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Aberrant alternative splicing (AS) is a prominent hallmark of cancer. AS can perturb protein-protein interactions (PPIs) by adding or removing interface regions encoded by individual exons. Identifying prognostic exon-exon interactions (EEIs) from PPI interfaces can help discover AS-affected cancer-driving PPIs that can serve as potential drug targets. Here, we assessed the prognostic significance of EEIs across 15 cancer types by integrating RNA-seq data with three-dimensional (3D) structures of protein complexes. By analyzing the resulting EEI network we identified patient-specific perturbed EEIs (i.e., EEIs present in healthy samples but absent from the paired cancer samples or vice versa) that were significantly associated with survival. We provide the first evidence that EEIs can be used as prognostic biomarkers for cancer patient survival. Our findings provide mechanistic insights into AS-affected PPI interfaces. Given the ongoing expansion of available RNA-seq data and the number of 3D structurally-resolved (or confidently predicted) protein complexes, our computational framework will help accelerate the discovery of clinically important cancer-promoting AS events., (© The Author(s) 2024. Published by Oxford University Press on behalf of NAR Genomics and Bioinformatics.)

Poisoning with the organophosphorus nerve agent VX can be life-threatening due to limitations of the standard therapy with atropine and oximes. To date, the underlying pathomechanism of VX affecting the neuromuscular junction has not been fully elucidated structurally. Results of recent studies investigating the effects of VX were obtained from cells of animal origin or immortalized cell lines limiting their translation to humans. To overcome this limitation, motor neurons (MN) of this study were differentiated from in-house feeder- and integration-free-derived human-induced pluripotent stem cells (hiPSC) by application of standardized and antibiotic-free differentiation media with the aim to mimic human embryogenesis as closely as possible. For testing VX sensitivity, MN were initially exposed once to 400 µM, 600 µM, 800 µM, or 1000 µM VX and cultured for 5 days followed by analysis of changes in viability and neurite outgrowth as well as at the gene and protein level using µLC-ESI MS/HR MS, XTT, IncuCyte, qRT-PCR, and Western Blot. For the first time, VX was shown to trigger neuronal cell death and decline in neurite outgrowth in hiPSC-derived MN in a time- and concentration-dependent manner involving the activation of the intrinsic as well as the extrinsic pathway of apoptosis. Consistent with this, MN morphology and neurite network were altered time and concentration-dependently. Thus, MN represent a valuable tool for further investigation of the pathomechanism after VX exposure. These findings might set the course for the development of a promising human neuromuscular test model and patient-specific therapies in the future., (© 2024. The Author(s).)

Motor neurons (MNs) derived from human-induced pluripotent stem cells (hiPSC) hold great potential for the treatment of various motor neurodegenerative diseases as transplantations with a low-risk of rejection are made possible. There are many hiPSC differentiation protocols that pursue to imitate the multistep process of motor neurogenesis in vivo . However, these often apply viral vectors, feeder cells, or antibiotics to generate hiPSC and MNs, limiting their translational potential. In this study, a virus-, feeder-, and antibiotic-free method was used for reprogramming hiPSC, which were maintained in culture medium produced under clinical good manufacturing practice. Differentiation into MNs was performed with standardized, chemically defined, and antibiotic-free culture media. The identity of hiPSC, neuronal progenitors, and mature MNs was continuously verified by the detection of specific markers at the genetic and protein level via qRT-PCR, flow cytometry, Western Blot, and immunofluorescence. MNX1- and ChAT-positive motoneuronal progenitor cells were formed after neural induction via dual-SMAD inhibition and expansion. For maturation, an approach aiming to directly mature these progenitors was compared to an approach that included an additional differentiation step for further specification. Although both approaches generated mature MNs expressing characteristic postmitotic markers, the direct maturation approach appeared to be more efficient. These results provide new insights into the suitability of two standardized differentiation approaches for generating mature MNs, which might pave the way for future clinical applications., Competing Interests: The authors declare that they have no conflict of interest., (Copyright © 2022 Catherine Schaefers et al.)

Introduction: Cigarette smoking represents the main risk factor for cancer development; however, less is known about the effects of active smoking on the outcome of cancer patients receiving systemic treatment, radiation therapy, or surgery., Methods: A systematic review and meta-analysis were conducted searching the PubMed® and Web of Science® Library databases using specific Medical Subject Headings terms. Studies reporting on the prognostic impact of the smoking status concerning survival endpoints in cancer patients treated with systemic treatment, radiation therapy, or surgery were eligible for inclusion., Results: Of 1.380 articles reviewed, 12 reports including data from 31.785 patients with six different cancer types were considered eligible for inclusion. According to the meta-analysis of the overall effect, active smoking during cancer treatment was associated with an impaired overall survival (OS) and cancer-specific mortality (CSM) as compared to former or never smokers (OS: hazard ratio (HR) = 1.61, 95% CI: 1.19-2.17, p = 0.007; CSM: HR = 1.25, 95% CI: 1.01-1.54, p = 0.046). Moreover, smoking cessation led to a similar OS and CSM when comparing former to never smoking patients (OS: HR = 1.01, 95% CI: 0.87-1.18, p = 0.818; CSM: HR = 1.04, 95% CI: 0.91-1.20, p = 0.324)., Conclusion: These results underline active smoking during cancer treatment as an independent adverse prognostic factor, while smoking cessation can result in similar outcomes compared to never smokers. Limitations of the study were a substantial study heterogeneity concerning different cancer entities and variations of treatment modalities., Competing Interests: Conflict of interest statement 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 Ltd. All rights reserved.)

Introduction: Auricular acupuncture at the "relaxation point" and lavender oil aromatherapy can reduce preoperative anxiety associated with increased mortality and morbidity. Data on the effect of combined auricular acupuncture and lavender oil aromatherapy in patients undergoing cardiovascular interventions with the use of local anesthesia or under conscious sedation are sparse. The authors sought to evaluate the efficacy of auricular acupuncture and lavender oil aromatherapy in reducing preinterventional anxiety in cardiovascular patients. Materials and Methods: Data of 80 consecutive patients undergoing diagnostic coronary angiography ( n  = 56) with or without percutaneous coronary intervention ( n  = 9) and right heart catheterization ( n  = 6), transcatheter aortic valve replacement ( n  = 17) and percutaneous mitral valve repair (MitraClip; n  = 2) were analyzed. Patients were prospectively randomized to receive either preinterventional auricular acupuncture and lavender oil ( Lavandula angustifolia ) aromatherapy (verum group, n  = 39) or combined sham auricular acupuncture and placebo oil aromatherapy (placebo group, n  = 41). For the verum group bilateral auricular acupuncture was performed at the "relaxation point." State anxiety and blood pressure were assessed before and at 30 min after acupuncture and presternal oil application. State anxiety was defined as primary outcome measure and assessed using the Spielberger State Anxiety Inventory (STAI) for Adults form Y6. Intervention-specific anxiety was assessed by a 10-point numerical rating scale, and perceived treatment success by a single dichotomous question. Clinical blood pressure was further assessed. Results: After the intervention, the verum group had significantly decreased anxiety on the STAI compared with the placebo group (Δ = -4.18; 95% confidence interval = -8.31 to -0.05; p  = 0.047). Significantly more patients reported subjective treatment success in the verum group (87.2%) than in the placebo group (65.9%, p  = 0.035). No significant differences were observed regarding intervention-specific anxiety and blood pressure between the two groups. No serious adverse events occurred in any group. Conclusions: Combined auricular acupuncture and lavender oil aromatherapy can decrease preinterventional anxiety in cardiovascular patients and requires further investigation. German Clinical Trials Register (registration no. DRKS00023686).

There are currently few suitable test systems for the chronic toxicity testing of aquatic macroinvertebrates under stream conditions. Therefore, a new test system mimicking running water conditions was developed for testing with lotic insects. This system uses small test cages, with 10 of these suspended inside each 25-L container and rotating at 0.1 m/s, to create a water flow for the individual organism inside each cage. To test the performance of the new exposure system, chronic effects (21 d) of the neonicotinoid imidacloprid were investigated with field-collected larvae of the stonefly Protonemura sp. Endpoints were survival, growth, and/or emergence (depending on the developmental stage of the larvae at the start of the exposure). Two experiments conducted 1 yr apart showed good reproducibility: growth 10% effect concentration (EC10) values were 15.3 and 18.5 μg/L and no-observed-effect concentration (NOEC) values were 30.3 and 21.5 μg/L. A third experiment, performed with further-developed larval instars, showed a significant effect of imidacloprid on emergence (with EC10 of 5.97 μg/L and NOEC of 2.89 μg/L) and a significant effect on survival (with median lethal concentration of 44.7 µg/L). The results of the present study show that the newly developed test system provides a suitable approach for toxicity testing with stonefly larvae and potentially for other lotic macroinvertebrate species. Environ Toxicol Chem 2021;40:2229-2239. © 2021 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC., (© 2021 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.)

A dysbalance between effector T cells (Tconv) and regulatory T cells (Tregs) and impaired Treg function can cause autoimmune liver disease. Therefore, it is important to identify molecular mechanisms that control Treg homeostasis. Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1; CD66a) is an immune coreceptor with dichotomous roles in T-cell regulation: its short isoform (CEACAM1S) can activate T cells and induce Tregs, whereas its long isoform (CEACAM1L), containing two intracellular immune receptor tyrosine-based inhibitory motifs, can inhibit activated T-cell function. In the liver, CEACAM1 has antifibrotic effects in models of nonalcoholic steatohepatitis. However, its role in immune-mediated hepatitis is unknown. In the mouse model of concanavalin A-induced CD4 + T-cell-dependent liver injury, liver damage was aggravated and persisted in Ceacam1 -/- mice. Concomitantly, we observed hyperexpansion of Tconv, but reduction of interleukin (IL)-2 production and hepatic forkhead box protein P3 + (Foxp3 + )CD4 + Treg numbers. CEACAM1 -/- CD4 + T cells showed impaired IL-2-mediated signal transducer and activator of transcription 5 (STAT5) phosphorylation, which correlated with a failure of naïve CEACAM1 -/- CD4 + T cells to convert into Tregs in vitro. Furthermore, CEACAM1 -/- Tregs expressed reduced levels of Foxp3, CD25, and B-cell lymphoma 2. Adoptive transfer experiments demonstrated that hepatic Treg expansion and suppressive activity required CEACAM1 expression on both CD4 + T cells and Tregs. We identified predominant CEACAM1S expression on hepatic CD4 + T cells and Tregs from mice with acute liver injury and expression of both isoforms in liver-derived CD4 + T-cell clones from patients with liver injury., Conclusion: Our data suggest that CEACAM1S expression in CD4 + T cells augments IL-2 production and STAT5 phosphorylation leading to enhanced Treg induction and stability, which, ultimately, confers protection from T-cell-mediated liver injury. (Hepatology 2018;68:200-214)., (© 2018 by the American Association for the Study of Liver Diseases.)

A SETAC Pellston Workshop ® "Environmental Hazard and Risk Assessment Approaches for Endocrine-Active Substances (EHRA)" was held in February 2016 in Pensacola, Florida, USA. The primary objective of the workshop was to provide advice, based on current scientific understanding, to regulators and policy makers; the aim being to make considered, informed decisions on whether to select an ecotoxicological hazard- or a risk-based approach for regulating a given endocrine-disrupting substance (EDS) under review. The workshop additionally considered recent developments in the identification of EDS. Case studies were undertaken on 6 endocrine-active substances (EAS-not necessarily proven EDS, but substances known to interact directly with the endocrine system) that are representative of a range of perturbations of the endocrine system and considered to be data rich in relevant information at multiple biological levels of organization for 1 or more ecologically relevant taxa. The substances selected were 17α-ethinylestradiol, perchlorate, propiconazole, 17β-trenbolone, tributyltin, and vinclozolin. The 6 case studies were not comprehensive safety evaluations but provided foundations for clarifying key issues and procedures that should be considered when assessing the ecotoxicological hazards and risks of EAS and EDS. The workshop also highlighted areas of scientific uncertainty, and made specific recommendations for research and methods-development to resolve some of the identified issues. The present paper provides broad guidance for scientists in regulatory authorities, industry, and academia on issues likely to arise during the ecotoxicological hazard and risk assessment of EAS and EDS. The primary conclusion of this paper, and of the SETAC Pellston Workshop on which it is based, is that if data on environmental exposure, effects on sensitive species and life-stages, delayed effects, and effects at low concentrations are robust, initiating environmental risk assessment of EDS is scientifically sound and sufficiently reliable and protective of the environment. In the absence of such data, assessment on the basis of hazard is scientifically justified until such time as relevant new information is available. Integr Environ Assess Manag 2017;13:267-279. © 2017 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals, Inc. on behalf of Society of Environmental Toxicology & Chemistry (SETAC)., (© 2017 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals, Inc. on behalf of Society of Environmental Toxicology & Chemistry (SETAC).)