Cancer remains a leading cause of mortality worldwide and calls for novel therapeutic targets. Membrane proteins are key players in various cancer types but present unique challenges compared to... Show moreCancer remains a leading cause of mortality worldwide and calls for novel therapeutic targets. Membrane proteins are key players in various cancer types but present unique challenges compared to soluble proteins. The advent of computational drug discovery tools offers a promising approach to address these challenges, allowing for the prioritization of "wet-lab" experiments. In this review, we explore the applications of computational approaches in membrane protein oncological characterization, particularly focusing on three prominent membrane protein families: receptor tyrosine kinases (RTKs), G protein-coupled receptors (GPCRs), and solute carrier proteins (SLCs). We chose these families due to their varying levels of understanding and research data availability, which leads to distinct challenges and opportunities for computational analysis. We discuss the utilization of multi-omics data, machine learning, and structure-based methods to investigate aberrant protein functionalities associated with cancer progression within each family. Moreover, we highlight the importance of considering the broader cellular context and, in particular, cross-talk between proteins. Despite existing challenges, computational tools hold promise in dissecting membrane protein dysregulation in cancer. With advancing computational capabilities and data resources, these tools are poised to play a pivotal role in identifying and prioritizing membrane proteins as personalized anticancer targets. Show less
Setia, S.; Chhabra, A.; Arjun, V.A.; Saxena, A. 2024
Since the invention of the Indian writing system around the third century BC, Sanskrit literature was no longer exclusively oral. However, not all genres immediately adopted the new possibilities.... Show moreSince the invention of the Indian writing system around the third century BC, Sanskrit literature was no longer exclusively oral. However, not all genres immediately adopted the new possibilities. In order to fully understand the orality and writing of Sanskrit literature, I will first define a threefold division of what I call ‘the compositional complex’, the totality of processes involved in the creation of texts and their subsequent usages. The first stage is the composition of the text, the second is its preservation for the sake of future generations, and the third is its transmission to the audience. Each stage can be oral or written. After a brief discussion of secondary literature on the compositional complex of the Vedas, the Mahābhārata and the Purāṇas, I look for textinternal evidence for the compositional complex of Purāṇas in the Bhaviṣyapurāṇa, ‘the Purāṇa of the future’. On the basis of this single Purāṇa, it is possible to make a reconstruction of the composition, preservation, and transmission of Purāṇas, where orality and writing intertwine. Show less
Biggelaar, R.H.G.A. van den; Walburg, K.V.; Eeden, S.J.F. van den; Doorn, C.L.R. van; Meiler, E.; Ries, A.S. de; ... ; Saris, A. 2024
The increasing prevalence of antimicrobial-resistant Staphylococcus aureus strains, especially methicillin-resistant S. aureus (MRSA), poses a threat to successful antibiotic treatment.... Show moreThe increasing prevalence of antimicrobial-resistant Staphylococcus aureus strains, especially methicillin-resistant S. aureus (MRSA), poses a threat to successful antibiotic treatment. Unsuccessful attempts to develop a vaccine and rising resistance to last-resort antibiotics urge the need for alternative treatments. Host-directed therapy (HDT) targeting critical intracellular stages of S. aureus emerges as a promising alternative, potentially acting synergistically with antibiotics and reducing the risk of de novo drug resistance. We assessed 201 ATP-competitive kinase inhibitors from Published Kinase Inhibitor Sets (PKIS1 and PKIS2) against intracellular MRSA. Seventeen hit compounds were identified, of which the two most effective and well-tolerated hit compounds (i.e., GW633459A and GW296115X) were selected for further analysis. The compounds did not affect planktonic bacterial cultures, while they were active in a range of human cell lines of cervical, skin, lung, breast and monocyte origin, confirming their host-directed mechanisms. GW633459A, structurally related to lapatinib, exhibited an HDT effect on intracellular MRSA independently of its known human epidermal growth factor receptor (EGFR)/(HER) kinase family targets. GW296115X activated adenosine monophosphate-activated protein kinase (AMPK), thereby enhancing bacterial degradation via autophagy. Finally, GW296115X not only reduced MRSA growth in human cells but also improved the survival rates of MRSA-infected zebrafish embryos, highlighting its potential as HDT. Show less
Dam, P.H. van; Achterberg, W.P.; Husebo, B.S.; Caljouw, M.A. 2024
BackgroundPain medication may have an impact on the quality of life (QoL) in persons with dementia, but may also influence care dependency and daily functioning. The aim of this study is to... Show moreBackgroundPain medication may have an impact on the quality of life (QoL) in persons with dementia, but may also influence care dependency and daily functioning. The aim of this study is to investigate the effect of regularly scheduled paracetamol on care dependency and daily functioning in persons with advanced dementia with low QoL living in long-term care facilities.MethodsThe Quality of life and Paracetamol In advanced Dementia (Q-PID) study was a (block) randomized double-blind placebo-controlled crossover trial with paracetamol and placebo across seventeen long-term care facilities across 9 care organizations in the western region of the Netherlands. Participants were >= 65 years, had advanced dementia (Global Deterioration Scale 5-7), and low QoL (QUALIDEM-6D score <= 70). Measurements were performed by nursing staff at the start and at the end of each treatment period of six weeks. Repeated linear mixed models were used to compute differences between randomization groups, with adjustment for period and order effects, and psychotropic use.ResultsNinety-five persons (mean age of 83.9 years, 57.4% female) were enrolled in the Q-PID study. The mean Care Dependency Scale total score was 37.8 (Standard Deviation [SD] 12.9) and the mean Katz-15 total score was 11.9 (SD 2.4). Repeated linear mixed models showed no difference in mean differences of care dependency (paracetamol - 1.0 [95% Confidence Interval (CI) -2.4-0.3], placebo + 0.1 [-1.3-1.5]), and daily functioning (paracetamol + 0.2 [95% CI -0.2-0.6], placebo + 0.1 [-0.3-0.4]).ConclusionsCompared to placebo, no effect of scheduled administration of paracetamol was found on care dependency and daily functioning in persons with advanced dementia with low QoL. Future research should focus on which specific items of care dependency need special attention to improve the care for persons with advanced dementia. A multi-domain approach is needed to enhance and/or maintain QoL of persons with advanced dementia.Trial registrationNetherlands Trial Register (NTR6766); http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=6766; Trial registration date: 20/10/2017. Show less
The present study investigated the use of the iBrainstorm app in a collaborative argumentation-based learning context for developing listening comprehension skills by EFL learners. Two groups of... Show moreThe present study investigated the use of the iBrainstorm app in a collaborative argumentation-based learning context for developing listening comprehension skills by EFL learners. Two groups of students were formed. All of them studied English as a foreign language at the BA level at Bu-Ali Sina University, Iran. Participants were assigned to groups at random. Participants took a pre-test of listening comprehension skills before starting the programme. The control group listened to authentic audio tracks in English and discussed their contents, watched authentic English movies, discussed issues in the movies in pairs in the classroom. The experimental group spent part of the time on theoretical explanation of, and practical exercises with, argumentation-based learning by the iBrainstorm application. The total instruction time was the same for two groups, i.e., 32 hours. Students then took a post-test and, a month later, a delayed post-test in listening comprehension skills. The results show that the use of the iBrainstorm app significantly improved the students’ listening comprehension skills, and significantly more so than those of the control group. These results have pedagogical implications for curriculum designers, material producers, and all who are involved in language study and pedagogy Show less
Migrant populations have been consistently more vulnerable than others, with their vulnerability being exacerbated in crises such as the Covid-19 pandemic. In the meantime, in their effort to ... Show moreMigrant populations have been consistently more vulnerable than others, with their vulnerability being exacerbated in crises such as the Covid-19 pandemic. In the meantime, in their effort to “flatten the curve,” governments have been adopting policies that have significantly impacted migration in various ways. The effect of these policies has found migrants suffering disproportionately from the social and economic consequences of the pandemic crisis. Mobility restrictions have stranded them in the host countries, often without decent housing conditions, exacerbating xenophobic and discriminatory treatment of migrants. The study focuses on the case of Portugal and, more specifically, aims to provide a contextual feature of historical discussions of migration in Portugal and explore the perceptions and branding of migration policies in a crisis environment during the Covid-19 pandemic through the framing lens. Using empirical evidence from a frame analysis of parliamentary debates, the article investigates how immigration policies are branded and framed within Portugal, while it also evaluates the role of branding in migration policy-making, particularly in crisis scenarios. Overall, the article underscores the importance of branding in shaping migration policies, emphasising its significance in policy making. Show less
Viral infections have been associated with the progression of atherosclerosis and CD8+ T-cells directed against common viruses, such as influenza, Epstein-Barr virus, and cytomegalovirus, have been... Show moreViral infections have been associated with the progression of atherosclerosis and CD8+ T-cells directed against common viruses, such as influenza, Epstein-Barr virus, and cytomegalovirus, have been detected inside human atherosclerotic lesions. These virus-specific CD8+ T-cells have been hypothesized to contribute to the development of atherosclerosis; however, whether they affect disease progression directly remains unclear. In this study, we aimed to characterize the activation status of virus-specific CD8+ T-cells in the atherosclerotic lesion.\nThe presence, clonality, tissue enrichment, and phenotype of virus-associated CD8+ T-cells in atherosclerotic lesions were assessed by exploiting bulk T-cell receptor-β sequencing and single-cell T-cell receptor (α and β) sequencing datasets on human endarterectomy samples and patient-matched blood samples. To investigate if virus-specific CD8+ T-cells can be activated through T-cell receptor stimulation in the atherosclerotic lesion, the immunopeptidome of human plaques was determined.\nVirus-associated CD8+ T-cells accumulated more in the atherosclerotic lesion (mean=2.0%), compared with patient-matched blood samples (mean=1.4%; P=0.05), and were more clonally expanded and tissue enriched in the atherosclerotic lesion in comparison with nonassociated CD8+ T-cells from the lesion. Single-cell T-cell receptor sequencing and flow cytometry revealed that these virus-associated CD8+ T-cells were phenotypically highly similar to other CD8+ T-cells in the lesion and that both exhibited a more activated phenotype compared with circulating T-cells. Interestingly, virus-associated CD8+ T-cells are unlikely to be activated through antigen-specific interactions in the atherosclerotic lesion, as no virus-derived peptides were detected on HLA-I in the lesion.\nThis study suggests that virus-specific CD8+ T-cells are tissue enriched in atherosclerotic lesions; however, their potential contribution to inflammation may involve antigen-independent mechanisms. Show less
Advanced in vitro models that recapitulate the structural organization and function of the human heart are highly needed for accurate disease modeling, more predictable drug screening, and safety... Show moreAdvanced in vitro models that recapitulate the structural organization and function of the human heart are highly needed for accurate disease modeling, more predictable drug screening, and safety pharmacology. Conventional 3D Engineered Heart Tissues (EHTs) lack heterotypic cell complexity and culture under flow, whereas microfluidic Heart-on-Chip (HoC) models in general lack the 3D configuration and accurate contractile readouts. In this study, an innovative and user-friendly HoC model is developed to overcome these limitations, by culturing human pluripotent stem cell (hPSC)-derived cardiomyocytes (CMs), endothelial (ECs)- and smooth muscle cells (SMCs), together with human cardiac fibroblasts (FBs), underflow, leading to self-organized miniaturized micro-EHTs (µEHTs) with a CM-EC interface reminiscent of the physiological capillary lining. µEHTs cultured under flow display enhanced contractile performance and conduction velocity. In addition, the presence of the EC layer altered drug responses in µEHT contraction. This observation suggests a potential barrier-like function of ECs, which may affect the availability of drugs to the CMs. These cardiac models with increased physiological complexity, will pave the way to screen for therapeutic targets and predict drug efficacy. Show less
Rijs, Z.; Kawsar, K.A.; Saha, P.; Sande, M. van de; Lui, D.R. 2024
This study evaluated artefacts on computed tomography (CT) images using Hounsfeld units (HU) in patients with spinal oligometastatic disease who received carbon-fber (CF; n= 11) or titanium (n= 11)... Show moreThis study evaluated artefacts on computed tomography (CT) images using Hounsfeld units (HU) in patients with spinal oligometastatic disease who received carbon-fber (CF; n= 11) or titanium (n= 11) spine implants and underwent stereotactic ablative radiotherapy (SABR). Pre- and postoperative HU were measured at the vertebral body, pedicle, and spinal cord at three diferent levels: the lower instrumented vertebra, the level of metastatic spinal cord compression, and an uninvolved level. Areas measured at each level were delicately matched pre- and postoperatively. Signifcant diferences in HU were observed at the vertebral body, the pedicle, and the spinal cord at the lowest instrumented vertebra level for both CF and titanium (average increase 1.54-fold and 5.11-fold respectively). At the metastatic spinal cord compression level, a trend towards a higher HU-increase was observed in titanium compared with CF treated patients (average increase 2.51-fold and 1.43-fold respectively). The relatively high postoperative HU-increase after insertion of titanium implants indicated CT artefacts, while the relatively low HU-increase of CF implants was not associated with artefacts. Less CT artefacts could facilitate an easier contouring phase in radiotherapy planning. In addition, we propose a CT artefact grading system based on postoperative HU-increase. This system could serve as a valuable tool in future research to assess if less CT artefacts lead to time savings during radiotherapy treatment planning and, potentially, to better tumoricidal efects and less adverse efects if particle therapy would be administered. Show less
Importance Multiple patient-reported outcome measures (PROMs) for health-related quality of life (HRQL) exist for patients with psoriasis. Evidence for the content validity and other measurement... Show moreImportance Multiple patient-reported outcome measures (PROMs) for health-related quality of life (HRQL) exist for patients with psoriasis. Evidence for the content validity and other measurement properties of these PROMs is critical to determine which HRQL PROMs could be recommended for use.Objective To systematically review the validity of HRQL-focused PROMs used in patients with psoriasis.Evidence Review Using PubMed and Embase, full-text articles published in English or Spanish on development or validation studies for psoriasis-specific, dermatology-specific, or generic HRQL PROMs were included. Development studies included original development studies, even if not studied in psoriasis patients per Consensus-Based Standards for the Selection of Health Measurement Instruments (COSMIN) recommendations. If a study included multiple diagnoses, more than 50% of patients had to have psoriasis or psoriasis-specific subgroup analyses available. Data extraction and analysis followed the COSMIN guidelines. Two independent reviewers extracted and analyzed the data, including PROM characteristics, quality of measurement properties (structural validity, internal consistency, cross-cultural validity, reliability, measurement error, criterion validity, construct validity, and responsiveness), and level of evidence. PROMs were classified into 3 levels of recommendations: (1) PROM recommended for use; (2) PROM requires further validation; and (3) PROM not recommended for use.Findings Overall, 97 articles were identified for extraction. This included 19 psoriasis-specific, 8 skin-specific, and 6 generic PROMs. According to COSMIN standards, most measures identified received a B recommendation for use, indicating their potential but requiring further validation. Only the Rasch reduced version of the Impact of Psoriasis Questionnaire (IPSO-11 Rasch) received an A recommendation for use given that it had sufficient content validity, structural validity, and internal consistency.Conclusions and Relevance This study identified a significant lack of information concerning the quality of HRQL measures in psoriasis. This gap in knowledge can be attributed to the fact that traditional measures were developed using validation criteria that differ from the current standards in use. Consequently, additional validation studies in accordance with contemporary standards will be useful in aiding researchers and clinicians in determining the most suitable measure for assessing HRQL in patients with psoriasis. Show less
Yordanova, N.; Khokhlova, A.; Ershova, A.; Schmidt, F. D.; Glavaš, G. 2024
BACKGROUND\nOBJECTIVES\nMETHODS\nRESULTS\nDISCUSSION\nUnderstanding the variability across the human population with respect to toxicodynamic responses after exposure to chemicals, such as... Show moreBACKGROUND\nOBJECTIVES\nMETHODS\nRESULTS\nDISCUSSION\nUnderstanding the variability across the human population with respect to toxicodynamic responses after exposure to chemicals, such as environmental toxicants or drugs, is essential to define safety factors for risk assessment to protect the entire population. Activation of cellular stress response pathways are early adverse outcome pathway (AOP) key events of chemical-induced toxicity and would elucidate the estimation of population variability of toxicodynamic responses.\nWe aimed to map the variability in cellular stress response activation in a large panel of primary human hepatocyte (PHH) donors to aid in the quantification of toxicodynamic interindividual variability to derive safety uncertainty factors.\n signaling. Using a population mixed-effect framework, the distribution of benchmark concentrations (BMCs) and maximum fold change were modeled to evaluate the influence of PHH donor panel size on the correct estimation of interindividual variability for the various stimuli.\n signaling-related genes, respectively. Population modeling revealed that small PHH panel sizes systematically underestimated the variance and gave low probabilities in estimating the correct human population variance. Estimated toxicodynamic variability factors of stress response activation in PHHs based on this dataset ranged between 1.6 and 6.3.\nOverall, by combining high-throughput transcriptomics and population modeling, improved understanding of interindividual variability in chemical-induced activation of toxicity relevant stress pathways across the human population using a large panel of plated cryopreserved PHHs was established, thereby contributing toward increasing the confidence of in vitro-based prediction of adverse responses, in particular hepatotoxicity. https://doi.org/10.1289/EHP11891. Show less
Purpose: This clinical fluoroscopy study investigated knee kinematics of two different cemented fixed‐bearing, posterior‐stabilised (PS) total knee arthroplasty (TKA) designs: an asymmetric tibial... Show morePurpose: This clinical fluoroscopy study investigated knee kinematics of two different cemented fixed‐bearing, posterior‐stabilised (PS) total knee arthroplasty (TKA) designs: an asymmetric tibial component including an asymmetric insert designed to optimise personalised balance and fit and its precursor symmetrical design with symmetric insert. Methods: A consecutive series of patients (16 TKAs from each treatment group) participating in a randomised controlled trial comparing TKA migration was included. The exclusion criterion was the use of walking aids. Flat‐panel fluoroscopic recordings of step‐up and lunge motions were acquired 1‐year postoperatively. Medial and lateral contact points (CPs) were determined to calculate CP displacement, femoral axial rotation and pivot position. Using linear mixed‐effects modelling techniques, kinematics between TKA designs were compared. Results: During knee extension between 20° flexion and full extension, the CPs moved anteriorly combined with a small internal femoral rotation (a screw‐home mechanism). Whereas CP movement was reversed: femoral rollback, external femoral rotation while flexing the knee between full extension and 20° knee flexion, At larger flexion angles, femoral axial rotation (FAR) occurred around a lateral pivot point both during step‐up and lunge. The symmetric design had a 2.3° larger range of FAR compared to the asymmetric design during lunge (p = 0.02). All other kinematics were comparable. Conclusion: Despite the differences in design, this study showed that the asymmetric and symmetric PS TKA designs had mostly comparable knee kinematics during step‐up and lunge motions. It is therefore expected that the functionality of the successor TKA design is similar to that of its precursor design. Show less
