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Smart dendrimer nanogels boost mRNA-based cancer therapy via synergistic glycolysis inhibition and immune activation
No full textCancer mRNA vaccine has emerged as a promising immunotherapy approach. However, development of functional vehicles for safe and efficient mRNA delivery into immune cells (e.g., dendritic cells, DCs) remains to be challenging, and most of the mRNA-based vaccines just act on immune cells for improved anticancer immunity without additional input to tackle cancer cells, ultimately limiting the anticancer efficacy. Herein, we report the development of pH-responsive dual-action dendrimer nanogels (DNGs) to deliver gp100 mRNA as a potential nanovaccine. Mannose-conjugated generation 3 poly(amidoamine) dendrimers were crosslinked through dual functional polyethylene glycol with both ends of aldehyde groups to form pH-responsive DNGs. The DNGs with a size of 45.7 nm show excellent colloidal stability and cytocompatibility and allow dual-actions for DC-targeted mRNA delivery and cancer cell glycolysis inhibition. In a subcutaneous mouse melanoma model, the DNG/mRNA vaccine exerted glycolytic inhibition effect and triggered robust antitumor immune responses to suppress the tumor growth, especially in combination with anti-PD-L1 antibody-mediated immune checkpoint blockade. Meanwhile, the local vaccination of the vaccine enabled effective tumor occurrence prevention. Such a DNGbased mRNA vaccine with dual actions on both DCs and cancer cells may be applied for improved immunotherapy of other cancer types
Determining fair medicines prices. What do citizens think?
No full textObjectives: There is a lively debate about the fair price of medicines, mainly led by experts. Little is known about the public's opinion, although in most health systems with universal coverage medicines are procured by public money through payers or governments. This study assesses public opinion about fair medicine prices, the criteria that define fairness, and the policy implications. Methods: A population survey amongst 1000 people across the Swiss population in all 3 language regions has been conducted between September and October 2024. Results: Access for all (986), transparency of the cost structure (914) and a price reflecting the costs of a medicine (911) have ranked as the most relevant factors for a fair price of medicine. In contrast, the additional benefit of a new therapy is considered less important as a criterion. A large majority supports pharmaceutical companies making a profit. Asked how to align the different objectives, the majority supports the statement that medicines prices should be the result of a fair process (568), followed by the statement that governments should control profits (431). Conclusions: This study suggests that citizens consider the balance between patient access and investment in research and development as the most relevant for a fair price of a medicine. When access and cost create a dilemma, citizens favour fair procedures. In contrast to expert opinions, the additional benefit of a medicine seems to be a less relevant criterion. The survey results indicate a nuanced and pragmatic approach to fairness, considering societal, scientific, and economic factors
Nuances in the memory undermining effects of EMDR and imagery rescripting
No full textWe reviewed the evidence on the memory undermining ef(EMDR) and imagery rescripting. Both therapies appear to undermine memory quality by making memories less vivid and emotionally-negative. Also, while eye movements used in EMDR seem to increase spontaneous false memories, they do not increase the susceptibility to suggestion. Inconsistent findings have emerged on the effects of imagery rescripting on false memory generation. Furthermore, a substantial number of clinicians who use EMDR strongly believe in the notion of repressed memory and EMDR has been associated with the occurrence of recovered memories. The belief in repressed memory might encourage suggestive therapeutic techniques, thereby increasing the risk of false memory creation. Overall, nuance is required on potential memory undermining effects of EMDR and imagery rescripting
Signals of excellence or indifference? Dutch employers' perceptions of liberal arts bachelor's degrees
No full textThis paper investigates how Dutch employers perceive university college bachelor's degrees. These programmes were introduced as part of an excellence initiative in Dutch higher education, offering broad, interdisciplinary, and selective undergraduate degrees in liberal arts and sciences. By conducting semi-structured interviews with 20 recruiters based in the Netherlands, the study explores the graduate job selection process, examining the relative importance of different factors in employers' decisions and the signals sent by university college degrees to employers. The findings reveal that the signalling effect associated with university college degrees is either entirely absent or neutral. Dutch employers demonstrate limited familiarity with university colleges and tend to assign less significance to the bachelor's degree when it is accompanied by a master's degree in a relevant field. This underscores the challenge of integrating innovative educational models into the traditionally egalitarian research university segment of Dutch higher education
Spectrum of Interstitial Cell of Cajal Deficits in Chronic Gastroduodenal Disorders:Systematic Review and Meta-Analysis
No full textBackground and Aims:Chronic neurogastroduodenal disorders are heterogeneous and thought to lie on a spectrum of disease encompassing both sensory and neuromuscular pathologies. Abnormalities of interstitial cells of Cajal (ICC), a subset of which generate pacemaker signals and subsequently motility, have been implicated in their pathophysiology. We systematically reviewed the literature to pool ICC deficits observed in chronic neurogastroduodenal disorders.Methods:Studies quantifying gastric ICC from the corpus or antrum, in adult patients with gastroparesis, functional dyspepsia (FD) or chronic nausea and vomiting syndromes (CNVS) were analysed (PROSPERO: CRD42024613226). MEDLINE, Embase and CENTRAL databases were searched systematically. Random effects meta-analyses were used to compare ICC counts by disorder group with subgroup analysis by quantification methodology.Results:2158 studies were screened and 22 included. Comparative studies (n=12) showed patients with chronic neurogastroduodenal disorders (n=167 with gastroparesis, n=19 with FD±CNVS) had lower ICC counts than non-diabetic controls (n=130); standardised mean difference -1.58, 95% confidence interval -2.09 to -1.07, p<0.0001, with more severe deficits in gastroparesis compared to FD±CNVS (SMD -0.44, p=0.048). A spectrum of ICC deficits was evident in a subgroup of studies using gold-standard methods with c-KIT antibody and DAPI-stained nuclei confirmation (7 studies, 246 patients: mean ICC counts 2.29 in gastroparesis vs 3.49 in FD±CNVS, and 5.27 in controls; p<0.001 all comparisons). Most studies were at high risk of bias (n=21).Conclusion:Marked depletion of ICC is a consistent finding in neurogastroduodenal disorders. A spectrum of disease is revealed, with greater depletion associated with delayed emptying. Techniques for clinically defining ICC-driven gastric neuromuscular dysfunction should be prioritized.</p
Neural and Behavioral Markers of Negative Symptoms and Cognitive Impairment in Patients with Psychosis
No full textNegative and cognitive symptoms impair functioning in patients with psychotic illnesses [i.e., schizophrenia spectrum disorders (SZ) and bipolar I disorder with psychotic features (BD)]. Disruptions in mesocorticolimbic circuitry are hypothesized to underpin negative symptoms and cognitive impairment in patients with psychosis and may also facilitate reward-motivational deficits. In male and female patients with psychosis (N = 44) and healthy controls (HC = 27), we used neuroimaging to define gray matter morphology and white matter microstructure. We examined negative symptom severity with the Clinical Assessment Interview for Negative Symptoms (CAINS), effort allocation during reward processing with the Effort Expenditure for Rewards Task (EEfRT), and cognitive performance with the MATRICS cognitive consensus battery (MCCB). Reduced nucleus accumbens volumes in patients with psychosis were associated with higher CAINS total and motivation and pleasure subscale scores as well as lower effort expenditure for medium (50%) and high (88%) reward probability conditions during EEfRT. The fornix showed reduced fractional anisotropy in patients with psychosis. Negative associations were present between CAINS motivation and pleasure subscores and MCCB composite and subscale scores. Lower gray matter volume in cerebellar Lobule IV corresponded with impaired effort allocation during medium and high reward probability conditions and lower cognitive performance. However, Lobule IV was not correlated with CAINS scores. While nucleus accumbens volume may serve as a marker of negative symptoms in psychotic illnesses, cerebellar Lobule IV morphology may inform on cognitive impairment in patients with SZ and BD. The nucleus accumbens and Lobule IV may each contribute to reduced effort allocation during reward processing.</p
Assessing the composition of myofibrillar and muscle connective protein fractions within skeletal muscle tissue
No full textABSTRACT (195 WORDS): It has been suggested that different nutritional stimuli are required to augment myofibrillar versus muscle connective protein synthesis rates. To study such different aspects of skeletal muscle remodeling, researchers often isolate myofibrillar or connective protein fractions from muscle tissue samples. However, the composition of these muscle protein fractions remains poorly defined. Here, we evaluated the amino acid profiles and protein compositions of the myofibrillar and muscle connective protein fractions within skeletal muscle tissue. The muscle connective protein fraction was shown to contain ∼70% of the total mixed muscle collagen content, with 4.4 ± 0.9% collagen relative to total protein content. This was 3–4 fold greater than the collagen content in mixed muscle tissue (1.2 ± 0.2%; p < 0.05). Myofibrillar proteins, such as actin and myosin, accounted for 39% of the myofibrillar protein fraction and 32% of the muscle connective protein fraction. The muscle connective protein fraction contained a higher proportion (42%) of key scaffolding proteins compared to the myofibrillar protein fraction (11%). In conclusion, the muscle connective protein fraction contains an enriched proportion of collagen among a large proportion of intra- and extracellular scaffolding and cell adhesion proteins, all of which are far less abundant in the myofibrillar protein fraction.</p
Autonomous Construction Crack Vision-Based Repair Using an Aerial Platform and a Delta Manipulator
No full textAutonomous inspections of civil and critical infrastructure and the ability to perform basic repair operations with drones may lead to increased safety. However, the development of autonomous solutions faces many challenges. To address some of the underlying challenges of autonomous construction repair we developed and present a custom-made aerial robotic platform. Equipped with computer vision for autonomous detection and localization of cracks, a delta manipulator, and a syringe-based cement extruder the presented solution is capable of finding, landing on top, and filling cracks in constructions under lab conditions
Unresectable stage III non-small-cell lung cancer:state of the art and challenges
No full textDespite advances in immunotherapy, unresectable stage III non-small-cell lung cancer (NSCLC) remains a highly challenging disease, with only around one-third of patients remaining disease-free at 5 years. The PACIFIC trial established consolidation with the anti-PD-L1 antibody durvalumab after concurrent chemoradiotherapy as the standard-of-care approach. Furthermore, the LAURA trial has redefined the treatment of patients with stage III unresectable EGFR-mutant NSCLC, demonstrating unprecedented progression-free survival durations with osimertinib consolidation. Despite these advances, novel approaches are urgently needed. Circulating tumour DNA-based monitoring of minimal residual disease is emerging as a personalized method of tailoring treatment duration and escalation strategies. Novel radiotherapy techniques have the potential to provide synergy with immunotherapy while minimizing toxicities. Additionally, ongoing trials evaluating chemoimmunotherapy combinations adapted from the neoadjuvant setting with the potential for conversion to resectable disease might, in the near future, redefine the boundary of surgical resectability. In this Review, we describe the rapidly evolving field of unresectable stage III NSCLC, providing a state-of-the-art overview that includes challenging topics such as biomarkers, personalization of therapy and the role of immunotherapy rechallenge
Let's (not) escalate this! Leadership and communication in a group contest
No full textEconomic and social situations where groups have to compete are ubiquitous. Such group contests create both a coordination problem within and between groups. Introducing leaders may help to mitigate these coordination problems, but little is known about the effect of leadership in group contests. In a group contest experiment, we compare two types of leadership-leading-by-example and transactional leadership-and also investigate the effect of communication between leaders under both leadership styles. We find that the introduction of leaders mostly increases contest investment. Transactional leaders increase followers' investment through the allocation of a relatively larger share of the prize to followers who have invested more. Communication between leaders decreases contest investments when there is leading-by-example but not when there is transactional leadership. Overall, leaders do not mitigate the over-investment problem in group contests