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Evaluation of HER4 as a potential predictive biomarker for the treatment of estrogen receptor-positive breast cancer with tamoxifen and abemaciclib – preclinical analyses in-vitro and in-vivo
Full text linkIn this study, the impact of HER4 expression in hormone receptor-sensitive breast cancer cells on tumor growth and therapy response was systematically investigated. For this purpose, stable HER4 knockout cell lines were generated using CRISPR Cas9 (MCF-7, T-47D and ZR-75-1) and systematic comparative treatments with tamoxifen, abemaciclib and AMG 232, among others, were performed. Furthermore, preclinical in vivo treatment studies were done on a MCF-7 based humanized tumor mouse model with and without HER4 expression
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Full text linkUnconventional Josephson supercurrent diode effect induced by chiral spin-orbit coupling
Full text linkChiral materials lacking mirror symmetry can exhibit unconventional spin-orbit fields, including fully momentum-aligned radial Rashba fields as seen in twisted van der Waals homobilayers. We theoretically study Cooper-pair transfer in superconductor/ferromagnet/superconductor Josephson junctions with crossed (tangential and radial) interfacial Rashba fields. We find that their interplay leads to what we call the unconventional supercurrent diode effect (SDE), where supercurrent rectification occurs even with collinear (with respect to the current) barrier magnetization, not possible for conventional spin-orbit fields. This SDE, distinct from conventional Rashba-induced effects on Cooper-pair momenta, arises from the spin precession in the magnetic barrier. We propose it as a sensitive probe of chiral spin textures
Was Schwarz-rot verspricht (5): Bezahlbar, verfügbar, umweltverträglich - Der Koalitionsvertrag verspricht eine moderate Neuausrichtung der Wohnungspolitik
No full textSubstrate Polarization Alters the Jahn-Teller Effect in a Single Molecule
Full text linkCharge-state transitions of a single Cu-phthalocyanine molecule adsorbed on an insulating layer of NaCl on Cu(111) are probed by means of alternate charging scanning tunneling microscopy. Real-space imaging of the electronic transitions reveals the Jahn-Teller distortion occurring upon formation of the first and second anionic charge states. The experimental findings are rationalized by a theoretical many-body model that highlights the crucial role played by the substrate. The latter enhances and stabilizes the intrinsic Jahn-Teller distortion of the negatively charged molecule hosting a degenerate pair of single-particle frontier orbitals. Consequently, two excess electrons are found to occupy, in the ground state, the same localized orbital, despite a larger Coulomb repulsion than the one for the competing delocalized electronic configuration. Control over the charging sequence by varying the applied bias voltage is also predicted
Usual walking Pace and risk of 28 cancers– results from the UK biobank
Full text linkBackground
Usual walking pace represents a practical indicator of overall health. However, its association with cancer development remains unexplored. We investigated the relation between self-reported walking pace and cancer risk.
Methods
Using baseline UK Biobank data from 2006 to 2010, excluding the first two years of follow-up to reduce reverse causation, we employed multivariable Cox regression to assess the association between walking pace (slow, steady average, brisk) and risk of 28 cancer types, accounting for overall physical activity and walking volume.
Results
After a median follow-up of 10.9 years (interquartile range 10.1–11.8), 8.3% of 334,924 participants received a cancer diagnosis. Brisk compared to slow walking pace was associated with multivariable-adjusted lower risks of five cancers, including anal (hazard ratio 0.30; 95% confidence interval: 0.14–0.63), hepatocellular carcinoma (0.39; 0.23–0.66), small intestine (0.46; 0.24–0.87), thyroid (0.50; 0.29–0.86), and lung cancer (0.60; 0.51–0.70). Our findings were consistent across various sensitivity analyses, which assessed sex and age differences, residual confounding, and reverse causation.
Conclusions
Self-reported walking pace was inversely associated with risk of five cancer types, even when accounting for overall physical activity and walking volume. Adopting a brisk walking pace may represent a pragmatic target for public health interventions to decrease cancer risk, particularly in circumstances where increases in walking volume or frequency prove impractical
Long-term outcomes of out-of-center veno-arterial ECMO cannulation for cardiopulmonary failure: investigation of prognostic parameters for a decision support tool – a 16-year retrospective study
Full text linkBackground
Veno-arterial extracorporeal membrane oxygenation (VA ECMO) has served as a crucial intervention for critically ill patients with persistent cardiopulmonary failure. A standardized approach improves VA ECMO outcomes, which is why ECMO is currently limited to specialized centers. However, transferring critically ill patients to these ECMO centers is not without risk. Portable ECMO devices allow implantation in out-of-center settings prior to transportation. Despite efforts to standardize decision-making, significant variability remains, particularly in out-of-center (OoC) settings with limited data. Due to persistently high mortality, accurate indications are needed to optimize outcomes. This study aims to identify key factors associated with favorable outcomes in OoC VA ECMO and to develop practical decision-making tools for clinicians in these settings.
Methods
We retrospectively investigated the outcomes of VA ECMO implantation in out-of-center settings between 2006 and 2022 at our institution. Parameters assessed prior to VA ECMO implantation, including organ failure count, mean arterial pressure (MAP), and laboratory data, were analyzed. Follow-up data were collected to evaluate functional (Eastern Cooperative Oncology Group [ECOG] performance status) and neurological (cerebral performance category score [CPC]) (outcomes. Statistical analyses were performed using non-parametric methods and SHAP importance analysis.
Results
A total of 56.5% (195 of 345 patients) who underwent VA ECMO implantation in OoC survived, and 43.8% had a favorable neurological outcome (CPC 1). 37.6% of patients had good functional outcomes (ECOG 0–1). Patients with a MAP > 54 mmHg had better long-term functional outcomes, and those with a MAP > 64 mmHg had better mid-term neurological outcomes. Poor outcomes were associated with reduced coagulation activity and increased thrombogenicity. Renal and multi-organ failure prior to VA ECMO implantation were associated with poor neurological and functional outcomes.
Conclusions
Through importance analyses, we identified key and secondary factors associated with favorable outcomes in OoC VA ECMO. The extent and severity of organ failure prior to VA ECMO implantation are crucial in determining outcomes. Hemodynamic status, as reflected by MAP, along with organ failure prior to VA-ECMO implantation, significantly influences neurological and functional outcomes. Patients with better hemodynamic stability and coagulation profiles had significantly improved chances of survival with favorable neurological and functional outcomes
MCSP+ metastasis founder cells activate immunosuppression early in human melanoma metastatic colonization
Full text linkTo investigate the early, poorly understood events driving metastatic progression, we searched for the earliest detectable disseminated cancer cells (DCCs), also often referred to as disseminated tumor cells (DTCs), in sentinel lymph node (SLN) biopsies of 492 patients with stage I–III melanoma. Using micromanipulator-assisted isolation of rare DCCs, single-cell mRNA and DNA sequencing, codetection by indexing immunofluorescence imaging and survival analysis, we identified melanoma-associated chondroitin sulfate proteoglycan (MCSP)+ melanoma cells as metastasis founder cells (MFCs). We found that DCCs entering SLNs predominantly exhibited a transitory phenotype that, upon interferon-γ exposure triggered by CD8 T cells, dedifferentiated into a neural-crest-like phenotype. This was accompanied by increased production of small extracellular vesicles (sEVs) carrying the immunomodulatory proteins CD155 and CD276 but rarely programmed cell death protein 1 ligand 1. The sEVs suppressed CD8 T cell proliferation and function, facilitating colony formation. Targeting MCSP+ MFCs or their immune escape mechanisms could be key to curing melanoma early by preventing manifestation of metastasis
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