Antibody-mediated cancer immunotherapy targets inhibitory surface molecules, such as PD1, PD-L1, and CTLA-4, aiming to re-invigorate dysfunctional T cells. We purified and characterized tumor-infiltrating lymphocytes (TILs) and their patient-matched non-tumor counterparts from treatment-naïve NSCLC patient biopsies to evaluate the effect of PD1 expression on the functional and molecular profiles of tumor-resident T cells. We show that PD1+ CD8+ TILs have elevated expression of the transcriptional regulator ID3 and that the cytotoxic potential of CD8 T cells can be improved by knocking down ID3, defining it as a potential regulator of T cell effector function. PD1+ CD4+ memory TILs display transcriptional patterns consistent with both helper and regulator function, but can robustly facilitate B cell activation and expansion. Furthermore, we show that expanding ex vivo-prepared TILs in vitro broadly preserves their functionality with respect to tumor cell killing, B cell help, and TCR repertoire. Although purified PD1+ CD8+ TILs generally maintain an exhausted phenotype upon expansion in vitro, transcriptional analysis reveals a downregulation of markers of T-cell dysfunction, including the co-inhibitory molecules PD1 and CTLA-4 and transcription factors ID3, TOX and TOX2, while genes involved in cell cycle and DNA repair are upregulated. We find reduced expression of WNT signaling components to be a hallmark of PD1+ CD8+ exhausted T cells in vivo and in vitro and demonstrate that restoring WNT signaling, by pharmacological blockade of GSK3β, can improve effector function. These data unveil novel targets for tumor immunotherapy and have promising implications for the development of a personalized TIL-based cell therapy for lung cancer.
Background Since 2021, pharmacists in Poland have been authorised to administer vaccinations against COVID-19, which is of particular significance in the efforts towards preventing the spread of the pandemic. The primary objective of this study was to evaluate the patients’ satisfaction with delivering vaccinations through national vaccination centres. Methods This study was conducted in 2021. The research tool was an anonymous questionnaire distributed to patients after vaccination. The questionnaire was developed specifically for the purpose of the study. Ultimately, 628 patients participated in this study. Results Nearly 97% of the respondents agreed that the administration of vaccinations by pharmacists had been convenient, and pharmacists possessed the relevant skills to provide this service. Almost 90% of the respondents expressed their readiness to be vaccinated by pharmacists again. Nearly all the respondents indicated that pharmacists should also provide other vaccinations. Conclusions Patients in Poland have a positive attitude toward vaccinations administered by pharmacists in national vaccination centres.
Treatment with anaplastic lymphoma kinase (ALK) inhibitors significantly improves outcome for non‐small cell lung cancer (NSCLC) patients with ALK‐rearranged tumors. However, clinical resistance typically develops over time and, in the majority of cases, resistance mechanisms are ALK‐independent. We generated tumor cell cultures from multiple regions of an ALK‐rearranged clinical tumor specimen and deployed functional drug screens to identify modulators of ALK‐inhibitor response. This identified a role for PI3Kβ and EGFR inhibition in sensitizing the response regulating resistance to ALK inhibition. Inhibition of ALK elicited activation of EGFR, and subsequent MAPK and PI3K‐AKT pathway reactivation. Sensitivity to ALK targeting was enhanced by inhibition or knockdown of PI3Kβ. In ALK‐rearranged primary cultures, the combined inhibition of ALK and PI3Kβ prevented the EGFR‐mediated ALK‐inhibitor resistance, and selectively targeted the cancer cells. The combinatorial effect was seen also in the background of TP53 mutations and in epithelial‐to‐mesenchymal transformed cells. In conclusion, combinatorial ALK‐ and PI3Kβ‐inhibitor treatment carries promise as a treatment for ALK‐rearranged NSCLC.
Background Any reliable allergy diagnosis depends on the quality of the testing material. In case of fungal allergy, fungal extracts, commonly used as test solutions, show considerable differences in their allergenicity. A better knowledge about fungal allergen expression would enable the production of diagnostic fungal extracts of higher quality and thus improve the specificity and sensitivity of fungal allergy diagnosis. Objective The aim of our study was to find optimal cultivation conditions for the highest expression of fungal allergens. Methods Fungal species (Alternaria alternata, Ulocladium chartarum, Aspergillus fumigatus, Cladosporium herbarum, and Paecilomyces variotii) were cultivated under different conditions and extracts were prepared from fungal material. To detect the expression of the homologous major allergens Alt a 1 and Ulo c 1 and of different fungal enolases, Western blots with allergen-specific antibodies were carried out. Results Western blots performed with antibodies directed against Alt a 1 and against enolases showed that the expression of fungal allergens is highly species dependent. Even allergens of closely related fungal species and highly conserved, cross-reactive allergens display different expression patterns. Conclusion This study shows the impact of different environmental conditions on the expression of the fungal allergens Alt a 1, Ulo c 1, and different fungal enolases. It further, broadens the knowledge about the expression pattern of the major fungal allergens Alt a 1 and Ulo c 1. Information obtained in this study will help to optimize fungal cultivation to produce diagnostic fungal extracts of high quality and therefore improve diagnosis’ specificity and sensitivity.
Background Early detection of cognitive impairment can slow progression to dementia when using appropriate therapy. For early detection of dementia dual task combining cognitive tasks and walking might be suitable, since individuals with cognitive impairment have shown greater changes in gait specific parameters on dual task test (DT) compared to single task test (ST). This study investigates whether these changes correlate with poorer cognitive function in healthy older adults. Methods In a cross-sectional study 174 healthy adults (66,48±4,26years; 40%female) completed the Cognitive Functions Dementia Test (CFD), with a lower CFD index indicating lower cognitive function. Participants performed ST (walking 20m) and DT (walking 20m & counting backwards), in which step frequency, stride length and gait speed were monitored by Pablo sensors. Cognitive cost (CC) was determined for each gait variable. CC represents a change score between SD & DT and quantifies cognitive demands, with higher CC indicating poorer cognitive function. Pearson correlations and stepwise linear regression adjusted for age and gender were applied to analyze the association between CFD Index (dependent variable) and CC gate variables (predictors) (α = 5%). Results Significant correlations were observed between CFD Index and CC step frequency (p=.014, r=-.187), CC stride length (p=.037, r=-.160) and CC gait speed (p=.002, r=-.232). Since gait variables were intercorrelated (multicollinearity), only gait speed was significant predictor for CFD Index (ß = -.243, p<.001, R2 = .053) in a stepwise adjusted regression model. Conclusions Changes in gait speed might be sensitive enough to indicate differences of cognitive performance among older individuals. Therefore, DT could be included in screening procedures as alert for potential cognitive decline. Key messages
Democracies have been invented in Greece approximately 2500 years ago, as principle of dividing political power. Since then the basic principle has not been developed substantially further, although modern democracies have invented improvements. The objective of this paper is to introduce a new understanding principle into the direction of a technology driven democracy. After a problem focused analysis we use the axiomatic systemic method and natural language logic argumentation for a basic system construction for a new general system of democracy in general by the personalization of nations or states and more specific as an illustration by division of state dimensions into (a) person mapping and (b) territory. The personalized state or nation culminates then in a world-nation-trade-map, for personal implementation of market value oriented nation selection. This leads then, when technologically implemented, to the ability of every person in the world to choose every traded nation to be its future valued member. This further development of democracy means then effectively a phase reversal of world to nation into the human right direction of the individual, by this fulfilling highest ethical standards and giving back the control of the world to each individual and personal responsibility, by making possible the choice of being part of his favourite nation or state. Although this is only a very short sketch of a new kind of higher ordered democracy, we invite people from all over the world to join this vision into the human right direction of peace- and powerful humanity.
The demand to develop and produce eco-friendly alternatives for food packaging is increasing. The huge negative impact that the disposal of so-called "single-use plastics" has on the environment is propelling the market to search for new solutions, and requires initiatives to drive faster responses from the scientific community, the industry, and governmental bodies for the adoption and implementation of new materials. Bioplastics are an alternative group of materials that are partly or entirely produced from renewable sources. Some bioplastics are biodegradable or even compostable under the right conditions. This review presents the different properties of these materials , mechanisms of biodegradation, and their environmental impact, but also presents a holistic overview of the most important bioplastics available in the market and their potential application for food packaging, consumer perception of the bioplastics, regulatory aspects, and future challenges. Citation: Cruz, R.M.S.; Krauter, V.; Krauter, S.; Agriopoulou, S.; Weinrich, R.; Herbes, C.; Scholten, P.B.V.; Uysal-Unalan, I.; Sogut, E.; Kopacic, S.; et al. Bioplastics for Food Packaging: Environmental Impact, Trends and Regulatory Aspects. Foods 2022, 11, 3087. https://
Efficient processing of absolute magnitude and relative order of numbers is key for arithmetic development. This longitudinal study tested 1) whether there is a developmental shift in the contribution of symbolic magnitude and order processing to arithmetic between Grades 1 and 2, and 2) whether the development of symbolic numerical abilities is characterized by reciprocal predictive relations. In two independent samples (UK: N = 195, Austria: N = 161), order processing did not predict early developmental change in arithmetic, but emerged as a predictor in Grade 2. Symbolic magnitude processing in Grade 1 predicted subsequent developmental change in arithmetic, but not later on. Moreover, we observed cross-lagged relations between symbolic magnitude and order processing. Our findings confirm that the contributions of symbolic magnitude and order processing to arithmetic development are interactive and change across the first years of schooling. This may be driven by a developmental shift from procedural strategies to retrieval of arithmetic facts.
Background: Sepsis is often associated with liver dysfunction, which is an indicator of poor outcomes. Specific diagnostic tools that detect hepatic dysfunction in its early stages are scarce. So far, the immune modulatory effects of hemoadsorption with CytoSorb® on liver function are unclear. Method: We assessed the hepatic function by using the dynamic LiMAx® test and biochemical parameters in 21 patients with sepsis or septic shock receiving CytoSorb® in a prospective, observational study. Points of measurement: T1: diagnosis of sepsis or septic shock; T2 and T3: 24 h and 48 h after the start of CytoSorb®; T4: 24 h after termination of CytoSorb®. Results: The hepatic biotransformation capacity measured by LiMAx® was severely impaired in up to 95 % of patients. Despite a rapid shock reversal under CytoSorb®, a significant improvement in LiMAx® values appeared from T3 to T4. This decline and recovery of liver function were not reflected by common parameters of hepatic metabolism that remained mostly within the normal range. Conclusions: Hepatic dysfunction can effectively and safely be diagnosed with LiMAx® in ventilated ICU patients under CytoSorb®. Various static liver parameters are of limited use since they do not adequately reflect hepatic dysfunction and impaired hepatic metabolism.
S8.3 How the fungal cell wall glycan can modulate the immune response?, September 23, 2022, 3:00 PM - 4:30 PM Being an extracellular organelle, the cell wall plays a crucial role in fungal life, by protecting fungal cells from a hostile environments and providing cells with mechanical strength. Exploiting the essentiality of this cell wall, available antifungal drugs target cell wall biosynthesis directly or by altering the fungal cell membrane. However, the emergence of resistance to antifungal drugs, new at risk-cohorts, and drug-drug interaction issue with antifungals demand new/alternative therapeutic strategy. In this regard, we have identified that surfactant protein-D (SP-D; a host humoral immune component) has growth inhibitory activity on Aspergillus fumigatus, a ubiquitous airborne opportunistic pathogen. SP-D, a soluble pattern recognition receptor of the collection family, targets galactosaminogalactan and galactomannan, the cell wall glycans of A. fumigatus hyphae, as the ligands. Hyphae grown in presence of SP-D show a significant decrease in the growth and are hyperbranched compared to control hyphae. SP-D treatment alters surface exposure of hyphal cell wall polysaccharides, thereby modifying hyphal immunoreactivity. SP-D pre-treatment increases the efficacy of the echinocandin and azole classes of antifungals against A. fumigatus. Interestingly, SP-D show hyphal growth inhibitory activity against multi-/pan-azole-resistant isolates of A. fumigatus. Overall, SP-D seems to target A. fumigatus cell wall glycans to execute its fungistatic activity. We are currently investigating the exact mechanism of anti-A. fumigatus activity associated with SP-D.
Industry 4.0 has led to the emergence of various digital technologies. To keep pace with the digital transformation, manufacturing companies must adapt to the new conditions imposed by the business market and increasingly strive to implement so-called smart factories. This paper points out the most common digital technologies related to the management of manufacturing systems. In addition to identification, a systematic literature review was conducted to investigate their impact on increasing productivity. Results indicate that a significant increase in the number of research began in 2015 and is experiencing its greatest expansion in 2018. Important methodologies observed during the literature analysis are a systematic review of the literature for the largest number of theoretically oriented papers, and case studies, practical models for the minority that make up the practice-oriented papers. Also, 68 percent of papers focus more on the theoretical than on the practical implications, and 72 papers indicate a direct link between productivity and digital technologies used in the digital transformation and implementation of smart factories.
Pathogen inactivation techniques for blood products have been implemented to optimize clinically safe blood components supply. The INTERCEPT system uses amotosalen together with ultraviolet light wavelength A (UVA) irradiation. Irradiation-induced inactivation of nucleic acids may actually be accompanied by modifications of chemically reactive polyunsaturated fatty acids known to be important mediators of platelet functions. Thus, here, we investigated eicosanoids and the related fatty acids released upon treatment and during storage of platelet concentrates for 7 days, complemented by the analysis of functional and metabolic consequences of these treatments. Metabolic and functional issues like glucose consumption, lactate formation, platelet aggregation, and clot firmness hardly differed between the two treatment groups. In contrast to gamma irradiation, here, we demonstrated that INTERCEPT treatment immediately caused new formation of trans-arachidonic acid isoforms, while 11-hydroxyeicosatetraenoic acid (11-HETE) and 15-HETE were increased and two hydroperoxyoctadecadienoic acid (HpODE) isoforms decreased. During further storage, these alterations remained stable, while the release of 12-lipoxygenase (12-LOX) products such as 12-HETE and 12-hydroxyeicosapentaenoic acid (12-HEPE) was further attenuated. In vitro synthesis of trans-arachidonic acid isoforms suggested that thiol radicals formed by UVA treatment may be responsible for the INTERCEPT-specific effects observed in platelet concentrates. It is reasonable to assume that UVA-induced molecules may have specific biological effects which need to be further investigated.
In this paper, we develop the basic idea that universal growth processes, that are part of evolutionary processes, and especially concurrent are an ensemble of double contingent part processes. These perform in quasi synchronicity a lock stepping, that we might call a sigmoidal growth curve with no time, or as long as the terminus time can be thought existing, with a subcritical lockstep size called time. This property of logistic curve dependency is subsequently responsible for the emerging lockstepping property of subcritical time window growth processes that we call in quantum theory quantum jumps. The analysis method of this paper is to define axioms for the analysed problem in combination with an investigation of the properties of singularities for the logistic curve. The findings are a set of six axioms that can be used as part of more complex existing growth related systems and theories or as a general heuristics for description and analysis of interdisciplinary systems. We conclude from this process and the findings that future research programs may overcome the Heisenberg uncertainty relation by determining the critical time steps, inferring towards a sigmoidal growth process. Furthermore as the lockstepping principle is universal and linked to any growth process, this allows for general lockstepping design on all size scales of growth processes and to get a possibly deeper insight or accuracy by relating to the critical room-time-event step.KeywordsSystems theoryOrgiton theorySelf-organisational theoryCybernetics of second orderGrowthQuantum stepLockstepping principle
In this paper, we introduce a software-based heuristic approach for scoring the grade of digitalization for business processes modeled in BPMN: The DigiTrack tool. Our tool enables the measurement of the digitalization maturity of a business process by calculating scores for each task. This new method is shown though a case study with a simplified check in process at airport.
Due to the new remote working conditions driven by the consequences of the Covid-19 pandemic, we extend our previous work on sentiment-enabled business process modeling by including crowdsourcing capabilities with a web interface: SentiProMoWeb. These capabilities enable us to perform sentiment-driven business process re-design method with remote stakeholders from different locations. SentiProMoWeb implements an enterprise social information system to capture the feedback from stakeholders in a crowdsourced manner. We demonstrate the crowdsourcing capabilities of our approach with an illustrative scenario by using our SentiProMoWeb software.
The importance of patient empowerment among people with intellectual disabilities (ID) is steadily growing, yet multiple health and health literacy challenges still make this population more vulnerable to health disparities. Inadequate access to essential health and other basic services and the lack of involvement in health and educational research are some of the most crucial factors contributing to this inequality. A greater effort must be made to include people with ID in health literacy and communication research, preliminary focusing on language, including pictorial language. This community case study aimed to document the experiences of answering a pilot questionnaire to evaluate the problems of people with mild to moderate ID, 6A00.0 and 6A00.1 according to ICD-11. Our results show that most patients acquire health information from their physician or a medical professional. In preparing appropriate questionnaires, special education teachers can give valuable insight. However, participants were easily distracted and needed support in focusing on the questionnaire. Easy-to-read language, a simple format, big fonts and the presence of confidential caretakers are needed. This indicates, that semi-structured interviews with a trained interviewer might be most suitable for measuring the knowledge transfer of people with ID. The results of this case study highlight the need to develop an appropriate questionnaire and emphasize the need for a continued dialogue between people with ID and healthcare providers.
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