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The high degree of thickness uniformity of the extruded polymer tube is one of its most important geometric features. A factor that has a direct impact on this is the die, especially the mandrel. Correctly designed, it ensures, among other things, a high degree of homogenization of the processed polymer and uniform distribution of the volume flow rate along the circumference, which has a key impact on the quality of the extruded film. Due to the number of variables affecting the flow of polymer through the die, a number of simulations are required to find the optimal design. This paper presents the validation of a tool based on Chris Rauwendaal's mathematical model for performing fast numerical calculations to determine the geometric parameters of the spiral mandrel to ensure the thickness of the extruded film is as uniform as possible. Simulations were carried out based on 13 geometric and processing variables, from which 3 key geometric parameters were selected. In order to select a set of parameters that ensure the optimal distribution of polymer flow at the exit, a series of simulations were carried out for several levels of values of the aforementioned key parameters. The obtained set of geometric parameters was used to manufacture a spiral mandrel, which was used in the process of validation of the computer aided engineering tool by the experimental method. [ABSTRACT FROM AUTHOR]

Topoisomerase I (TOP1) Inhibitors constitute an emerging payload class to engineer antibody-drug conjugates (ADC) as next-generation biopharmaceutical for cancer treatment. Existing ADCs are using camptothecin payloads with lower potency and suffer from limited stability in circulation. With this study, we introduce a novel camptothecin-based linker-payload platform based on the highly potent camptothecin derivative exatecan. First, we describe general challenges that arise from the hydrophobic combination of exatecan and established dipeptidyl p-aminobenzyl-carbamate (PAB) cleavage sites such as reduced antibody conjugation yields and ADC aggregation. After evaluating several linker-payload structures, we identified ethynyl-phosphonamidates in combination with a discrete PEG24 chain to compensate for the hydrophobic PAB-exatecan moiety. Furthermore, we demonstrate that the identified linker-payload structure enables the construction of highly loaded DAR8 ADCs with excellent solubility properties. Head-to-head comparison with Enhertu, an approved camptothecin-based ADC, revealed improved target-mediated killing of tumor cells, excellent bystander killing, drastically improved linker stability in vitro and in vivo and superior in vivo efficacy over four tested dose levels in a xenograft model. Moreover, we show that ADCs based on the novel exatecan linker-payload platform exhibit antibody-like pharmacokinetic properties, even when the ADCs are highly loaded with eight drug molecules per antibody. This ADC platform constitutes a new and general solution to deliver TOP1 inhibitors with highest efficiency to the site of the tumor, independent of the antibody and its target, and is thereby broadly applicable to various cancer indications., (©2023 The Authors; Published by the American Association for Cancer Research.)

Introduction: Lactate levels have been recognized as a reliable tool for monitoring critically ill patients requiring venoarterial extracorporeal membrane oxygenation (VA ECMO) or venovenous extracorporeal membrane oxygenation (VV ECMO) but the reasons behind the overproduction of lactate are different and the influance for survival remains controversial. We analyzed the lactate values and lactate clearance in adult patients in these two forms of extracorporeal support., Methods: Patient demographics, ECMO duration, 30-day mortality, lactate values and lactate clearance at 24, 48 and 72 h from ECMO initiation of patients supported with VV and VA ECMO at Silesian Centre for Heart Deasese, between January 2011 and April 2020 were retrospectively analyzed. The changes in lactate levels were analyzed using the non-parametric U Mann-Whitney tests and Chi-square test. The ROC curves were draw and the area under the curve was calculated., Results: The study comprised 91 adult patients, Mortality in the first 30 days from initiation of VV and VA ECMO was 39% and 66%, respectively. Lactate levels were significantly higher in non-survivors that received VV and VA ECMO ( p < .001), while lactate clearance was similar ( p = .256 and p = 1.000, respectively). Survival curves for patients with elevated (>2.0 mmol/L) vs normal (≤2.0 mmol/L) lactate levels at 72 h were significantly different for VV ECMO ( p = .007) and VA ECMO ( p = .037) but in both groups of ECMO, lactate levels above 2.0 mmol/L at 72 h from ECMO initiation predicted 30 day-mortality., Conclusion: This results emphasized the importance of lactate levels below 2.0 mmol/L at 72 h from both VV and VA ECMO initiation., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: This single-centre study investigated factors influencing death in coronavirus disease 2019 (COVID-19) patients treated in an intensive care unit (ICU)., Methods: Data of 113 consecutive patients with a severe form of COVID-19 infection, who completed their ICU stay in a large COVID-19-dedicated hospital in the Silesian Region of Poland during one year of the pandemic (between 10 March, 2020 and 10 March, 2021), were reviewed. Comprehensive comparison of all available ICU pre-admission, admission and treatment variables was performed. Variables that independently influenced ICU death were identified., Results: ICU mortality in the whole group was 64.6%. Mean age was higher in non-survivors (64.6 ± 9.5 vs. 60.0 ± 12.8 years, P = 0.036), but the distribution of sex and body mass index was similar in both groups. Non-survivors had a marginally higher mean Charlson Comorbidity Index (5.9 ± 3.6 vs. 4.5 ± 4.1 points, P = 0.063), and significantly higher mean Clinical Frailty Score (4.8 ± 1.5 vs. 3.9 ± 1.4 points, P = 0.004), admission APACHE II score (22.9 ± 7.9 vs. 19.1 ± 7.8 points, P = 0.017) and SAPS II score (62.1 ± 18.1 vs. 54.0 ± 16.7 points, P = 0.023). Factors that independently influenced ICU death were limited to: admission total protein 2.0 ng mL-1 (OR = 11.3, P = 0.026) and lactate level > 2.0 mmol L-1 (OR = 4.2, P = 0.003) as well as Clinical Frailty Score ≥ 5 points (OR = 3.1, P = 0.021)., Conclusions: The presence of low total protein, frailty and increased procalcitonin and lactate levels at ICU admission are associated with ICU death in patients with severe COVID-19 infection.

BACKGROUND Data on the outcomes of patients with coronavirus disease 2019 (COVID-19) requiring Intensive Care Unit (ICU) care in Poland are limited. There are no data on critically ill patients with COVID-19 who did not meet criteria for ICU admission. MATERIAL AND METHODS We analyzed patients admitted to the ICU and those ineligible for ICU admission in a large COVID-19-dedicated hospital, during the first 3 months of the pandemic in Poland. Data from 67 patients considered for ICU admissions due to COVID-19 infection, treated between 10 March and 10 June 2020, were reviewed. Following exclusions, data on 32 patients admitted to the ICU and 21 patients ineligible for ICU admission were analyzed. RESULTS In 38% of analyzed patients, symptoms of COVID-19 infection occurred during a hospital stay for an unrelated medical issue. The mean age of ICU patients was 62.4 (10.4) years, and the majority of patients were male (69%), with at least one comorbidity (88%). The mean admission APACHE II and SAPS II scores were 20.1 (8.1) points and 51.2 (15.3) points, respectively. The Charlson Comorbidity Index and Clinical Frailty Scale were lower in ICU patients compared with those disqualified: 5.9 (4.3) vs. 9.1 (3.5) points, P=0.01, and 4.7 (1.7) vs. 6.9 (1.2) points, P<0.01, respectively. All ICU patients required intubation and mechanical ventilation. ICU mortality was 67%. Hospital mortality among patients admitted to the ICU and those who were disqualified was 70% and 79%, respectively. CONCLUSIONS Patients with COVID-19 requiring ICU admission in our studied population were frail and had significant comorbidities. The outcomes in this group were poor and did not seem to be influenced by ICU admission.

The formation of a zygote via the fusion of an egg and sperm cell and its subsequent asymmetric division herald the start of the plant's life cycle. Zygotic genome activation (ZGA) is thought to occur gradually, with the initial steps of zygote and embryo development being primarily maternally controlled, and subsequent steps being governed by the zygotic genome. Here, using maize ( Zea mays ) as a model plant system, we determined the timing of zygote development and generated RNA-seq transcriptome profiles of gametes, zygotes, and apical and basal daughter cells. ZGA occurs shortly after fertilization and involves ∼10% of the genome being activated in a highly dynamic pattern. In particular, genes encoding transcriptional regulators of various families are activated shortly after fertilization. Further analyses suggested that chromatin assembly is strongly modified after fertilization, that the egg cell is primed to activate the translational machinery, and that hormones likely play a minor role in the initial steps of early embryo development in maize. Our findings provide important insights into gamete and zygote activity in plants, and our RNA-seq transcriptome profiles represent a comprehensive, unique RNA-seq data set that can be used by the research community., (© 2017 American Society of Plant Biologists. All rights reserved.)

The EGG CELL1 (EC1) gene family of Arabidopsis (Arabidopsis thaliana) comprises five members that are specifically expressed in the egg cell and redundantly control gamete fusion during double fertilization. We investigated the activity of all five EC1 promoters in promoter-deletion studies and identified SUF4 (SUPPRESSOR OF FRIGIDA4), a C 2 H 2 transcription factor, as a direct regulator of the EC1 gene expression. In particular, we demonstrated that SUF4 binds to all five Arabidopsis EC1 promoters, thus regulating their expression. The down-regulation of SUF4 in homozygous suf4-1 ovules results in reduced EC1 expression and delayed sperm fusion, which can be rescued by expressing SUF4-β-glucuronidase under the control of the SUF4 promoter. To identify more gene products able to regulate EC1 expression together with SUF4, we performed coexpression studies that led to the identification of MOM1 (MORPHEUS' MOLECULE1), a component of a silencing mechanism that is independent of DNA methylation marks. In mom1-3 ovules, both SUF4 and EC1 genes are down-regulated, and EC1 genes show higher levels of histone 3 lysine-9 acetylation, suggesting that MOM1 contributes to the regulation of SUF4 and EC1 gene expression., (© 2017 American Society of Plant Biologists. All Rights Reserved.)

During the angiosperm (flowering-plant) life cycle, double fertilization represents the hallmark between diploid and haploid generations [1]. The success of double fertilization largely depends on compatible communication between the male gametophyte (pollen tube) and the maternal tissues of the flower, culminating in precise pollen tube guidance to the female gametophyte (embryo sac) and its rupture to release sperm cells. Several important factors involved in the pollen tube reception have been identified recently [2-6], but the underlying signaling pathways are far from being understood. Here, we report that a group of female-specific small proteins, early nodulin-like proteins (ENODLs, or ENs), are required for pollen tube reception. ENs are featured with a plastocyanin-like (PCNL) domain, an arabinogalactan (AG) glycomodule, and a predicted glycosylphosphatidylinositol (GPI) anchor motif. We show that ENs are asymmetrically distributed at the plasma membrane of the synergid cells and accumulate at the filiform apparatus, where arriving pollen tubes communicate with the embryo sac. EN14 strongly and specifically interacts with the extracellular domain of the receptor-like kinase FERONIA, localized at the synergid cell surface and known to critically control pollen tube reception [6]. Wild-type pollen tubes failed to arrest growth and to rupture after entering the ovules of quintuple loss-of-function EN mutants, indicating a central role of ENs in male-female communication and pollen tube reception. Moreover, overexpression of EN15 by the endogenous promoter caused disturbed pollen tube guidance and reduced fertility. These data suggest that female-derived GPI-anchored ENODLs play an essential role in male-female communication and fertilization., (Copyright © 2016 Elsevier Ltd. All rights reserved.)