or by intra-molecular folding, depending on the number of cytidine tracts, the nucleotide sequences between them, and the experimental conditions. We have found that a natural fragment of the human centromeric satellite III, d(CCATTCCATTCCTTTCC), can form two monomeric i-motif structures that differ in their intercalation topology and that are favored at pH values higher (the eta-form) and lower (the lambda-form) than 4.6. The change in intercalation may be related to adenine protonation in the loops. We studied the uridine derivative methylated on the first cytidine base, d(5mCCATTCCAUTCCUTTCC), whose proton spectrum is better resolved. The intercalation topologies are (C7.C17)/(5mC1.C11)/(C6.C16)/(C2.C12) for form lambda and (5mC1.C11)/(C7.C17)/(C2.C12)/(C6.C16) for form eta. We have solved the structure of the eta-form, and we present a model for the lambda-form. The switch from eta to lambda involves disruption of the i-motif. In both forms, the central AUT linker crosses the wide groove, and the first and the third linkers loop across the minor grooves. The i-motif core is extended in the eta-form by the inter-loop reverse Watson-Crick A3.U13 pair, whose dissociation constant is around 10(-2) at 0 degrees C, and in the lambda-form by the interloop T5.T15 pair. In contrast, d(5mCCATTCCTTACCTTTCC) folds into a pH-independent structure that has the same intercalation topology as the lambda-form. The i-motif core is extended below by the interloop T5.T15 pair and closed on top by the T8.A10 pair.Thus, the C-rich strand of the human satellite III tandem repeats, like the G-rich strand, can fold into various compact structures. The relevance of these features to centromeric function remains unknown.

Cesium-133: a potential reporter of the hepatic uptake of contrast agents.

NMR spectroscopy of intracellularly located (133)Cs has been used to monitor the uptake of Gd-EOB-DTPA by the isolated rat liver. As shown by (31)P spectroscopy, accumulation of (133)Cs ions in hepatocytes does not produce detectable effects on the metabolism. The hepatic internalization of Gd-EOB-DTPA was followed by the paramagnetic relaxation enhancement of the intracellular (133)Cs ions, and confirmed by parallel quantitations of Gd and Cs run by inductively coupled plasma (ICP) analysis of liver samples and aliquots of perfusate. The relaxation data significantly underestimate the Gd content, suggesting a potential compartmentation of Cs(+) and/or the contrast agent. Magn Reson Med 45:711-715, 2001.