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Carbohydrate markers of immature cells during prenatal human development can be aberrantly expressed in cancers and deserve evaluation as immune targets. A candidate target in Ewing sarcoma is the globo-series ganglioside stage-specific embryonic antigen-4 (SSEA-4). We detected SSEA-4 expression on the cell surface of all of 14 EwS cell lines and in 21 of 31 (68%) primary EwS tumor biopsies. Among paired subpopulations of tumor cells with low versus high SSEA-4 expression, SSEA-4 high expression was significantly and consistently associated with functional characteristics of tumor aggressiveness, including higher cell proliferation, colony formation, chemoresistance and propensity to migrate. SSEA-4 low versus SSEA-4 high expression was not related to expression levels of the EWSR1-FLI1 fusion transcript or markers of epithelial/mesenchymal plasticity. SSEA-4 low cells selected from bulk populations regained higher SSEA-4 expression in vitro and during in vivo tumor growth in a murine xenograft model. T cells engineered to express SSEA-4-specific chimeric antigen receptors (CARs) specifically interacted with SSEA-4 positive EwS cells and exerted effective antigen-specific tumor cell lysis in vitro. In conclusion, with its stable expression and functional significance in EwS, SSEA-4 is an attractive therapeutic immune target in this cancer that deserves further evaluation for clinical translation., (© 2024. The Author(s).)

Aims: We investigated the implementation of new guidelines in ST-segment elevation myocardial infarction (STEMI) patients in a large real-world patient population in the metropolitan area of Berlin (Germany) over a 20-year period., Methods: From January 2000 to December 2019, a total of 25 792 patients were admitted with STEMI to one of the 34 member hospitals of the Berlin-Brandenburg Myocardial Infarction Registry (B2HIR) and were stratified for sex and age < 75 and ≥ 75 years., Results: The median age of women was 72 years (IQR 61-81) compared to 61 years in men (IQR 51-71). PCI treatment as a standard of care was implemented in men earlier than in women across all age groups. It took two years from the 2017 class IA ESC STEMI guideline recommendation to prefer the radial access route rather than femoral until > 60% of patients were treated accordingly. In 2019, less than 60% of elderly women were treated via a radial access. While the majority of patients < 75 years already received ticagrelor or prasugrel as antiplatelet agent in the year of the class IA ESC STEMI guideline recommendation in 2012, men ≥ 75 years lagged two years and women ≥ 75 three years behind. Amongst the elderly, in-hospital mortality was 22.6% (737) for women and 17.3% (523) for men (p < 0.001). In patients < 75 years fatal outcome was less likely with 7.2% (305) in women and 5.8% (833) in men (p < 0.001). After adjustment for confounding variables, female sex was an independent predictor of in-hospital mortality in patients ≥ 75 years (OR 1.37, 95% CI 1.12-1.68, p = 0.002), but not in patients < 75 years (p = 0.076)., Conclusion: In-hospital mortality differs considerably by age and sex and remains highest in elderly patients and in particular in elderly females. In these patient groups, guideline recommended therapies were implemented with a significant delay., (© 2023. The Author(s).)

Background: It is under discussion whether female patients with non-ST-elevation myocardial infarction (NSTEMI) benefit from routine invasive treatment strategy. We accordingly applied our data from the Berlin Myocardial Infarction Registry (BMIR) to analyze the association between early percutaneous coronary intervention (PCI) and hospital mortality in NSTEMI patients., Methods: Data prospectively collected in the BMIR between 2004 and 2008 from 2808 patients (m=1820/w=988) directly admitted to hospitals with 24-h PCI facilities were included in the analysis. After adjustment for confounding variables, we compared in-hospital mortality for patients of both sexes with vs. without early PCI., Results: Women with NSTEMI were, on average, 7years older than men and demonstrated significantly more comorbidities. A GPIIb/IIIa antagonist was applied in women less often than in men (31.4% vs. 38.4%, p=0.001), and an early PCI was also performed less often in women than in men (64.0% vs. 76.2%, p<0.001). In-hospital mortality was higher in women than in men (5.4% vs. 3.6%, p=0.027). In female patients with NSTEMI, after adjustment for differences in patients' characteristics, hospital mortality did not differ between those treated with early PCI and those managed conservatively (OR: 1.24, 95% CI 0.53-2.91). In contrast, hospital mortality in male patients was lower in those treated with an early PCI (OR: 0.41, 95% CI 0.21-0.78)., Conclusion: In our clinical registry, early PCI in female patients with NSTEMI was not associated with lower hospital mortality. Further randomized-controlled trials are needed to better understand which women may benefit from early invasive therapy, and under which conditions such benefits are possible., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

In order to find new peptide inhibitors for voltage-dependent potassium (Kv) channels, we examined the effects of venom from Theraphosa leblondi on Kv channel-mediated currents with the whole-cell patch-clamp technique. Both A-type currents in cultured hippocampal neurons and A-type currents recorded from HEK 293 cells transiently expressing recombinant Kv4.2 channels were selectively inhibited by T. leblondi venom. No venom activity was observed on recombinant Kv1.3, Kv1.4, Kv2.1 or Kv3.4 channels. We purified and sequenced three novel homologous peptides from this venom, which are related to previously identified Kv4 channel-specific peptide inhibitors and were named T. leblondi toxin (TLTx) 1, 2 and 3. The mode of action of TLTx1 on recombinant Kv4.2 channels was studied in more detail. TLTx1 inhibited Kv4.2-mediated currents with an IC50 of approximately 200 nM, and macroscopic current inactivation was slowed in the presence of TLTx1. Notably, TLTx1 also caused a shallower voltage dependence of Kv4.2 peak conductance and a shift of the activation midpoint to more positive potentials (DeltaV1/2 = +35 mV). TLTx1 caused a noticable slowing of Kv4.2 activation kinetics, and Kv4.2 deactivation kinetics were accelerated by TLTx1 as infered from Rb+ tail current measurements. Chimeric Kv2.1(4.2L3-4) channels, in which the linker region between S3 and S4 of the TLTx1-insensitive Kv2.1 channel was replaced by the corresponding Kv4.2 domain, were sensitive to TLTx1. Apparently, TLTx1 can act as a gating modifier of Kv4.2 channels., (Copyright 2004 Elsevier Ltd.)