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We performed multiscale simulations of analyte sorption and diffusion in hierarchical porosity models of monolithic silica columns for reversed-phase liquid chromatography to investigate how the mean mesopore size of the chromatographic bed and the analyte-specific interaction with the chromatographic interface influence the analyte diffusivity at various length scales. The reproduced experimental conditions comprised the retention of six analyte compounds of low to moderate solute polarity on a silica-based, endcapped, C 18 stationary phase with water‒acetonitrile and water-methanol mobile phases whose elution strength was varied via the volumetric solvent ratio. Detailed information about the analyte-specific interfacial dynamics received from molecular dynamics simulations was incorporated through appropriate linker schemes into Brownian dynamics diffusion simulations in three hierarchical porosity models received from physical reconstructions of silica monoliths with a mean macropore size of 1.23 µm and mean mesopore sizes of 12.3, 21.3, or 25.7 nm. The mean mesopore size was found to have a similar influence on the effective mesopore diffusivity as the analyte polarity and the mobile-phase elution strength, which together determine the analyte residence time on a column. A smaller mesopore size attenuated the increase of the effective mesopore diffusivity with increasing mobile-phase elution strength significantly. The effective bed diffusivity was limited by the analyte residence time rather than by morphological details of the mesopore space. The stronger an analyte was retained by the chromatographic interface inside the mesopores, the slower became the mass transfer between the pore space hierarchies and the lower was the effective bed diffusivity. The B-terms of the plate height equation were finally generated with the bed diffusivities and phase-based retention factors derived from the hierarchical porosity models using additional information about the stationary-phase limit obtained from the analysis of analyte-bonded phase contacts. The B-terms highlight analyte- and mobile phase-specific behavior relevant to isocratic and gradient elution conditions in chromatographic practice. In particular, U-shaped B-term curves are observed due to the dominating contribution of the retention factor and the bed diffusivity to the B-term at low and high elution strength of the mobile phase, respectively., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Recent clinical and theoretical frameworks suggest that social skills and theory of mind impairments characteristic of autism spectrum disorder (ASD) are distributed in the general population on a continuum between healthy individuals and patients. The present multimodal study aimed at investigating the amygdala's function, perfusion, and volume in 56 non-clinical subjects from the general population with high (n = 28 High-SOC) or low (n = 28 Low-SOC) autistic-like social skills traits. Participants underwent magnetic resonance imaging to evaluate the amygdala's functional connectivity at rest, blood perfusion by means of arterial spin labelling, its activation during a face evaluation task and lastly grey matter volumes. The High-SOC group was characterised by higher blood perfusion in both amygdalae, lower volume of the left amygdala and higher activations of the right amygdala during processing of human faces with fearful value. Resting state analyses did not reveal any significant difference between the two groups. Overall, our results highlight the presence of overlapping morpho-functional alterations of the amygdala between healthy individuals and ASD patients confirming the importance of the amygdala in this disorder and in social and emotional processing. Our findings may help disentangle the neurobiological facets of ASD elucidating aetiology and the relationship between clinical symptomatology and neurobiology., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

In nature, the majority of known RNA-protein interactions are transient. Our recent study has depicted a novel mechanism known as RNAylation, which covalently links proteins and RNAs. This novel modification bridges the realms of RNA and protein modifications. This review specifically explores RNAylation catalyzed by bacteriophage T4 ADP-ribosyltransferase ModB, with a focus on its protein targets and RNA substrates in the context of Escherichia coli-bacteriophage T4 interaction. Additionally, we discuss the biological significance of RNAylation and present perspectives on RNAylation as a versatile bioconjugation strategy for RNAs and proteins., Competing Interests: Declaration of competing interest K.H. is in the process of applying for a patent (PCT/EP2021/071295) covering the RNAylation that lists K.H. as inventor. The remaining authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

In liquid chromatography (LC), discrepancies in liquid properties such as elution strength and viscosity lead to a mismatch between the sample diluent and mobile phase. This mismatch can result in peak deformation, including peak splitting or even breakthrough, particularly when large sample volumes are injected. The formation of a T-junction between sample solution and mobile phase flow stream, a technique previously used in supercritical fluid chromatography, is the key enabler of feed injection in LC. This T-junction allows the injection needle to infuse the sample directly into the mobile phase. It ensures that the diluent is continuously mixed with the mobile phase before introduced onto the column, thereby reducing the initial solvent mismatch. The degree of dilution depends on the ratio between mobile phase flow rate (Q mp ) and feed rate (Q feed ) at which the sample is infused. Our study examined the effect of several parameters on the feed injection of large sample volumes from purely organic diluents in reversed-phase LC. These parameters included the type of diluent, compound retention factor (k), injected sample volume (V inj ), and Q mp . With varied Q feed , all compounds revealed a similar range of optimal values for Q r = (Q mp -Q feed )/Q feed between 2 and 5, a range unaffected by V inj and Q mp . For Q r > 5, the slope of the plate height curves (H vs. Q r ) decreases with increasing k, potentially extending the range of optimal Q r -values. However, the best Q r -value for a separation is determined by the compound with the smallest k, simplifying optimization. Using feed injection, we were able to reduce plate heights by up to a factor of 8 compared to classic flow-through injection of large sample volumes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Farnesylated chalcones were favored by researchers due to their different biological activities. However, only five naturally occurring farnesylated chalcones were described in the literature until now. Here, the farnesylation of six chalcones by the Aspergillus terreus aromatic prenyltransferase AtaPT was reported. Fourteen monofarnesylated chalcones (1F1-1F5, 2F1-2F3, 3F1, 3F2, 4F1, 4F2, 5F1, 6F1, and 6F2) and a difarnesylated product (2F3) were obtained, enriching the diversity of natural farnesylated chalcones significantly. Ten of them are C-farnesylated products, which complement O-farnesylated chalcones by chemical synthesis. Fourteen products have not been reported prior to this study. Nine of the produced compounds (1F2-1F5, 2F1-2F3, 5F1, and 6F1) exhibited inhibitory effect on α-glucosidase with IC 50 values ranging from 24.08 ± 1.44 to 190.0 ± 0.28 μM. Among them, compounds 2F3 with IC 50 value at 24.08 ± 1.44 μM and 1F4 with IC 50 value at 30.09 ± 0.59 μM showed about 20 times stronger than the positive control acarbose with an IC 50 at 536.87 ± 24.25 μM in α-glucosidase inhibitory assays., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Mass transport through the mesopore space of a reversed-phase liquid chromatography (RPLC) column depends on the properties of the chromatographic interface, particularly on the extent of the organic-solvent ditch that favors the analyte surface diffusivity. Through molecular dynamics simulations in cylindrical RPLC mesopore models with pore diameters between 6 and 12 nm we systematically trace the evolution of organic-solvent ditch overlap due to spatial confinement in the mesopore space of RPLC columns for small-molecule separations. Each pore model of a silica-based, endcapped, C 18 -stationary phase is equilibrated with two mobile phases of comparable elution strength, namely 70/30 (v/v) water/acetonitrile and 60/40 (v/v) water/methanol, to consider the influence of the mobile-phase composition on the onset of organic-solvent ditch overlap. The simulations show that, as the pore diameter decreases from 9 to 6 nm, the bonded-phase density extends and compacts towards the pore center, which leads to increased accumulation of organic-solvent excess and thus enhanced organic-solvent diffusivity in the ditch. Because the acetonitrile ditch is more pronounced than the methanol ditch, acetonitrile ditch overlap sets in at less severe spatial confinement than methanol ditch overlap. The pore-averaged methanol and acetonitrile diffusivities are considerably raised by ditch overlap in the 6 nm-diameter pore, but also benefit from the ditch (without overlap) in the 7 to 12 nm-diameter pores, whereby local and pore-averaged effects are generally larger for acetonitrile than methanol., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: Neuroinflammation affects brain tissue integrity in multiple sclerosis (MS) and may have a role in major depressive disorder (MDD). Whether advanced magnetic resonance imaging characteristics of the gray-to-white matter border serve as proxy of neuroinflammatory activity in MDD and MS remain unknown., Methods: We included 684 participants (132 MDD patients with recurrent depressive episodes (RDE), 70 MDD patients with a single depressive episode (SDE), 222 MS patients without depressive symptoms (nMS), 58 MS patients with depressive symptoms (dMS), and 202 healthy controls (HC)). 3 T-T1w MRI-derived gray-to-white matter contrast (GWc) was used to reconstruct and characterize connectivity alterations of GWc-covariance networks by means of modularity, clustering coefficient, and degree. A cross-validated support vector machine was used to test the ability of GWc to stratify groups according to their depression symptoms, measured with BDI, at the single-subject level in MS and MDD independently., Findings: MS and MDD patients showed increased modularity (ANOVA partial-η 2  = 0.3) and clustering (partial-η 2  = 0.1) compared to HC. In the subgroups, a linear trend analysis attested a gradient of modularity increases in the form: HC, dMS, nMS, SDE, and RDE (ANOVA partial-η 2  = 0.28, p < 0.001) while this trend was less evident for clustering coefficient. Reduced morphological integrity (GWc) was seen in patients with increased depressive symptoms (partial-η 2  = 0.42, P < 0.001) and was associated with depression scores across patient groups (r = -0.2, P < 0.001). Depressive symptoms in MS were robustly classified (88 %)., Conclusions: Similar structural network alterations in MDD and MS exist, suggesting possible common inflammatory events like demyelination, neuroinflammation that are caught by GWc analyses. These alterations may vary depending on the severity of symptoms and in the case of MS may elucidate the occurrence of comorbid depression., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Borderline personality disorder (BPD) is characterised by structural and functional brain alterations. Yet, there is little data on functional connectivity (FC) across different levels of brain networks and parameters. In this study, we applied a multi-level approach to analyse abnormal functional connectivity. We analysed resting-state functional magnetic resonance imaging (fMRI) data sets of 69 subjects: 17 female BPD patients and 51 age-matched psychiatrically healthy female controls. fMRI was analysed using CONN toolbox including: a) seed-based FC analysis of amygdala connectivity, b) independent component analysis (ICA) based network analysis of intra- and inter-network FC of selected resting-state networks (DMN, SN, FPN), as well as c) graph-theory based measures of network-level characteristics. We show group-level seed FC differences with higher amygdala to contralateral (superior) occipital cortex connectivity in BPD, which correlated with schema-therapy derived measures of symptoms/traits across the entire cohort. While there was no significant group effect on DMN, SN, or FPN intra-network or inter-network FC, we show a significant group difference for local efficiency and cluster coefficient for a DMN-linked cerebellum cluster. Our findings demonstrate BPD-linked changes in FC across multiple levels of observation, which supports a multi-level analysis for future studies to consider different aspects of functional connectome alterations., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

In this work, poly(lactide) nanoparticles were equipped with a bioinspired coating layer based on poly[2-(methacryloyloxy)ethyl phosphorylcholine] and then evaluated when administered to the lungs and after intravenous injection. Compared to the plain counterparts, the chosen zwitterionic polymer shell prevented the coated colloidal formulation from aggregation and conditioned it for lower cytotoxicity, protein adsorption, complement activation and phagocytic cell uptake. Consequently, no interference with the biophysical function of the lung surfactant system could be detected accompanied by negligible protein and cell influx into the bronchoalveolar space after intratracheal administration. When injected into the central compartment, the coated formulation showed a prolonged circulation half-life and a delayed biodistribution to the liver. Taken together, colloidal drug delivery vehicles would clearly benefit from the investigated poly[2-(methacryloyloxy)ethyl phosphorylcholine]-based polymer coatings., Competing Interests: Declaration of Competing Interest The author discloses authors declare that they have no conflicting known competing financial interests associated with or personal relationships that could have appeared to influence the work reported in this manuscript paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

This study describes the synthesis and characterization of triblock copolymers composed of poly[2-(methacryloyloxy)ethyl phosphorylcholine]-block-poly(propylene glycol)-block-poly[2-(methacryloyloxy)ethyl phosphorylcholine] (PMPC-b-PPG-b-PMPC) intended for, but not limited to, applications in colloidal drug delivery. Atom transfer radical polymerization led to a library of well-defined PMPC-b-PPG-b-PMPC triblock copolymers with varying overall molecular weight (ranging from ∼5 to ∼25 kDa) and composition (weight fraction of the hydrophobic PPG block ranged from ∼10 to ∼50 wt%). The properties of the synthesized triblock copolymers were linked to the PPG to bioinspired PMPC block(s) ratio, where the more hydrophilic species showed adequate aqueous solubility, surface activity and biocompatibility (non-toxicity) in in vitro cell culture. Their amphiphilic nature makes them adsorb efficiently onto polymer nanoparticles, what improves colloidal stability under stress conditions and, furthermore, depletes proteins from unwanted adsorption to the underlying surface. The current findings strengthen our insights into structure-function relationships of PMPC-based coatings leading to protecting shells on relevant polymer nanoparticle formulations. PMPC-b-PPG-b-PMPC triblock copolymers composed of a hydrophobic PPG block of 2-4 kDa flanked by two hydrophilic PMPC blocks each of 5-10 kDa seem to be most promising to enhance colloidal drug delivery vehicles., (Copyright © 2024 Elsevier B.V. All rights reserved.)

During differentiation, keratinocytes acquire a strong, hyper-adhesive state, where desmosomal cadherins interact calcium ion independently. Previous data indicate that hyper-adhesion protects keratinocytes from pemphigus vulgaris autoantibody-induced loss of intercellular adhesion, although the underlying mechanism remains to be elucidated. Thus, in this study, we investigated the effect of hyper-adhesion on pemphigus vulgaris autoantibody-induced direct inhibition of desmoglein (DSG) 3 interactions by atomic force microscopy. Hyper-adhesion abolished loss of intercellular adhesion and corresponding morphological changes of all pathogenic antibodies used. Pemphigus autoantibodies putatively targeting several parts of the DSG3 extracellular domain and 2G4, targeting a membrane-proximal domain of DSG3, induced direct inhibition of DSG3 interactions only in non-hyper-adhesive keratinocytes. In contrast, AK23, targeting the N-terminal extracellular domain 1 of DSG3, caused direct inhibition under both adhesive states. However, antibody binding to desmosomal cadherins was not different between the distinct pathogenic antibodies used and was not changed during acquisition of hyper-adhesion. In addition, heterophilic DSC3-DSG3 and DSG2-DSG3 interactions did not cause reduced susceptibility to direct inhibition under hyper-adhesive condition in wild-type keratinocytes. Taken together, the data suggest that hyper-adhesion reduces susceptibility to autoantibody-induced direct inhibition in dependency on autoantibody-targeted extracellular domain but also demonstrate that further mechanisms are required for the protective effect of desmosomal hyper-adhesion in pemphigus vulgaris., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Neoadjuvant chemotherapy (NACT) is routinely used for patients with triple-negative breast cancer (TNBC). Upfront breast-conserving therapy (BCT) consisting of breast-conserving surgery (BCS) and adjuvant radiotherapy (RT) has been shown to be associated with improved outcome in patients with early TNBC as compared to mastectomy., Methods: We identified 2632 patients with early TNBC from the German Breast Group meta-database. Patients with cT1-2 cN0 and ypN0, available surgery and follow-up data were enrolled. Data of 1074 patients from 8 prospective NACT trials were available. Endpoints of interest were locoregional recurrence as first site of relapse (LRR), disease-free survival (DFS) and overall survival (OS). We performed univariate and multivariate Fine-Gray analysis and Cox regression models., Results: After a median follow-up of 64 months, there were 94 (8.8%) locoregional events as first site of relapse. Absence of pathologic complete response (pCR) was associated with increased LRR upon uni- and multivariate analysis (hazard ratio [HR] = 2.28; p < 0.001 and HR = 2.22; p = 0.001). Type of surgery was not associated with LRR. Patients in the BCS-group had better DFS and OS (DFS: HR = 0.47; p < 0.001 and OS: HR = 0.40; p < 0.001). BCS was associated with improved DFS and OS upon multivariate analysis (DFS: HR = 0.51; p < 0.001; and OS HR = 0.43; p < 0.001), whereas absence of pCR was associated with worse DFS and OS (DFS: HR = 2.43; p < 0.001; and OS: HR = 3.15; p < 0.001)., Conclusions: In this retrospective analysis of patients with early stage node-negative TNBC treated with NACT, BCS was not associated with an increased risk of LRR but with superior DFS and OS., Competing Interests: Declaration of competing interest DK reports honoraria from Merck Sharp & Dome, med update, onkowissen, best practice onkologie, ESO, ESMO, Astra Zeneca and Pfizer, advisory boards for Gilead as well as research funding from Merck KGaA, all outside the submitted work. MU declares honoraria from AstraZeneca, Art tempi, Amgen, Daiji Sankyo, Lilly, Roche, Pfizer, MSD Oncology, Pierre Fabre, Sanofi-Aventis, Myriad, Seagen, Gilead and Novartis; he also reports honoraria or fees for consulting or advisory role from Amgen, Lilly, Roche, Pfizer, Lilly, MSD, Pierre Fabre, Novartis, MSD Oncology, Roche, Agendia, Pierre Fabre, Seagen, Gilead, Lily, Stemline and Genzyme. All honoraria and fees paid to the employer/institution. TK reports honoraria from MSD, Pfizer, Gilead, Astra Zeneca, Daiichi Sankyo, Roche, Merit Medical, Endomagnetics, Sirius Medical, Hologic. AS declares grants from Celgene, Roche and AbbVie; personal fees from Celgene, Roche, Pfizer and AstraZeneca for travel expenses outside the submitted work. AS received honoraria from Roche, Celgene, Pfizer, AstraZeneca, Novartis, MSD, Tesaro, Lilly, Seagen, Gilead, GSK, Bayer, Amgen and Pierre Fabre outside the submitted work outside the submitted work. BA reports honoraria for lectures from Roche, Astra Zeneca, GSK, MSD, Celgene, Lilly, Novartis, Eisai and advisory board for MSD, GSK, Amgen, Sanofi-Aventis, Eisai. SS reports personal fees from Abbvie outside the submitted work. SS declares to be an employee of GBG Forschungs GmbH. GBG Forschungs GmbH received funding for research grants from Abbvie, Amgen, AstraZeneca, BMS, Daiichi-Sankyo, Gilead, Molecular Health, Novartis, Pfizer and Roche (paid to the institution); other (non-financial/medical writing) from Daiichi-Sankyo, Gilead, Novartis, Pfizer, Roche and Seagen (paid to the institution). GBG Forschungs GmbH has licensing fees from VMscope GmbH. In addition, GBG Forschungs GmbH has a patent EP21152186.9 pending, a patent EP19808852.8 pending, and a patent EP14153692.0 pending. VN declares to be GBG Forschungs GmbH employee. GBG Forschungs GmbH received funding for research grants from Abbvie, Amgen, AstraZeneca, BMS, Daiichi-Sankyo, Gilead, Molecular Health, Novartis, Pfizer and Roche (paid to the institution); other (non-financial/medical writing) from Daiichi-Sankyo, Gilead, Novartis, Pfizer, Roche and Seagen (paid to the institution). GBG Forschungs GmbH has licensing fees from VMscope GmbH. In addition, GBG Forschungs GmbH has a patent EP21152186.9 pending, a patent EP19808852.8 pending, and a patent EP14153692.0 pending. JH reports personal fees and non-financial support from Daiichi Sankyo, non-financial support from Hologic, personal fees from MSD Oncology, personal fees from Novartis, personal fees from Palleos Health Care, personal fees from Pfizer, personal fees from Roche Pharma, personal fees from Seagen, outside the submitted work. JH declares to be GBG Forschungs GmbH employee. GBG Forschungs GmbH received funding for research grants from Abbvie, Amgen, AstraZeneca, BMS, Daiichi-Sankyo, Gilead, Molecular Health, Novartis, Pfizer and Roche (paid to the institution); other (non-financial/medical writing) from Daiichi-Sankyo, Gilead, Novartis, Pfizer, Roche and Seagen (paid to the institution). GBG Forschungs GmbH has licensing fees from VMscope GmbH. In addition, GBG Forschungs GmbH has a patent EP21152186.9 pending, a patent EP19808852.8 pending, and a patent EP14153692.0 pending. SL reports institutional COIs: The institute receives grants and other from Abbvie, other from Amgen, grants and other from AstraZeneca, other from BMS, grants and other from Celgene, grants, non-financial support and other from Daiichi-Sankyo, other from Eirgenix, other from Eisai Europe Ltd, other from GSK, grants, non-financial support and other from Immunomedics/Gilead, other from Lilly, other from Merck, grants from Molecular Health, grants, non-financial support and other from Novartis, grants, non-financial support and other from Pfizer, other from Pierre Fabre, other from Relay Therapeutics, grants, non-financial support and other from Roche, other from Sanofi, non-financial support and other from Seagen, other from Olema Pharmaceutics, other from VMscope GmbH, outside the submitted work; In addition, Dr. Loibl has a patent EP21152186.9 pending, a patent EP19808852.8 pending, and a patent EP14153692.0 pending. All other authors report that they have no conflicts to declare., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

According to predictive processing theories, vision is facilitated by predictions derived from our internal models of what the world should look like. However, the contents of these models and how they vary across people remains unclear. Here, we use drawing as a behavioral readout of the contents of the internal models in individual participants. Participants were first asked to draw typical versions of scene categories, as descriptors of their internal models. These drawings were converted into standardized 3d renders, which we used as stimuli in subsequent scene categorization experiments. Across two experiments, participants' scene categorization was more accurate for renders tailored to their own drawings compared to renders based on others' drawings or copies of scene photographs, suggesting that scene perception is determined by a match with idiosyncratic internal models. Using a deep neural network to computationally evaluate similarities between scene renders, we further demonstrate that graded similarity to the render based on participants' own typical drawings (and thus to their internal model) predicts categorization performance across a range of candidate scenes. Together, our results showcase the potential of a new method for understanding individual differences - starting from participants' personal expectations about the structure of real-world scenes., Competing Interests: Declaration of competing interest The authors declare that there are no competing interests., (Copyright © 2023. Published by Elsevier B.V.)

Background: Persisting cancer-related fatigue impairs health-related quality of life (HRQoL) and social reintegration in patients with Hodgkin's lymphoma (HL). The GHSG HD18 trial established treatment de-escalation for advanced-stage HL guided by positron emission tomography after two cycles (PET-2) as new standard. Here, we investigate the impact of treatment de-escalation on long-term HRQoL, time to recovery from fatigue (TTR-F), and time to return to work (TTR-W)., Patients and Methods: Patients received European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) and life situation questionnaires at baseline, interim, end of treatment, and yearly follow-up. TTR-F was defined as time from the end of chemotherapy until the first fatigue score <30. TTR-W was analyzed in previously working or studying patients and measured from the end of treatment until the first documented work or education. We compared duration of treatment on TTR-F and TTR-W using Cox proportional hazards regression adjusted for confounding variables., Results: HRQoL questionnaires at baseline were available in 1632 (83.9%) of all randomized patients. Overall, higher baseline fatigue and age were significantly associated with longer TTR-F and TTR-W and male sex with shorter TTR-W. Treatment reduction from eight to four chemotherapy cycles led to a significantly shorter TTR-F [hazard ratio (HR) 1.41, P = 0.008] and descriptively shorter TTR-W (HR 1.24, P = 0.084) in PET-2-negative patients. Reduction from six to four cycles led to non-significant but plausible intermediate accelerations. The addition of rituximab caused significantly slower TTR-F (HR 0.70, P = 0.0163) and TTR-W (HR 0.64, P = 0.0017) in PET-2-positive patients. HRQoL at baseline and age were the main determinants of 2-year HRQoL., Conclusions: Individualized first-line treatment in patients with advanced-stage HL considerably shortens TTR-F and TTR-W in PET-2-negative patients. Our results support the use of response-adapted shortened treatment duration for patients with HL., Competing Interests: Disclosure The authors have declared no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Chronic obstructive pulmonary disease (COPD) is one of the leading causes of morbidity and mortality. Here we present a large observational study on the association of COPD and exacerbations with mortality (AvoidEx Mortality)., Methods: A real-world, observational cohort study with longitudinal analyses of German healthcare claims data in patients ≥40 years of age with a COPD diagnosis from 2011 to 2018 (n = 250,723) was conducted. Patients entered the cohort (index date) upon the first COPD diagnosis. To assess the impact of COPD on all-cause death, a propensity score-matched control group of non-COPD patients was constructed. The number and severity of exacerbations during a 12-month pre-index period were used to form subgroups. For each exacerbation subgroup the exacerbations during 12 months prior to death were analysed., Results: COPD increases the all-cause mortality risk by almost 60% (HR 1.57 (95% CI 1.55-1.59)) in comparison to matched non-COPD controls, when controlling for other baseline covariates. The cumulative risk of death after 8 years was highest in patients with a history of more than one moderate or severe exacerbation. Among all deceased COPD patients, 17.2% had experienced a severe, and 34.8% a moderate exacerbation, within 3 months preceding death. Despite increasing exacerbation rates towards death, more than the half of patients were not receiving any recommended pharmacological COPD therapy in the year before death., Conclusion: Our study illustrates the impact of COPD on mortality risk and highlights the need for consequent COPD management comprising exacerbation assessment and treatment., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Joanna Diesing reports financial support was provided by WIG2 GmbH Scientific Institute for Health Economics and Health Service Research. Patrick Timpel reports financial support was provided by WIG2 GmbH Scientific Institute for Health Economics and Health Service Research. Nils Kossack reports financial support was provided by WIG2 GmbH Scientific Institute for Health Economics and Health Service Research. Marc Pignot reports financial support was provided by ZEG - Berlin Center for Epidemiology and Health Research GmbH. Felix W Friedrich reports financial support for data analysis and medical writing provided by AstraZeneca. Melanie Abram reports financial support was provided by AstraZeneca. Marija Halbach reports financial support was provided by AstraZeneca. Claus F Vogelmeier reports financial support was provided by AstraZeneca. Claus F Vogelmeier reports a relationship with Boehringer Ingelheim that includes: consulting or advisory and funding grants. Claus F Vogelmeier reports a relationship with CSL Behring that includes: consulting or advisory and funding grants. Claus F Vogelmeier reports a relationship with Chiesi Pharmaceuticals GMBH that includes: consulting or advisory and funding grants. Claus F Vogelmeier reports a relationship with GlaxoSmithKline that includes: consulting or advisory and funding grants. Claus F Vogelmeier reports a relationship with Grifols Deutschland GmbH Head Office that includes: consulting or advisory and funding grants. Claus F Vogelmeier reports a relationship with A Menarini Pharma GmbH that includes: consulting or advisory and funding grants. Claus F Vogelmeier reports a relationship with Novartis that includes: consulting or advisory and funding grants. Claus F Vogelmeier reports a relationship with Nuvaira Inc that includes: consulting or advisory and funding grants. Claus F Vogelmeier reports a relationship with MedUpdate that includes: consulting or advisory and funding grants. Claus F Vogelmeier reports a relationship with Aerogen Ltd that includes: consulting or advisory and funding grants. Claus F Vogelmeier reports a relationship with Sanofi-Aventis Deutschland GmbH that includes: consulting or advisory and funding grants. Claus F Vogelmeier reports a relationship with Roche that includes: consulting or advisory and funding grants., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Psychological inflexibility is defined as the rigid responding to stimuli (e.g., unpleasant thoughts and feelings) that interferes with well-being and valued actions. It is the treatment target in acceptance and commitment therapy (ACT). Despite the centrality of the link between inflexibility and well-being to ACT theory, an empirical review clarifying the nature of this relationship has not been conducted. As such, the current meta-analysis examined the meta-correlation between psychological inflexibility, measured by the Acceptance and Action Questionnaire (AAQ) and its variants, and well-being. A systematic review yielded 151 studies, including 25 versions of the AAQ and 43 well-being measures. Consistent with ACT theory, higher psychological inflexibility was associated with worse well-being (r = -.47, 95% CI[-.49, -.45]). In addition, sample diagnosis, type of AAQ, and type of well-being measure significantly moderated this relationship. Overall, our findings support the hypothesized link between psychological inflexibility and worse well-being. Limitations include reliance on cross-sectional data, precluding causal interpretation., (Copyright © 2023 Association for Behavioral and Cognitive Therapies. Published by Elsevier Ltd. All rights reserved.)

Purpose: This phase II study evaluated the impact of adding ribociclib to maintenance endocrine therapy (ET) treatment of physicians' choice following the first palliative chemotherapy in pre- and post-menopausal women with hormone receptor positive (HR+)/human epidermal growth factor 2 negative (HER2-) metastatic breast cancer (mBC)., Patients and Methods: The initial randomized study design was later amended into a single-arm study, and all subsequent patients received ribociclib and ET. The primary end point was locally assessed progression-free survival (PFS). Secondary end points included overall survival (OS), clinical benefit rate (CBR), safety, compliance, and quality of life (QoL)., Results: A total of 43 patients received ribociclib + ET and 10 patients received ET only. Median PFS was 12.4 months [95% CI 8.7-24.4] for patients who received ribociclib + ET and 4.75 months [95% CI 1.0-10.3] for those who received ET only. Median OS was not reached for patients who received ribociclib + ET, and 28 (65.1%) patients experienced clinical benefit [95% CI 49.1-79.0]. For patients who received ribociclib + ET, grade 3-4 hematological adverse events (AEs) occurred in 25 (58.1%) patients, and grade 3-4 non-hematological AEs occurred in 17 (39.5%) patients. During the study, 15 patients died - 14 of whom due to tumor-related reasons, and one patient due to pneumonia, which was not treatment-related., Conclusion: The results of the AMICA study show a promising efficacy and safety of maintenance treatment with ribociclib added to ET after at least stable disease following the first metastatic chemotherapy in patients with HR+/HER2-mBC., Trial Registration: Anti-hormonal Therapy With Ribociclib in HR-positive/HER2- Negative Metastatic Breast Cancer (AMICA), NCT03555877, https://clinicaltrials.gov/ct2/show/NCT03555877., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. T. Decker reports ad boards from Lilly, Novartis, and IOMEDICO. K. Luedtke-Heckenkamp reports personal fees from AstraZeneca, Gilead, Novartis, and Pfizer. She is on the advisory board of Daiichi Sankyo, Lilly, and Roche. K. Lübbe is on the advisory board of Genomic Health, Roche, Daiichy Sankyo, Lilly, MSD, EISAI, Seagen, and Novartis, and has received lecture fees from Novartis, AstraZeneca, Genomic Health, Roche, and Lilly. M. Schmidt reports personal fees from AstraZeneca, personal fees from BioNTech, personal fees from Daiichi Sankyo, personal fees from Eisai, personal fees from Lilly, personal fees from MSD, personal fees from Novartis, personal fees from Pfizer, personal fees from Pierre-Fabre, personal fees from Roche, and personal fees from SeaGen outside the submitted work; in addition, M. Schmidt has a patent for EP 2390370 B1: A method for predicting the response of a tumor in a patient suffering from or at risk of developing recurrent gynecologic cancer towards a chemotherapeutic agent issued and a patent for EP 2951317 B1: A method for predicting the benefit from inclusion of a taxane in a chemotherapy regimen in patients with breast cancer issued. C. Denkert reports grants from European Commission H2020, grants from German Cancer Aid Translational Oncology, grants from German Breast Group; personal fees from Novartis, Roche, MSD Oncology, Daiichi Sankyo, AstraZeneca, Lilly, Molecular Health, Merck, grants from Myriad to his institution, other from Sividon diagnostics (cofounder and former shareholder until 2016); In addition, C. Denkert has a patent VMScope digital pathology software with royalties paid, a patent WO2020109570A1 - cancer immunotherapy pending, and a patent WO2015114146A1 and WO2010076322A1- therapy response issued. V. Müller received speaker honoraria from Amgen, Astra Zeneca, Daiichi-Sankyo, Eisai, GSK, Pfizer, MSD, Medac, Novartis, Roche, Teva, Seagen, Onkowissen, high5 Oncology, Medscape, Gilead, and Pierre Fabre; consultancy honoraria from Hexal, Roche, Pierre Fabre, Amgen, ClinSol, Novartis, MSD, Daiichi-Sankyo, Eisai, Lilly, Sanofi, Seagen, and Gilead; institutional research support from Novartis, Roche, Seagen, and Genentech; and travel grants from Roche, Pfizer, Daiichi Sankyo, and Gilead. M. Thill is on the advisory boards of Agendia, Amgen, AstraZeneca, Aurikamed, Becton/Dickinson, Biom‘Up, ClearCut, Clovis, Daiichi Sankyo, Eisai, Exact Sciences, Gilead Science, Grünenthal, GSK, Lilly, MSD, Norgine, Neodynamics, Novartis, Onkowissen, Organon, Pfizer, pfm Medical, Pierre-Fabre, Roche, RTI Surgical, Seagen, Sirius Pintuition, and Sysmex. He has received support from Amgen, AstraZeneca, Celgene, ClearCut, Clovis, Daiichi Sanyko, Hexal, Neodynamics, Novartis, Pfizer, pfm medical, Roche, Servier, and Sirius Medical. He reports travels expenses from Amgen, Art Tempi, AstraZeneca, Clearcut, Clovis, Connect Medica, Daiichi Sankyo, Eisai, Exact Sciences, Hexal, I-Med-Institute, Lilly, MCI, Medtronic, MSD, Neodynamics, Norgine, Novartis, Pfizer, pfm Medical, Roche, RTI Surgical, and Seagen. He has received honoraria and funding from Amgen, Art Tempi, AstraZeneca, Biom’Up, Celgene, Clearcut, Clovis, Connect Medica, Eisai, Endomag, Exact Sciences, Gedeon Richter, Gilead Science, GSK, Hexal, I-Med-Institute, Jörg Eickeler, Laborarztpraxis Walther et al., Lilly, MCI, Medscape, MSD, Medtronic, Neodynamics, Novartis, Onkowissen, Pfizer, pfm medical, Roche, RTI Surgical, Seagen, StreamedUp, Sysmex, Vifor, and Viatris. N. Hirmas and N. Filmann declare to be GBG Forschungs GmbH employees. GBG Forschungs GmbH received funding for research grants from Abbvie, AstraZeneca, BMS, Daiichi-Sankyo, Gilead, Novartis, Pfizer, and Roche (paid to the institution); other (non-financial/medical writing) from Daiichi-Sankyo, Gilead, Novartis, Pfizer, Roche and Seagen (paid to the institution). GBG Forschungs GmbH has following royalties/patents: EP14153692.0, EP21152186.9, EP15702464.7, EP19808852.8 and VM Scope GmbH. S. Loibl reports grants or contracts paid to institute from Abbvie, AstraZeneca, DSI, Celgene, Gilead, Novartis, Pfizer, Roche, Molecular H; in addition, S. Loibl has royalties or licenses for Digital Ki67 Evaluator from VM Scope GmbH that were paid to institute; in addition, S. Loibl receives honorary for lectures paid to the institute from AstraZeneca, DSI, Gilead, Novartis, Pfizer, and Roche; non-financial for Medical Writing from DSI, Gilead, Novartis, Pfizer, Roche, and Seagen; in addition, S. Loibl has patent for EP14153692.0, EP21152186.9, EP15702464.7 and EP19808852.8, all patents via institute; in addition, S. Loibl declares participation on a Data Safety Monitoring Board or Advisory Board from Abbvie, Amgen, AstraZeneca, BMS, Celgene, DSI, Eirgenix, Eisai Europe, GSK, Gilead, Lilly, Merck, Novartis, Pfizer, Pierre Fabre, Relay Therapeutics, Roche, Sanofi, and Seagen, all paid to institute., (Copyright © 2023. Published by Elsevier Ltd.)

Measuring long-range electric fields by 4-dimensional scanning transmission electron microscopy (4DSTEM) is on the verge to becoming an established method, though quantifying and understanding all underlying processes remains a challenge. To gain further insight into these processes, experimental studies employing the center-of-mass (COM) method of the model system of a GaAs p-n junction are carried out in which three ranges of the semi-convergence angle α are identified, with an intermediate one where measuring the built-in potential V bi is not feasible. STEM multislice simulations including both atomic and nm-scale fields prove that this intermediate range begins once diffraction disks start overlapping with the undiffracted beam. The range ends when the diffraction disks' intensities become so low that they do not affect the measurement significantly anymore and when high-intensity diffractions overlap the center disk completely. From simulations without influence of atoms it is concluded that measuring V bi has advantages over measuring the electric-field strength, as the potential difference does neither show a significant dependence on the beam size, nor on the specimen thickness., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

The 18th St Gallen International Breast Cancer Conference held in March 2023, in Vienna, Austria, assessed significant new findings for local and systemic therapies for early breast cancer with a focus on the evaluation of multimodal treatment options. The emergence of more effective, innovative agents in both the preoperative (primary or neoadjuvant) and post-operative (adjuvant) settings has underscored the pivotal role of a multidisciplinary approach in treatment decision making, particularly when selecting systemic therapy for an individual patient. The importance of multidisciplinary discussions regarding the clinical benefits of interventions was explicitly emphasized by the consensus panel as an integral part of developing an optimal treatment plan with the 'right' degree of intensity and duration. The panelists focused on controversies surrounding the management of common ductal/no special type and lobular breast cancer histology, which account for the vast majority of breast tumors. The expert opinion of the panelists was based on interpretations of available data, as well as current practices in their professional environments, personal and socioeconomic factors affecting patients, and cognizant of varying reimbursement and accessibility constraints around the world. The panelists strongly advocated patient participation in well-designed clinical studies whenever feasible. With these considerations in mind, the St Gallen Consensus Conference aims to offer guidance to clinicians regarding appropriate treatments for early-stage breast cancer and assist in balancing the realistic trade-offs between treatment benefit and toxicity, enabling patients and clinicians to make well-informed choices through a shared decision-making process., (Copyright © 2023 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Multiple-open-tubular columns enabling transverse diffusion (MOTTD) consist of straight and parallel flow-through channels separated by a mesoporous stationary phase. In Part 1, a stochastic model of band broadening along MOTTD columns accounting for longitudinal diffusion, trans-channel velocity bias, and mass transfer resistance in the stationary phase was derived to demonstrate the intrinsic advantage of MOTTD columns over classical particulate columns. In Part 2, the model was refined for the critical contribution of the channel-to-channel polydispersity and applied to address the best trade-off between analysis speed and performance. In this Part 3, a MOTTD column with a square array of quadratic channels is fabricated by 3D-printing (combining polymer stereolithography with photolithography using photomasks) to deliver unprecedently small apparent channel diameters of 117.6 ± 5.0 μm. The colors in the microscopy photographs of the actual 3D-printed channels are binarized to delimitate the mobile phase volume from the stationary phase volume. The same numerical simulations as those in Part 2 are then performed for two MOTTD columns (external porosity ϵ e =31.7%, same apparent channel diameter 117.6 μm): one containing 16 virtual perfect quadratic channels and the other 16 real 3D-printed channels. The reduced velocities (or Peclet numbers) are varied over a wide range from 0.2 to 5000 and the zone retention factors were fixed at k 1 =1.04, 5, and 25. The results demonstrate that smoothing the edges of the targeted quadratic channels by the 3D-printed technique is advantageous in terms of solute dispersion. It outperforms the negative effect of the channel-to-channel polydispersity which is mitigated by transverse diffusion of the analyte in the stationary phase. For Peclet numbers larger than 50, the HETP of the 3D-printed MOTTD column is found 7%, 15%, and 16% smaller than that of the MOTTD column consisting of a square array of perfect quadratic channels. This confirms the known effect of channel geometry on solute dispersion in microfluidic systems. Flow channels in fabricated MOTTD columns are preferred to be circular so that the distribution of transverse diffusion lengths across the open channels remains as tight as possible. Finally, the general theory of nonuniform columns of Giddings reveals that the polydispersity of the cross-sectional area (RSD 8.4%) along a single 3D-printed channel has no negative impact on solute dispersion in MOTTD columns. Overall, MOTTD columns could become a serious alternative technology to conventional particulate columns. This implies a novel fabrication process that delivers circular channel diameters smaller than 10 μm, cross-sectional area polydispersity no larger than 25%, external porosities in a range from 15% (high speed separations) to 75% (high performance separations), and conventional mesoporous silica as the stationary phase. It adresses new synthesis routes based on either organic fibers or tubular micelle templating agents in suspension with silica gel solutions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Molecular and antigen point-of-care tests (POCTs) have augmented our ability to rapidly identify and manage SARS-CoV-2 infection. However, their clinical performance varies among individual studies., Objectives: The evaluation of the performance of molecular and antigen-based POCTs in confirmed, suspected, or probable COVID-19 cases compared with that of laboratory-based RT-PCR in real-life settings., Data Sources: MEDLINE/PubMed, Scopus, Embase, Web of Science, Cochrane Library, Cochrane COVID-19 study register, and COVID-19 Living Evidence Database from the University of Bern., Study Eligibility Criteria: Peer-reviewed or preprint observational studies or randomized controlled trials that evaluated any type of commercially available antigen and/or molecular POCTs for SARS-CoV-2, including multiplex PCR panels, approved by the United States Food and Drug Administration, with Emergency Use Authorization, and/or marked with Conformitè Europëenne from European Commission/European Union., Participants: Close contacts and/or patients with symptomatic and/or asymptomatic confirmed, suspected, or probable COVID-19 infection of any age., Test/s: Molecular and/or antigen-based SARS-CoV-2 POCTs., Reference Standard: Laboratory-based SARS-CoV-2 RT-PCR., Assessment of Risk of Bias: Eligible studies were subjected to quality-control and risk-of-bias assessment using the Quality Assessment of Diagnostic Accuracy Studies 2 tool., Methods of Data Synthesis: Summary sensitivities and specificities with their 95% CIs were estimated using a bivariate model. Subgroup analysis was performed when at least three studies informed the outcome., Results: A total of 123 eligible publications (97 and 26 studies assessing antigen-based and molecular POCTs, respectively) were retrieved from 4674 initial records. The pooled sensitivity and specificity for 13 molecular-based POCTs were 92.8% (95% CI, 88.9-95.4%) and 97.6% (95% CI, 96.6-98.3%), respectively. The sensitivity of antigen-based POCTs pooled from 138 individual evaluations was considerably lower than that of molecular POCTs; the pooled sensitivity and specificity rates were 70.6% (95% CI, 67.2-73.8%) and 98.9% (95% CI, 98.5-99.2%), respectively., Discussion: Further studies are needed to evaluate the performance of molecular and antigen-based POCTs in underrepresented patient subgroups and different respiratory samples., (Copyright © 2022 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Electron tomography (ET) has attracted significant attention for a quantitative analysis of mesoporous materials, especially for complex disordered pore structures, as no priori assumption on the pore shape is needed, which is normally inevitable when using traditional bulk characterization techniques. However, a reliable quantification of such pore structures from ET critically depends on the fidelity of the segmented reconstruction, which can be significantly affected, e.g. by the raw data quality, the limited tilting range, artifacts introduced during alignment and further depends on the reconstruction algorithm. Therefore, we systematically investigated the reconstruction reliability of three main-stream algorithms including simultaneous iterative reconstruction technique (SIRT), total variation minimization (TVM) and discrete algebraic reconstruction technique (DART) for mesoporous materials using different imperfect (realistic) tilt-series based on a set of phantom simulations. We found that DART outperforms the other two methods in reliably revealing small pores and narrow channels, especially when the number of projections is strongly constrained. The accurately segmented reconstruction from DART makes it possible to achieve reliable quantification of the pores structure, which in turn leads to reliable evaluation of effective diffusion coefficients. We discuss the influence of different acquisition and reconstruction parameters on the reconstructed 3D volume and the quantitative analysis of pore features. We aim to provide a practical guideline for optimizing acquisition and reconstruction parameters and how to evaluate the accuracy when describing the mesoporous structure., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

An alternative method to the classical fit of semi-empirical, statistical, or artificial intelligence-based models to retention data is proposed to predict surface excess adsorption and retention factors in liquid chromatography. The approach is based on a fundamental, microscopic description of the liquid-to-solid adsorption of analytes taking place at the interface between a bulk liquid phase and a solid surface. Molecular dynamics (MD) simulations are performed at T=300 K in a 100 Å wide slit-pore model (β-cristobalite-C 18 surface in contact with an acetonitrile/water mobile phase) to quantify a priori the retention factors of small molecules expected in reversed phase liquid chromatography (RPLC). Uracil is chosen as the reference "non-retained" marker, whereas benzyl alcohol, acetophenone, benzene, and ethylbenzene are four selected retained, neutral compounds. The MD simulations allow to determine the pore-level density profiles of these five compounds, i.e., the variation of the analyte concentration as a function of distance from the silica surface. The retention factors of the retained analytes are expressed using their respective calculated surface excess adsorption relative to uracil. By definition, the retention factors are proportional to the surface excess adsorbed and the proportionality constant is directly scaled to the retention time of the "non-retained" marker. Experimentally, a 4.6 mm × 150 mm RPLC-C 18 column packed with 5 μm 100 Å High Strength Silica (HSS)-C 18 particles is used and the retention times of these five compounds are measured. The volume fraction of acetonitrile in water increases from 20 to 90% generating a wide range of retention factors from 0.15 to 183 at T=300 K. The results demonstrate very good agreement between the MD-predicted surface excess adsorption data and measured retention factors (R 2 > 0.985). A systematic error is observed as the proportionality constant is not exactly scaled to the retention time of uracil. This is most likely caused by the differences between the chemical and morphological features of the slit-pore model adopted in the MD simulations and those of the actual HSS-C 18 particles: the average surface coverage with C 18 chains, the geometry of the mesopores, and the pore size distribution. Specifically, the impact on RPLC retention of slight, local variations in surface chemistry (e.g., functional group density and uniformity) and how this aspect is affected by the pore space morphology (e.g., pore curvature and size) is worth investigating by future MD simulations., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The diagnostic evaluation of homologous recombination deficiency (HRD) is central to define targeted therapy strategies for patients with ovarian carcinoma. We evaluated HRD in 514 ovarian carcinoma samples by next-generation sequencing of DNA libraries, including BRCA1/BRCA2 and 26,523 single-nucleotide polymorphisms using the standardized Myriad HRD assay, with the predefined cut point of ≥42 for a positive genomic instability score (GIS). All samples were measured in the central Myriad laboratory and in an academic molecular pathology laboratory. A positive GIS was detected in 196 (38.1%) of tumors, whereas 318 (61.9%) were GIS negative. Combining GIS and BRCA mutations, a total of 200 (38.9%) of the 514 tumors were HRD positive. A positive GIS was significantly associated with high-grade serous histology (P < 0.000001), grade 3 tumors (P = 0.001), and patient age <60 years (P = 0.0003). The concordance between both laboratories for the GIS status was 96.9% (P < 0.000001), with a sensitivity of 94.6% and a specificity of 98.4%. Concordance for HRD status was 97.1% (499 of 514 tumors). The percentage of HRD-positive tumors in our real-life cohort was similar to the proportion observed in the recently published PAOLA-1 trial, with high concordance between central and local laboratories. Our results support introduction of the standardized HRD assay in academic molecular pathology laboratories, thus broadening access to personalized oncology strategies for patients with ovarian cancer worldwide., (Copyright © 2022 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background: Stomatitis is one of the main reasons to discontinue everolimus in patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC). To decrease stomatitis and subsequently early treatment discontinuations or dose reductions, the DESIREE trial investigated the use of a stepwise dose-escalation schedule of everolimus (EVE esc)., Patients and Methods: DESIREE is a phase II, multicentre, randomised, double-blind, placebo-controlled trial in patients with HR+/HER2- mBC and progression/relapse after nonsteroidal aromatase inhibitor treatment. Patients were randomised to EVE esc (2.5 mg/day, week 1; 5 mg/day, week 2; 7.5 mg/day, week 3; 10 mg/day, weeks 4-24) or everolimus 10 mg/day (EVE 10mg) for 24 weeks plus exemestane. The primary endpoint was the incidence of stomatitis episodes grade ≥2 within 12 weeks of treatment. The secondary endpoints included toxicity, relative total dose intensity (RTDI) and quality of life (QoL)., Results: A total of 160 patients were randomised and 156 started treatment (EVE esc: 80; EVE 10mg: 76). The median age of patients was 64 years (range 33-85), 56.3% patients in the EVE esc arm versus 42.1% in the EVE 10mg arm had liver metastasis (P = 0.081) and 62.5% versus 51.3% received over one metastatic therapy line (P = 0.196). Within 12 weeks, the incidence of stomatitis episodes grade ≥2 was significantly lower in the EVE esc arm compared with the EVE 10mg arm (28.8% versus 46.1%; odds ratio 0.47, 95% confidence interval 0.24-0.92; P = 0.026). Toxicity was in line with the known safety profile without new safety concerns. The median RTDI was 91.1% in the EVE esc arm versus 80.0% in the EVE 10mg arm (P = 0.329). Discontinuation rate in the first 3 weeks was 6.3% versus 15.8%, respectively (P = 0.073). QoL was comparable between the two treatment arms., Conclusions: A dose-escalation schema of everolimus over 3 weeks can be successfully used to reduce the incidence of high-grade stomatitis in the first 12 weeks of treatment in patients with HR+/HER2- mBC., Trial Registration: ClinicalTrials.govNCT02387099; https://clinicaltrials.gov/ct2/show/NCT02387099., Competing Interests: Disclosure VM reports personal fees from Amgen, Astra Zeneca, Daiichi-Sankyo, Eisai, Pfizer, MSD, Novartis, Roche, Teva, Seagen, GSK, Gilead; personal fees from Genomic Health, Gilead, Hexal, Roche, Pierre Fabre, Amgen, Clin Sol, Novartis, MSD, Daiichi-Sankyo, Eisai, Lilly, GSK, Gilead, other from Novartis, Roche, Seagen, Genentech, outside the submitted work. MS reports grants or contracts to the Institution from AstraZeneca, BioNTech, Eisai, German Breast Group, Genentech, Novartis, Pantarhei Bioscience, Pfizer, Pierre Fabre, Roche; consulting fees from AstraZeneca, BioNTech, Eisai, Daiichi Sankyo, Lilly, MSD, Novartis, Pantarhei Bioscience, Pfizer, Pierre Fabre, Roche, Seagen; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AstraZeneca, Daiichi Sankyo, Lilly, MSD, Novartis, Pfizer, Roche, Seagen; support for attending meetings and/or travel from Pfizer and Roche; patents planned, issued or pending: EP 2951317 B1 and EP 2390370 B1; participation on a Data Safety Monitoring Board or Advisory Board for AstraZeneca, BioNTech, Daiichi Sankyo, Eisai, Lilly, Novartis, Pantarhei Bioscience, Pfizer, Pierre Fabre, Roche, Seagen; receipt of equipment, materials, drugs, medical writing, gifts or other services from Roche. MR reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Novartis, Pfizer; support for attending meetings and/or travel from Novartis, Pfizer. TD reports consulting fees from Novartis Adboard, iOMEDICO adboard. TL reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Amgen, Roche, Clovis, MSD, Novartis, Pfizer, Lilly, GSK, Gilead, AstraZeneca; support for attending meetings and/or travel from MSD, Celgene, Clovis, Gilead, Daiichi Sankyo, Pfizer; participation on a data safety monitoring board or advisory board for Amgen, MSD, Roche, Tesaro, Pfizer, Lilly, Myriad, Eisai, GSK, Daiichi Sankyo. KL reports payment for participation on Advisory Board from Seagen, Novartis, AstraZeneca, Genomic Health, Roche, Daiichi Sankyo, Lilly, MSD, Eisai; payment or honoraria for lectures from Novartis, Genomic Health, Roche, Lilly. MT reports trial funding, payment to the institution from Exact Sciences, Endomag; consulting fees or Advisory board from Agendia, Amgen, AstraZeneca, Becton/Dickinson, ClearCut, Clovis, Daiichi Sankyo, Eisai, Exact Sciences, Gilead, Grünenthal, GSK, Lilly, MSD, Neodynamics, Onkowissen, Organon, Pfizer, Pfm medical, Pierre-Fabre, Roche, Seagen, Sirius Pintuition, Sysmex; payment or honoraria for lectures, manuscript writing from Amgen, AstraZeneca, Art tempi, ClearCut, Clovis, Connect Medica, Daiichi Sankyo, Eisai, Gilead, Hexal, Exact Sciences, Eickeler, Onkowissen, Sysmex, Vifor, Viatris, I-Med-Institute, Lilly, MSD, Novartis, Pfizer, pfm medical, Roche, Seagen, Servier; support for attending meetings and/or travel from Amgen, Art tempi, AstraZeneca, Clearcut, Clovis, Connect medica, Daiichi Sankyo, Exact Sciences, I-Med-Institute, Lilly, MSD, Novartis, Pfizer, pfm medical, Neodynamics, Seagen; leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid from AWOgyn. MvM reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Amgen, AstraZeneca, Daiichi Sankyo, Genomic Health, Gilead, GSK, Lilly, Molecular Health, Mylan, Novartis, Pfizer, Pierre Fabre, Roche, Seagen; support for attending meetings and/or travel from Lilly. SL reports honoraria for Advisory board, lectures and research grant paid to the institution from Novartis, AstraZeneca, Daiichi-Sankyo, Pfizer, Roche; advisory board and research grant paid to the institution from AbbVie, BMS (Celgene), Gilead; honoraria for advisory board paid to the institution from Amgen, EirGenix, GSK, Lilly, Merck KGaA, Pierre-Fabre, Sanofi; honoraria for Advisory board and medical writing paid to the institution, and nonfinancial support from Seagen; patent issued and royalties (Digital Ki67 Evaluator) VM Scope GmbH paid to the institution; patents pending: EP14153692.0 (immunosignature in TNBC), EP21152186.9 (signature for CDK4/6 inhibitor), EP19808852.8. (GeparNUEVO) paid to the institution; patent issued: EP15702464.7 (Predicting response to an anti-HER2 containing therapy) paid to the institution. No other potential conflict of interest relevant to this article was reported. Data sharing, (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Addition of immune checkpoint inhibitors to neoadjuvant chemotherapy (NACT) is a promising strategy in early breast cancer, but the optimal duration of therapy is currently unknown. In the GeparNuevo (NCT02685059) trial, addition of durvalumab to NACT as previously reported led to a moderate increase in pathological complete response (pCR) rate by an absolute 9% (P = 0.287)., Patients and Methods: Patients with cT1b-cT4a-d triple-negative breast cancer (TNBC) received durvalumab 1.5 g or placebo every 4 weeks added to nab-paclitaxel 125 mg/m 2 weekly for 12 weeks, followed by durvalumab/placebo every 4 weeks plus epirubicin/cyclophosphamide every 2 weeks followed by surgery. Durvalumab was not continued after surgery. The primary objective was pCR. Secondary endpoints included invasive disease-free survival (iDFS), distant disease-free survival (DDFS) and overall survival (OS)., Results: A total of 174 patients were randomised between June 2016 and October 2017. After a median follow-up of 43.7 months, 34 events had occurred. Despite a non-significant increase in the pCR rate, significant differences were observed for 3-year iDFS, DDFS and OS: iDFS was 85.6% with durvalumab versus 77.2% with placebo [hazard ratio (HR) 0.48, 95% confidence interval (CI) 0.24-0.97, stratified log-rank P = 0.036]; DDFS 91.7% versus 78.4% (HR 0.31, 95% CI 0.13-0.74, P = 0.005); OS 95.2% versus 83.5% (HR 0.24, 95% CI 0.08-0.72, P = 0.006). pCR patients had 3-year iDFS of 95.5% with durvalumab and 86.1% without (HR 0.22, 95% CI 0.05-1.06). In the non-pCR cohort 3-year iDFS was 76.3% versus 69.7% (HR 0.67, 95% CI 0.29-1.54). Multivariable analysis confirmed a durvalumab effect independent of the pCR effect. No new safety signals occurred., Conclusions: Durvalumab added to NACT in TNBC significantly improved survival despite a modest pCR increase and no adjuvant component of durvalumab. Additional studies are needed to clarify the optimal duration and sequence of checkpoint inhibitors in the treatment of early TNBC., Competing Interests: Role of funding sources The funders had no role in the collection, analysis or interpretation of the data, and had no access to the study data. The study statisticians (JR, VN) had access to the raw data. The report was reviewed by all authors. The sponsor (GBG Forschungs GmbH) has developed the study design and written the study protocol in collaboration with the members of the neoadjuvant sub-board of the German Breast Group (GBG) and AGO-B. The corresponding author had full access to all data in the study and had final responsibility for the decision to submit for publication. Disclosure MU reports personal fees and non-financial support from AbbVie, Amgen GmbH, AstraZeneca, Celgene GmbH, Daiji Sankyo, Eisai GmbH, Lilly Int., Merck Sharp & Dohme (MSD), Merck, Mundipharma, Myriad Genetics, Pfizer GmbH, Roche, Sanofi Aventis Deutschland GmbH, Teva, Novartis, Clovis Oncology; personal fees from Bristol Myers Squibb (BMS), Lilly Deutschland, Pierre Fabre, Seattle Genetics, Seagen, outside the submitted work. AS reports grants from Celgene, Roche, AbbVie; personal fees from Roche, AstraZeneca, Celgene, Pfizer, AstraZeneca, Novartis, MSD, Tesaro, Lilly, Pfizer; other from Roche, outside the submitted work. CD reports grants from European Commission H2020, German Cancer Aid Translational Oncology, German Breast Group, during the conduct of the study; personal fees from Novartis, Roche, MSD Oncology, Daiichi Sankyo, AstraZeneca, Molecular Health, Merck, grants from Myriad; other from Sividon Diagnostics, outside the submitted work; has a patent VMScope digital pathology software with royalties paid, a patent WO2020109570A1-cancer immunotherapy pending, and a patent WO2015114146A1 and WO2010076322A1-therapy response issued. SL reports grants and other from AbbVie, non-financial support and other from Amgen, grants and other from AstraZeneca, other from Bayer, other from BMS, grants and other from Celgene, personal fees from Chugai, grants, non-financial support and other from Daiichi Sankyo, other from EirGenix, other from GSK, grants, non-financial support and other from Immunomedics/Gilead, other from Lilly, other from Merck, grants, non-financial support and other from Novartis, grants, non-financial support and other from Pfizer, other from Pierre Fabre, other from Prime/Medscape, non-financial support and other from Puma, grants, non-financial support and other from Roche, other from Samsung, non-financial support and other from Seagen, outside the submitted work; has a patent EP14153692.0 pending, a patent EP21152186.9 pending, a patent EP15702464.7 issued, a patent EP19808852.8 pending and a patent Digital Ki67 Evaluator with royalties paid. PAF reports personal fees from Novartis, grants from BioNTech, personal fees from Pfizer, Daiichi Sankyo, AstraZeneca, Eisai, MSD, Lilly, Pierre Fabre, Seagen, Roche, Hexal, Agendia; grants from Cepheid, during the conduct of the study. JH reports personal fees and other from Pfizer, grants and personal fees from Novartis, Lilly; personal fees and other from Roche, personal fees from AbbVie, AstraZeneca, MSD, Eisai, Seagen, Gilead; grants and personal fees from Hexal; other from Daiichi, outside the submitted work. KR reports personal fees from AstraZeneca, MSD, Pfizer, outside the submitted work. TL reports personal fees and non-financial support from Roche, personal fees from Novartis, personal fees and non-financial support from Pfizer, personal fees from Tesaro, personal fees and non-financial support from MSD, personal fees from Amgen, personal fees from Clovis, non-financial support from Clegene, personal fees from Lilly, Myriad, GSK, Esai, outside the submitted work. JUB reports personal fees from Amgen, AstraZeneca, MSD, Novartis, Lilly, Pfizer, Exact Sciences, Molecular Health, Seagen, outside the submitted work. CH reports personal fees for lectures, presentations, speaker’s bureaus, manuscript writing or educational events from AstraZeneca, Roche, Novartis, Lilly and Pfizer. PS reports personal fees, non-financial support and other from AbbVie, Janssen-Cilag, Amgen, Novartis, Pfizer, Gilead; grants, personal fees, non-financial support and other from Celgene; grants from AstraZeneca, outside the submitted work. All other authors have declared no conflicts of interest. Data sharing, (Copyright © 2022 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

High-angle annular dark-field scanning transmission electron microscopy (HAADF-STEM) is a valuable method for composition determination of nanomaterials. However, light elements do not scatter efficiently into the scattering angles employed for HAADF-STEM which hinders the composition determination of material systems containing light elements by HAADF-STEM. This makes the usage of lower scattering angles favourable. Moreover, static atomic displacements (SADs) caused by the small covalent radius of the substituting light elements in semiconductor alloys increase the scattering intensity at low angles. Nevertheless, at low angles, a quantitative match between complementary image simulations and experiments is not straight forward, since e.g. inelastic scattering and correlated phonon movement is often neglected in simulations. In this study, we establish a method to quantify material systems containing light elements at low angles by resolving the remaining sources of discrepancy. An outstanding agreement between simulations and experiments is achieved by using a combination of an in-column energy filter and a fast pixelated detector. By applying this method to GaN x As 1-x quantum wells, a good agreement of the TEM results with results from high-resolution x-ray diffraction is obtained. The method developed enables the nanoscale analysis of functional materials containing light elements, especially in the presence of SADs., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Morphology of the human cerebral cortex differs across psychiatric disorders, with neurobiology and developmental origins mostly undetermined. Deviations in the tangential growth of the cerebral cortex during pre/perinatal periods may be reflected in individual variations in cortical surface area later in life., Methods: Interregional profiles of group differences in surface area between cases and controls were generated using T1-weighted magnetic resonance imaging from 27,359 individuals including those with attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depressive disorder, schizophrenia, and high general psychopathology (through the Child Behavior Checklist). Similarity of interregional profiles of group differences in surface area and prenatal cell-specific gene expression was assessed., Results: Across the 11 cortical regions, group differences in cortical area for attention-deficit/hyperactivity disorder, schizophrenia, and Child Behavior Checklist were dominant in multimodal association cortices. The same interregional profiles were also associated with interregional profiles of (prenatal) gene expression specific to proliferative cells, namely radial glia and intermediate progenitor cells (greater expression, larger difference), as well as differentiated cells, namely excitatory neurons and endothelial and mural cells (greater expression, smaller difference). Finally, these cell types were implicated in known pre/perinatal risk factors for psychosis. Genes coexpressed with radial glia were enriched with genes implicated in congenital abnormalities, birth weight, hypoxia, and starvation. Genes coexpressed with endothelial and mural genes were enriched with genes associated with maternal hypertension and preterm birth., Conclusions: Our findings support a neurodevelopmental model of vulnerability to mental illness whereby prenatal risk factors acting through cell-specific processes lead to deviations from typical brain development during pregnancy., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Early MAXimisation of bronchodilation for improving COPD stability (EMAX) was a large, multicentre, multi-national, randomised, double-blind, 24-week trial. EMAX evaluated the efficacy and safety of dual bronchodilator therapy with umeclidinium bromide (UMEC)/vilanterol (VI) versus monotherapy with either UMEC or salmeterol (SAL) in symptomatic patients with chronic obstructive pulmonary disease (COPD) at low exacerbation risk who were not taking concomitant inhaled corticosteroid (ICS). EMAX generated evidence covering a wide range of patient-centred endpoints in COPD in addition to measures of lung function, clinical deterioration and safety. In addition, prospective and post hoc secondary analyses have generated clinically valuable information regarding the effects of baseline patient characteristics on treatment outcomes. Importantly, as concomitant ICS use was not permitted in this study, EMAX compared dual long-acting muscarinic antagonist (LAMA)/long-acting β 2 -agonist (LABA) therapy with LAMA or LABA monotherapy without potential confounding due to concurrent ICS use or withdrawal. EMAX demonstrated beneficial treatment effects of UMEC/VI over UMEC or SAL monotherapy as maintenance treatment across a range of different patient characteristics, with no forfeit in safety. Thus, the trial provided novel insights into the role of LAMA/LABA versus LABA and LAMA monotherapies as maintenance therapy for patients with symptomatic COPD at low risk of exacerbations. This article will explore the clinical implications of the main findings to date of the EMAX trial and consider the key learnings this trial offers for future trial design in COPD., Competing Interests: Disclosures FM has received research grants for participating in multicentre trials for AstraZeneca, Boehringer Ingelheim, GSK, Sanofi and Novartis, and has received unrestricted research grants and personal fees from Boehringer Ingelheim, Grifols and Novartis. CFV has received grants from AstraZeneca, Boehringer Ingelheim, GSK, Grifols and Novartis, and has received lecturing and personal fees from AstraZeneca, Boehringer Ingelheim, Berlin Chemie/Menarini, Chiesi, CSL Behring, GSK, Grifols, MedUpdate, Novartis, Aerogen and Nuvaira. EMK has served on advisory boards, speaker panels or received travel reimbursement for Amphastar, AstraZeneca, Boehringer Ingelheim, Connect Biopharma, GSK, Mylan, Novartis, Pearl, Sunovion, Teva and Theravance, and has received consulting fees from Cipla and GSK. LHB has received honoraria for giving a lecture or attending an advisory board for Airsonett, ALK-Abelló, AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Meda, Novartis and Teva. PWJ, IHB, DAL and CC are GSK employees and hold shares and stocks in GSK. LT is a contingent worker on assignment at GSK. IPN was an employee of GSK at the time of the EMAX trial, holds stocks and shares in GSK, and was a contingent worker on assignment at AstraZeneca., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Despite the awareness that green water is the main source of water to produce food, studies on green water use in cropland ecosystems are still rather limited, and almost no research has so far explored the relationship between green water utilization and socioeconomic development. In this study, with the help of CropWat 8.0, the green water footprint (GWF) of main crops in China was estimated from 1979 to 2016. On this basis, a novel concept, i.e., green water appropriation rate (GWar), was introduced to reveal the relationship between GWF and precipitation. Then, for the first time, the center of gravity trajectory of the GWar and the correlation between GWar and socioeconomic factors were further investigated. The results show that the provinces with the largest increases of GWF were Inner Mongolia (223%), Xinjiang (127%), and Ningxia (123%), while the GWF of 11 provinces has decreased, and 9 of them were municipalities or coastal areas. Generally, the GWar in the eastern and central provinces was higher than that in the western provinces. The center of gravity of the GWar has always been in Henan Province, but it has moved westward from Kaifeng City in 1979 to Sanmenxia City in 2016 and may further move to Shanxi Province soon. The total power of agricultural machinery and the effective irrigation rate had a positive correlation with the GWar, while the agricultural GDP was negatively correlated with the GWar. It is expected that the results will explicitly provide a scientific basis for the development of water-appropriate agriculture and the full utilization of rainwater., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Biallelic mutations of the CEBPA gene (CEBPAbi) define a distinct entity associated with favorable prognosis; however, the role of monoallelic mutations (CEBPAsm) is poorly understood. We retrospectively analyzed 4708 adults with acute myeloid leukemia (AML) who had been recruited into the Study Alliance Leukemia trials, to investigate the prognostic impact of CEBPAsm. CEBPA mutations were identified in 240 patients (5.1%): 131 CEBPAbi and 109 CEBPAsm (60 affecting the N-terminal transactivation domains [CEBPAsmTAD] and 49 the C-terminal DNA-binding or basic leucine zipper region [CEBPAsmbZIP]). Interestingly, patients carrying CEBPAbi or CEBPAsmbZIP shared several clinical factors: they were significantly younger (median, 46 and 50 years, respectively) and had higher white blood cell (WBC) counts at diagnosis (median, 23.7 × 109/L and 35.7 × 109/L) than patients with CEBPAsmTAD (median age, 63 years, median WBC 13.1 × 109/L; P < .001). Co-mutations were similar in both groups: GATA2 mutations (35.1% CEBPAbi; 36.7% CEBPAsmbZIP vs 6.7% CEBPAsmTAD; P < .001) or NPM1 mutations (3.1% CEBPAbi; 8.2% CEBPAsmbZIP vs 38.3% CEBPAsmTAD; P < .001). CEBPAbi and CEBPAsmbZIP, but not CEBPAsmTAD were associated with significantly improved overall (OS; median 103 and 63 vs 13 months) and event-free survival (EFS; median, 20.7 and 17.1 months vs 5.7 months), in univariate and multivariable analyses. Additional analyses revealed that the clinical and molecular features as well as the favorable survival were confined to patients with in-frame mutations in bZIP (CEBPAbZIP-inf). When patients were classified according to CEBPAbZIP-inf and CEBPAother (including CEBPAsmTAD and non-CEBPAbZIP-inf), only patients bearing CEBPAbZIP-inf showed superior complete remission rates and the longest median OS and EFS, arguing for a previously undefined prognostic role of this type of mutation., (© 2022 by The American Society of Hematology.)

Background: Current genetic and genomic tests measuring homologous recombination deficiency (HRD) show limited predictive value. This study compares the performance of an immunohistology-based RAD51 test with genetic/genomic tests to identify patients with HRD primary triple-negative breast cancer (TNBC) and evaluates its accuracy to select patients sensitive to platinum-based neoadjuvant chemotherapy (NACT)., Patients and Methods: This is a retrospective, blinded, biomarker analysis from the GeparSixto randomized clinical trial. TNBC patients received neoadjuvant paclitaxel plus Myocet®-nonpegylated liposomal doxorubicin (PM) or PM plus carboplatin (PMCb), both arms including bevacizumab. Formalin-fixed paraffin-embedded (FFPE) tumor samples were laid on tissue microarrays. RAD51, BRCA1 and γH2AX were quantified using an immunofluorescence assay. The predictive value of RAD51 was assessed by regression models. Concordance analyses were carried out between RAD51 score and tumor BRCA (tBRCA) status or genomic HRD score (Myriad myChoice®). Associations with pathological complete response (pCR) and survival were studied. Functional HRD was predefined as a RAD51 score ≤10% (RAD51-low)., Results: Functional HRD by RAD51-low was evidenced in 81/133 tumors (61%). RAD51 identified 93% tBRCA-mutated tumors and 45% non-tBRCA mutant cases as functional HRD. The concordance between RAD51 and genomic HRD was 87% [95% confidence interval (CI) 79% to 93%]. In patients with RAD51-high tumors, pCR was similar between treatment arms [PMCb 31% versus PM 39%, odds ratio (OR) 0.71, 0.23-2.24, P = 0.56]. Patients with RAD51-low tumors benefited from PMCb (pCR 66% versus 33%, OR 3.96, 1.56-10.05, P = 0.004; interaction test P = 0.02). This benefit maintained statistical significance in the multivariate analysis. Carboplatin addition showed similar disease-free survival in the RAD51-high [hazard ratio (HR) 0.40, log-rank P = 0.11] and RAD51-low (0.45, P = 0.11) groups., Conclusions: The RAD51 test identifies tumors with functional HRD and is highly concordant with tBRCA mutation and genomic HRD. RAD51 independently predicts clinical benefit from adding Cb to NACT in TNBC. Our results support further development to incorporate RAD51 testing in clinical decision-making., Competing Interests: Disclosure Personal fees and/or nonfinancial support from: Agendia (FM), Amgen (RD, MvM), AstraZeneca (JB, CD, MvM), Boehringer Ingelheim (RD), Celgene (FM), Chugai (SL), Clovis (FM), Daiichi-Sankyo (SL, CD), Genomic Health (MvM), GSK (FM), Immunomedics (FM), Ipsen (RD), Janssen-Cilag (FM), Libbs (RD), Lilly (FM), Merck-MSD (RD, FM, CD), Molecular Health (CD), Mylan (MvM), Novartis (FM, CD, MvM), Pfizer (FM, JB, MvM), Pierre Fabre (FM, MvM), Roche (RD, CD, MvM), Sanofi (RD), SeaGen (FM), Servier (RD). Research grants from: Abbvie (SL), Amgen (SL), AstraZeneca (SL, VS), Celgene (SL), Daiichi-Sankyo (SL), Merck (RD), Myriad Genetics (PJ, CD), Novartis (SL), Pierre Fabre (RD), Pfizer (SL), Roche (SL, CD), Tesaro (VS), Teva (SL), Vifor (SL), Immunomedics (SL). Other funding paid to institution from: BMS (SL), Eirgenix (SL), Lilly (SL), Merck (SL), MSD (SL), SeaGen (SL), Prime/Medscape (SL), Puma (SL), Samsung (SL), Pierre Fabre (SL). Stock ownership from: Myriad Genetics (PJ), Sividon Diagnostics (CD until 2016). Patents and other intellectual property: WO2019122411A1 (ALG, JB, VS), EP14153692.0 (SL), VMScope digital pathology software (CD), WO2015114146A1 (CD), WO2010076322A1 (CD), WO2020109570A1 (CD). All remaining authors have declared no conflicts of interest., (Copyright © 2021 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Tyrosine-decahydrofluorene derivatives feature a fused [6.5.6] tricarbocyclic core and a 13-membered para -cyclophane ether. Herein, we identified new xenoacremones A, B, and C ( 1 - 3 ) from the fungal strain Xenoacremonium sinensis ML-31 and elucidated their biosynthetic pathway using gene deletion in the native strain and heterologous expression in Aspergillus nidulans . The hybrid polyketide synthase-nonribosomal peptide synthetase (PKS-NRPS) XenE together with enoyl reductase XenG were confirmed to be responsible for the formation of the tyrosine-nonaketide skeleton. This skeleton was subsequently dehydrated by XenA to afford a pyrrolidinone moiety. XenF catalyzed a novel sigmatropic rearrangement to yield a key cyclohexane intermediate as a prerequisite for the formation of the multi-ring system. Subsequent oxidation catalyzed by XenD supplied the substrate for XenC to link the para -cyclophane ether, which underwent subsequent spontaneous Diels-Alder reaction to give the end products. Thus, the results indicated that three novel enzymes XenF, XenD, and XenC coordinate to assemble the [6.5.6] tricarbocyclic ring and para -cyclophane ether during biosynthesis of complex tyrosine-decahydrofluorene derivatives., Competing Interests: The authors have no conflicts of interest to declare., (© 2021 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

Quantitative scanning transmission electron microscopy (STEM) allows composition determination for nanomaterials at an atomic scale. To improve the accuracy of the results obtained, optimized imaging parameters should be chosen for annular dark field imaging. In a simulation study, we investigate the influence of imaging parameters on the accuracy of the composition determination with the example of ternary III-V semiconductors. It is shown that inner and outer detector angles and semi-convergence angle can be optimized, also in dependence on specimen thickness. Both, a minimum sampling of the image and a minimum electron dose are required. These findings are applied experimentally by using a fast pixelated detector to allow free choice of detector angles., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Chromodomain-Helicase DNA binding protein 7 (CHD7) is an ATP dependent chromatin remodeler involved in maintaining open chromatin structure. Mutations of CHD7 gene causes multiple developmental disorders, notably CHARGE syndrome. However, there is not much known about the molecular mechanism by which CHD7 remodels nucleosomes. Here, we performed biochemical and biophysical analysis on CHD7 chromatin remodeler and uncover that N-terminal to the Chromodomain (N-CRD) interacts with nucleosome and contains a high conserved arginine stretch, which is reminiscent of arginine anchor. Importantly, this region is required for efficient ATPase stimulation and nucleosome remodeling activity of CHD7. Furthermore, smFRET analysis shows the mutations in the N-CRD causes the defects in remodeling activity. Collectively, our results uncover the functional importance of a previously unidentified N-terminal region in CHD7 and implicate that the multiple domains in chromatin remodelers are involved in regulating their activities., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Anthocyanins are a type of well-known natural flavonoids for their various beneficial health effects. However, prenylated anthocyanins are not discovered in nature although prenylation is believed to generally enhance the biological accessibility of flavonoids. In this article, we demonstrate the first example for prenylation of anthocyanins. A chemo-enzymatic approach was achieved for the synthesis of a series of 7-O-prenylated anthocyanins, using the fungal prenyltransferase CdpC3PT from Neosartorya fischeri., (Copyright © 2021 Elsevier Inc. All rights reserved.)

We have undertaken a spectral deconvolution of the three FADs of EtfAB/bcd to the spectral changes seen in the course of reduction, including the spectrally distinct anionic and neutral semiquinone states of electron-transferring and bcd flavins. We also demonstrate that, unlike similar systems, no charge-transfer complex is observed on titration of the reduced M. elsdenii EtfAB with NAD + . Finally, and significantly, we find that removal of the et FAD from EtfAB results in an uncrossing of the half-potentials of the bifurcating FAD that remains in the protein, as reflected in the accumulation of substantial FAD• - in the course of reductive titrations of the depleted EtfAB with sodium dithionite., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Multiple-open-tubular columns enabling transverse diffusion (MOTTD) are made of straight, parallel, and cylindrical flow channels separated by a mesoporous stationary phase. In Part 1, a model of band broadening along MOTTD columns accounting for longitudinal diffusion, the trans-channel velocity bias, and mass transfer resistance in the stationary phase was proposed and validated. In this Part 2, the model is completed by considering the impact of short-range inter-channel velocity biases on the MOTTD plate number. These velocity biases are caused by the wide distribution of the channel diameters. Different ratios, ρ, of the average inner diameter, 2c >, of the flow channels to their closest center-to-center distance d (d= 5 μm, ρ= 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, and 0.9) with a relative standard deviation (RSD) increasing from 0 to 50% are considered. The zone retention factor k 1 was increased from 1 to 25. The complete model of band broadening is validated after adjustment to dispersion data obtained by 1) the lattice-Boltzmann method for modeling fluid flow, 2) a random-walk particle-tracking (RWPT) technique to address advective-diffusive transport, and 3) by considering two distinct populations of flow channels (inner radii r c,1 =c >(1-RSD) and r c,2 =c >(1+RSD)) arranged at the nodes of a hexagonal compact array. The completed model of band broadening in MOTTD columns reveals that the RSD of the channel diameters has only a moderate impact on the optimum plate number of MOTTD columns: the relative increase of the minimum plate height do not exceed 30% even for the largest RSDs. However, when the mass transfer of the analyte is governed by its slow rate of transverse diffusion across the MOTTD column, the plate height can be increased by up to 100% at high average velocities. Regarding the best trade-off between analysis speed and column performance at a fixed pressure drop of 400 bar, irrespective of the zone retention factor and RSD of the distribution of the channel diameters, the fastest analyses are recommended for MOTTD columns having a small structural parameter ρ. In contrast, for the longest analysis times, the largest values of ρ are required to maximize the performance of MOTTD columns., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Aims: Malaria is a serious health threat in tropical countries. The causative parasite of Malaria tropica, the severe form, is the protozoan Plasmodium falciparum. In humans, it infects red blood cells, compromising blood flow and tissue perfusion. This study aims to identify potential biomarkers and RNA networks in leukocyte transcriptomes from patients suffering from Malaria tropica., Materials and Methods: We identified differentially regulated mRNAs and microRNAs in peripheral blood leukocytes of healthy donors and Malaria patients. Genes whose expression changes were not attributable to changes in leukocyte composition were used for bioinformatics analysis and network construction. Using a previously published cohort of community-acquired pneumonia (CAP) patients, we established discriminating transcriptomic features versus Malaria. We aimed to establish differences between the patient groups by principal component (PCA) and receiving operator characteristic (ROC) analyses and in silico cell type deconvolution., Key Findings: We found 870 genes that were significantly differentially expressed between healthy donors and Malaria patients. E2F1, BIRC5 and CCNB1 were identified to be primarily responsible for PCA separation of these two groups. We searched for biological function and found that cell cycle processes were strongly activated. By in silico cell type deconvolution, we attribute this to an expansion of γδ T cells. Additional discrimination between CAP and Malaria yielded 445 differentially expressed genes, among which immune proteasome transcripts PSMB8, PSMB9 and PSMB10 were significantly induced in Malaria., Significance: We identified transcripts from patient leukocytes that differentiate between healthy, Malaria and CAP, and indicate a biological context with potential pathophysiological relevance., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Among the most popular compounds to estimate the hold-up time in reversed-phase liquid chromatography (RPLC) are acetone and uracil, which are considered as too small and too polar, respectively, for retention by the hydrophobic stationary phase, although their observed elution behavior does not fully support this assumption. We investigate how acetone and uracil as solutes interact with the chromatographic interface through molecular dynamics simulations in an RPLC mesopore model of a silica-supported, endcapped, C 18 phase equilibrated with a water (W)‒acetonitrile (ACN) mobile phase. The simulation results provide a molecular-level explanation for the observed elution behavior of acetone and uracil, but also question whether true dead time markers for RPLC exist. Both solutes have a density maximum in the interfacial region in addition to a low presence in the bonded-phase region, but these density peaks clearly differ from the adsorption and partitioning peaks of true analytes. Acetone partially behaves like a co-solvent of ACN and partially like the analyte acetophenone. Like ACN, acetone can be found in the first and second layer of solvent molecules at the silica surface; like acetophenone, acetone adsorbs to the bonded-phase chains by orienting its polar group to the bulk region to sustain hydrogen bonds with W molecules. Uracil behavior is governed by a need for extensive hydrogen-bond coordination by W molecules. Uracil adsorbs to the very edge of the bonded-phase chains, on the bulk-region side of the ACN density maximum in the interfacial region. Further penetration into the chains is prevented by the absence of W molecules, which are not found deeper in the bonded phase, except at the silica surface. Contrary to true analytes, accumulation of uracil and acetone in the interfacial region ceases at an equimolar presence of W and ACN in the mobile phase (at 70‒80% ACN volume fraction). Uracil achieves a closer approximation of the stationary-phase limit than acetone, but carries the risk of HILIC retention at high ACN fraction in the mobile phase., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Low-income and middle-income countries (LMICs) bear a disproportionately high burden of the global morbidity and mortality caused by chronic respiratory diseases (CRDs), including asthma, chronic obstructive pulmonary disease, bronchiectasis, and post-tuberculosis lung disease. CRDs are strongly associated with poverty, infectious diseases, and other non-communicable diseases (NCDs), and contribute to complex multi-morbidity, with major consequences for the lives and livelihoods of those affected. The relevance of CRDs to health and socioeconomic wellbeing is expected to increase in the decades ahead, as life expectancies rise and the competing risks of early childhood mortality and infectious diseases plateau. As such, the World Health Organization has identified the prevention and control of NCDs as an urgent development issue and essential to the achievement of the Sustainable Development Goals by 2030. In this Review, we focus on CRDs in LMICs. We discuss the early life origins of CRDs; challenges in their prevention, diagnosis, and management in LMICs; and pathways to solutions to achieve true universal health coverage., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

An interplay of early environmental and genetic risk factors with recent stressful life events (SLEs) in adulthood increases the risk for adverse mental health outcomes. The interaction of early risk and current SLEs on brain structure has hardly been investigated. Whole brain voxel-based morphometry analysis was performed in N = 786 (64.6% female, mean age = 33.39) healthy subjects to identify correlations of brain clusters with commonplace recent SLEs. Genetic and early environmental risk factors, operationalized as those for severe psychopathology (i.e., polygenic scores for neuroticism, childhood maltreatment, urban upbringing and paternal age) were assessed as modulators of the impact of SLEs on the brain. SLEs were negatively correlated with grey matter volume in the left medial orbitofrontal cortex (mOFC, FWE p = 0.003). This association was present for both, positive and negative, life events. Cognitive-emotional variables, i.e., neuroticism, perceived stress, trait anxiety, intelligence, and current depressive symptoms did not account for the SLE-mOFC association. Further, genetic and environmental risk factors were not correlated with grey matter volume in the left mOFC cluster and did not affect the association between SLEs and left mOFC grey matter volume. The orbitofrontal cortex has been implicated in stress-related psychopathology, particularly major depression in previous studies. We find that SLEs are associated with this area. Important early life risk factors do not interact with current SLEs on brain morphology in healthy subjects., (Copyright © 2021. Published by Elsevier Inc.)

Among the thioredoxin superfamily of proteins, the observation that numerous glutaredoxins bind iron-sulphur (Fe/S) clusters is one of the more recent and major developments concerning their functional properties. Glutaredoxins are present in most organisms. All members of the class II subfamily (including most monothiol glutaredoxins), but also some members of the class I (mostly dithiol glutaredoxins) and class III (land plant-specific monothiol or dithiol glutaredoxins) are Fe/S proteins. In glutaredoxins characterised so far, the [2Fe2S] cluster is coordinated by two active-site cysteine residues and two molecules of non-covalently bound glutathione in homo-dimeric complexes bridged by the cluster. In contrast to dithiol glutaredoxins, monothiol glutaredoxins possess no or very little oxidoreductase activity, but have emerged as important players in cellular iron metabolism. In this review we summarise the recent developments of the most prominent Fe/S glutaredoxins in eukaryotes, the mitochondrial single domain monothiol glutaredoxin 5, the chloroplastic single domain monothiol glutaredoxin S14 and S16, the nuclear/cytosolic multi-domain monothiol glutaredoxin 3, and the mitochondrial/cytosolic dithiol glutaredoxin 2., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Iron-sulfur (Fe/S) proteins are present in virtually all living organisms and are involved in numerous cellular processes such as respiration, photosynthesis, metabolic reactions, nitrogen fixation, radical biochemistry, protein synthesis, antiviral defense, and genome maintenance. Their versatile functions may go back to the proposed role of their Fe/S cofactors in the origin of life as efficient catalysts and electron carriers. More than two decades ago, it was discovered that the in vivo synthesis of cellular Fe/S clusters and their integration into polypeptide chains requires assistance by complex proteinaceous machineries, despite the fact that Fe/S proteins can be assembled chemically in vitro. In prokaryotes, three Fe/S protein biogenesis systems are known; ISC, SUF, and the more specialized NIF. The former two systems have been transferred by endosymbiosis from bacteria to mitochondria and plastids, respectively, of eukaryotes. In their cytosol, eukaryotes use the CIA machinery for the biogenesis of cytosolic and nuclear Fe/S proteins. Despite the structural diversity of the protein constituents of these four machineries, general mechanistic concepts underlie the complex process of Fe/S protein biogenesis. This review provides a comprehensive and comparative overview of the various known biogenesis systems in Biology, and summarizes their common or diverging molecular mechanisms, thereby illustrating both the conservation and diverse adaptions of these four machineries during evolution and under different lifestyles. Knowledge of these fundamental biochemical pathways is not only of basic scientific interest, but is important for the understanding of human 'Fe/S diseases' and can be used in biotechnology., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)