bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human sensory-like neuron cultivation—An optimized protocol
Authors: Schottmann Nicole Michelle , Grüner Julia , Bär Frederik , Karl-Schöller Franziska , Oerter Sabrina , Üçeyler Nurcan 
Published: October 2024

IntroductionReprogramming of human-induced pluripotent stem cells (iPSCs) and their differentiation into specific cell types, such as induced sensory-like neurons (iSNs), are critical for disease modeling and drug testing. However, the variability of cell populations challenges reliability and reproducibility. While various protocols for iSN differentiation exist, the development of non-iSN cells in these cultures remains an issue. Therefore, standardization of protocols is essential. This study aimed to improve iSN culture conditions by reducing the number of non-iSN cells while preserving the survival and quality of iSNs.MethodsiSNs were differentiated from a healthy control iPSC line using an established protocol. Interventions for protocol optimization included floxuridine (FdU) or 1-β-D-arabinofuranosyl-cytosine hydrochloride (AraC) treatment, magnetic-activated cell sorting (MACS), early cell passaging, and replating. Cell viability and iSN-to-total-cell-count ratio were assessed using a luminescent assay and immunocytochemistry, respectively.ResultsPassaging of cells during differentiation did not increase the iSN-to-total-cell-count ratio, and MACS of immature iSNs led to neuronal blebbing and reduced the iSN-to-total-cell-count ratio. Treatment with high concentrations and prolonged incubation of FdU or AraC resulted in excessive cell death. However, treatment with 10 μM FdU for 24 h post-differentiation showed the most selective targeting of non-iSN cells, leading to an increase in the iSN-to-total-cell count ratio without compromising the viability or functionality of the iSN population. Replating of iSNs shortly after seeding also helped to reduce non-iSN cells.ConclusionIn direct comparison with other methods, treatment with 10 μM FdU for 24 h after differentiation shows promise for improving iSN culture purity, which could benefit downstream applications in disease modeling and drug discovery. However, further investigations involving multiple iPSC lines and optimization of protocol parameters are warranted to fully exploit the potential of this method and enhance its reproducibility and applicability. Overall, this study provides valuable insights into optimizing culture conditions for iSN differentiation and highlights the importance of standardized protocols in iPSC-based research.
Conserved allomorphs of MR1 drive the specificity of MR1-restricted TCRs
Authors: Cornforth Terri V. , Moyo Nathifa , Cole Suzanne , Lam Emily P. S. , Lobry Tatiana , Wolchinsky Ron , Lloyd Angharad , Ward Katarzyna , Denham Eleanor M. , Masi Giulia , Qing Yun Phyllis Tea , Moore Colin , Dhaouadi Selsabil , Besra Gurdyal S. , Veerapen Natacha , Illing Patricia T. , Vivian Julian P. , Raynes Jeremy M. , Le Nours Jérôme , Purcell Anthony W. , Kundu Samit , Silk Jonathan D. , Williams Luke , Papa Sophie , Rossjohn Jamie , Howie Duncan , Dukes Joseph 
Published: October 2024

BackgroundMajor histocompatibility complex class-1-related protein (MR1), unlike human leukocyte antigen (HLA) class-1, was until recently considered to be monomorphic. MR1 presents metabolites in the context of host responses to bacterial infection. MR1-restricted TCRs specific to tumor cells have been described, raising interest in their potential therapeutic application for cancer treatment. The diversity of MR1-ligand biology has broadened with the observation that single nucleotide variants (SNVs) exist within MR1 and that allelic variants can impact host immunity.MethodsThe TCR from a MR1-restricted T-cell clone, MC.7.G5, with reported cancer specificity and pan-cancer activity, was cloned and expressed in Jurkat E6.1 TCRαβ− β2M− CD8+ NF-κB:CFP NFAT:eGFP AP-1:mCherry cells or in human donor T cells. Functional activity of 7G5.TCR-T was demonstrated using cytotoxicity assays and by measuring cytokine release after co-culture with cancer cell lines with or without loading of previously described MR1 ligands. MR1 allele sequencing was undertaken after the amplification of the MR1 gene region by PCR. In vivo studies were undertaken at Labcorp Drug Development (Ann Arbor, MI, USA) or Epistem Ltd (Manchester, UK).ResultsThe TCR cloned from MC.7.G5 retained MR1-restricted functional cytotoxicity as 7G5.TCR-T. However, activity was not pan-cancer, as initially reported with the clone MC.7.G5. Recognition was restricted to cells expressing a SNV of MR1 (MR1*04) and was not cancer-specific. 7G5.TCR-T and 7G5-like TCR-T cells reacted to both cancer and healthy cells endogenously expressing MR1*04 SNVs, which encode R9H and H17R substitutions. This allelic specificity could be overcome by expressing supraphysiological levels of the wild-type MR1 (MR1*01) in cell lines.ConclusionsHealthy individuals harbor T cells reactive to MR1 variants displaying self-ligands expressed in cancer and benign tissues. Described “cancer-specific” MR1-restricted TCRs need further validation, covering conserved allomorphs of MR1. Ligands require identification to ensure targeting MR1 is restricted to those specific to cancer and not normal tissues. For the wider field of immunology and transplant biology, the observation that MR1*04 may behave as an alloantigen warrants further study.
The role of ALBI score in patients treated with stereotactic body radiotherapy for locally advanced primary liver tumors: a pooled analysis of two prospective studies
Authors: Gkika Eleni , Radicioni Gianluca , Eichhorst Alexandra , Kirste Simon , Sprave Tanja , Nicolay Nils Henrik , Fichtner-Feigl Stefan , Thimme Robert , Wiehle Rolf , Brunner Thomas B. , Grosu Anca-Ligia 
Published: October 2024

IntroductionTo evaluate the outcomes after stereotactic body radiotherapy (SBRT) for locally advanced primary liver cancer.Materials and methodsPatients with locally advanced liver cancer unsuitable for other loco-regional treatments were treated with SBRT with 50–60 Gy in 3–12 fractions in two consecutive prospective trials.ResultsA total of 83 patients were included, of whom 14 were excluded, leaving 69 evaluable patients with 74 treated lesions. A total of 50 patients had hepatocellular carcinoma (HCC), and 11 patients had cholangiocarcinoma (CCC). Approximately 76% had a Child-Pugh (CP) score of A, while 54% had an albumin–bilirubin (ALBI) score of 1. With a median follow-up of 29 months, the median overall survival (OS) was 11 months, and the progression-free survival (PFS) was 18 months. The ALBI score was an important predictor of overall survival (HR 2.094, p = 0.001), which remained significant also in the multivariate analysis. Patients with an ALBI grade of ≥1 had an OS of 4 months versus 23 months in patients with an ALBI grade of 1 (p ≤ 0.001). The local control at 1 and 2 years was 91%. Thirteen patients developed grade ≥ 3 toxicities, of whom nine patients experienced liver toxicities. Patients with a higher ALBI score had a high risk for developing hepatic failure (OR 6.136, p = 0.006).DiscussionSBRT is a very effective treatment with low toxicity and should be considered as a local treatment option in patients with HCC and CCC. Patients with a higher ALBI grade are at risk for developing toxicities after SBRT and have a significantly lower survival rate.
Impaired neutrophil-mediated cell death drives Ewing’s Sarcoma in the background of Down syndrome
Authors: Peirone Serena , Tirtei Elisa , Campello Anna , Parlato Caterina , Guarrera Simonetta , Mareschi Katia , Marini Elena , Asaftei Sebastian Dorin , Bertero Luca , Papotti Mauro , Priante Francesca , Perrone Sarah , Cereda Matteo , Fagioli Franca 
Published: October 2024

IntroductionEwing Sarcoma (EWS) has been reported in seven children with Down syndrome (DS). To date, a detailed assessment of this solid tumour in DS patients is yet to be made.MethodsHere, we characterise a chemo-resistant mediastinal EWS in a 2-year-old DS child, the youngest ever reported case, by exploiting sequencing approaches.ResultsThe tumour showed a neuroectodermal development driven by the EWSR1-FLI1 fusion. The inherited myeloperoxidase deficiency of the patient caused failure of neutrophil-mediated cell death and promoted genomic instability.DiscussionIn this context, the tumour underwent genome-wide near haploidisation resulting in a massive overexpression of pro-inflammatory cytokines. Recruitment of defective neutrophils fostered rapid evolution of this EWS.
Efficacy and safety of anlotinib for triple-negative breast cancer with brain metastases
Authors: Liu Zeyu , Li Ming , Zhao Ziyi , Liu Aina , Sun Ping 
Published: October 2024

BackgroundThe anti-angiogenic agent anlotinib offers a new treatment option for triple-negative breast cancer (TNBC) patients with brain metastases. This study aimed to evaluate the efficacy and safety of anlotinib in the treatment of TNBC patients with brain metastases.MethodsBetween October 2019 and April 2024, 29 TNBC patients with brain metastases who had failed prior therapy and were treated with anlotinib were retrospectively analyzed. The primary endpoint was central nervous system (CNS) progression-free survival (PFS), and secondary endpoints included overall survival (OS), intracranial disease control rate (iDCR), intracranial objective response rate (iORR), and safety.ResultsThe median CNS PFS of 29 patients was 7.2 months (95% confidence interval [CI], 3.5-10.9 months), and the median OS was 10.2 months (95% CI, 5.6-14.8 months). The iORR and iDCR were 31.0% and 86.2%, respectively. Five patients (17.2%) experienced grade 3-4 adverse events (AEs), with bone marrow suppression (2/29, 6.9%) being the most common. Most AEs were clinically manageable, and no treatment-related death was observed.ConclusionAnlotinib demonstrated encouraging efficacy and manageable toxicity in the treatment of TNBC patients with brain metastases who had failed standard treatment.
A pilot randomized controlled trial comparing noradrenaline and adrenaline as a first-line vasopressor for fluid-refractory septic shock in neonates
Authors: Garegrat Reema , Patnaik Suprabha , Suryawanshi Sonali , Chetan Chinmay , Banait Nishant , Singh Pari , Kallimath Aditya , Soni Naharmal B. , Singh Yogen , Suryawanshi Pradeep 
Published: October 2024

Background and study designLimited data exists on noradrenaline therapy in neonatal septic shock. We compared the efficacy of noradrenaline with adrenaline in neonatal septic shock. This single center, open label, pilot randomized controlled trial included neonates with clinical evidence of sepsis and shock.Study outcomesPrimary outcomes were: 1) resolution of shock one hour after treatment, and 2) mortality during hospital stay. Secondary outcomes included: need for additional vasopressors; hemodynamic stability without further administration of vasopressors for ≥2 h; changes in blood pressure and heart rate after 1 h of vasopressor treatment; and morbidities during the hospital stay.ResultsOf 65 eligible neonates, 42 were randomized (21 each in adrenaline and noradrenaline treatment arms) between August 2020 and January 2022, at level III neonatal intensive care unit (NICU) of Bharati Vidyapeeth Deemed University Medical College and Hospital (BVDUMCH). The mean (SD) gestational age and mean (SD) birth weight were 36.1(4.2) weeks and 1.8 (0.2) kilograms birth weight for noradrenaline and 36.9 (4.1) weeks and 1.7 (0.7) kilograms for adrenaline. Shock resolved within 1 h of vasopressor therapy in 76.2% neonates in the noradrenaline arm and 61.9% in adrenaline arm (p value-0.53). Mortality during hospital stay was 28.6% (6/21) in noradrenaline group and 33.3% (7/21) in adrenaline group (p value- 0.58). Additional vasopressors were required in 23.8% neonates of the noradrenaline group compared to 38.1% neonates in adrenaline arm (p value-0.53). Median (SD) duration of intensive care stay was 6 (SD) days in the noradrenaline group and 10 (SD) days in the adrenaline group (p value-0.045).ConclusionAmong neonates with septic shock, the efficacy of noradrenaline was comparable to adrenaline in resolving septic shock after one hour of infusion and on the mortality during hospital stay.Clinical Trial Registrationhttps://ctri.nic.in/Clinicaltrials/pmaindet2.php?EncHid=NDI2NTc=&amp;Enc=&amp;userName=noradrenaline, Clinical Trials Registry – India with identifier CTRI/2020/08/027185 (17/08/2020).
A mathematical model for simulation of cardiovascular, renal, and hormonal responses to burn injury and resuscitation
Authors: ArabiDarrehDor Ghazal , Kramer George C. , Burmeister David M. , Salinas Jose , Hahn Jin-Oh 
Published: October 2024

IntroductionTreating extensive burn injury requires an individually tailored resuscitation protocol that includes hourly-titrated intravenous fluid infusion to avert both hypovolemic shock and edema. Due to the complexity of burn pathophysiology and significant variability in treatment protocols, there is an ongoing effort to optimize burn resuscitation. The goal of this work is to contribute to this effort by developing a mathematical model of burn pathophysiology and resuscitation for in silico testing of burn resuscitation protocols and decision-support systems.MethodsIn our previous work, we developed and validated a mathematical model consisting of volume kinetics, burn-induced perturbations, and kidney function. In this work, we expanded our previous mathematical model to incorporate novel mathematical models of cardiovascular system and hormonal system (renin-angiotensin-aldosterone (RAAS) system and antidiuretic hormone) which affect blood volume and pressure regulation. We also developed a detailed mathematical model of kidney function to regulate blood volume, pressure, and sodium levels, including components for glomerular filtration rate, reabsorption rates in nephron tubules, Tubuglomerular feedback, and myogenic mechanisms. We trained and validated the expanded mathematical model using experimental data from 15 pigs and 9 sheep with extensive burns to quantitatively evaluate its prediction accuracy for hematocrit, cardiac output, mean arterial pressure, central venous pressure, serum sodium levels, and urinary output. We then trained and tested the mathematical model using a clinical dataset of 233 human burn patients with demographic data and urinary output measurements.ResultsThe mathematical model could predict all tested variables very well, while internal variables and estimated parameters were consistent with the literature.DiscussionTo the best of our knowledge, this is the first mathematical model of burn injury and resuscitation which is extensively validated to replicate actual burn patients. Hence, this in silico platform may complement large animal pre-clinical testing of burn resuscitation protocols. Beyond its primary purpose, the mathematical model can be used as a training tool for healthcare providers delivering insight into the pathophysiology of burn shock, and offering novel mathematical models of human physiology which can be independently used for other purposes and contexts.
Aesthetic experiences and their transformative power: a systematic review
Authors: Pizzolante Marta , Pelowski Matthew , Demmer Theresa Rahel , Bartolotta Sabrina , Sarcinella Eleonora Diletta , Gaggioli Andrea , Chirico Alice 
Published: October 2024

BackgroundTransformative experiences (TEs) have been conceptualized in many ways, contexts, magnitudes, and durations, but at their heart, they entail some manner of adjustment, which contributes to changing individuals’ worldviews, actions, views of others and/or their own feelings, personality, and identity. Among the many elicitors identified as being able to foster TEs, an emerging body of literature has suggested that TEs might be prevalent in aesthetics or emerged from encounters with human art. Beyond denoting ordinary moments characterizing our daily lives, art and aesthetics could occasionally represent profound changes, causing shifts in our perceptions, beliefs and understanding of the world. However, in the realm of psychological inquiry, the extent to which art and aesthetics can be considered potential catalysts for transformation remains a topic of debate. Furthermore, a comprehensive identification of the key psychological components that contribute to the process of transformation before, during, and after aesthetic engagement is still missing.AimsThis systematic review endeavors to address these gaps by synthesizing literature on aesthetic transformative experiences either from the field of psychology or explicitly delving into the psychological impact of transformative experiences within the realm of art and aesthetics. It encompasses both theoretical and empirical papers to determine key aspects and psychological components that characterize TEs.MethodsTwo major electronic databases were systematically searched. The review was conducted in accordance with Liberati et al. (2009) and PRISMA guidelines. All stages of the review were conducted independently by three researchers, and the protocol was published on PROSPERO (Registration no.: CRD42022298655).ResultsAlthough 39.440 studies were identified, only 23 peer-reviewed articles were included in this review, as most studies did not explicitly delve into the long-lasting psychological impact of art and aesthetics.DiscussionThe results confirm the potential of art and aesthetics as elicitors of transformation regardless of the type of artwork and the usage context. Moreover, it also identifies some psychological components necessary for transformation in the realm of art and aesthetics, including facilitating conditions/pre-expectations, cognitive discrepancy, epiphany and insight, and several after-effects on the recipient.ConclusionThe review aids in refining and enriching the concept of transformative experience, paving the way for further research and applications in various fields, including not only psychology but also education and therapeutic interventions.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42022298655.
Drowning in emails: investigating email classes and work stressors as antecedents of high email load and implications for well-being
Authors: Kern Marcel , Ohly Sandra , Ďuranová Lenka , Friedrichs Juliane 
Published: October 2024

IntroductionHigh email load has been associated with impaired well-being because emails impose specific demands, disturb the workflow, and thereby overtax individuals’ action regulation toward prioritized goals. However, the causes and well-being-related consequences of email load are not yet well understood, as previous studies have neglected the interaction type and function of emails as well as co-occurring stressors as antecedents of high email load and have relied predominantly on cross-sectional designs.MethodsIn two studies, we aimed to clarify the nature of email load through the lens of action regulation theory. The first study, a two-wave investigation with a fortnightly interval, examined the lagged relationships among email load, work stressors, strain, and affective well-being. The sample included 444 individuals across various occupations and organizations, with 196 of them working from home or remotely at least part of the time. In the second cross-sectional study, we surveyed 257 individuals using a convenience sampling approach, 108 of whom worked from home or remotely at least partially. This study focused on evaluating how different email classes—distinguished by email interaction type (received vs. processed) and email function (communication vs. task)—serve as predictors of high email load.ResultsIn Study 1, we found a positive lagged effect of high email load on strain, even when controlling for the co-occurring stressors time pressure and work interruptions. In addition, lagged effects of email load on time pressure and interruptions were identified, while no evidence was found for the reverse direction. The results of Study 2 suggest that only the number of communication-related emails received, but not the number of task-related emails received, or the number of all emails processed contribute to high email load.ConclusionFindings suggest that email load can be considered a unique stressor and that different classes of email need to be distinguished to understand its nature. Clarifying the sources of email load can help develop effective strategies to address it.
Moderating effects of general self-efficacy on courtesy stigma and anxiety and depressive symptoms of parents of children with autism spectrum disorder
Authors: Tong Jiao , Chen Xu , Wang Bin , Wang Tao , Wang Xue , Ma Shan , Shi Dongdong , Wang Xin , Yan Dongmei 
Published: October 2024

BackgroundStigma, anxiety and depressive symptoms are highly prevalent in parents of children with autism spectrum disorder (ASD) and may have a detrimental impact on the rehabilitation and treatment of children with ASD, ultimately leading to more behavioral issues and higher rates of disability. Therefore, the purpose of this study was to identify the association between general self-efficacy, courtesy stigma, and anxiety and depressive symptoms, and to further discuss whether general self-efficacy moderated the association between courtesy stigma and anxiety and depressive symptoms in parents of children with ASD.MethodsA total of 409 parents of children with ASD from Lianyungang, Jiangsu Province, Eastern China participated in a cross-sectional survey. A structured questionnaire was used to collect sociodemographic characteristics, courtesy stigma, general self-efficacy, anxiety symptoms, and depressive symptoms. Hierarchical multiple regression was used to assess the associations of courtesy stigma, general self-efficacy and courtesy stigma × general self-efficacy interaction with anxiety and depressive symptoms. Simple slope analysis was used to visualize the interaction.ResultsThe courtesy stigma of parents of children with ASD was positively correlated with anxiety (B = 0.374, P &lt; 0.001) and depressive symptoms (B = 0.366, P &lt; 0.001). General self-efficacy was negatively correlated with anxiety (B = -0.200, P &lt; 0.001) and depressive symptoms (B = -0.210, P &lt; 0.001). The association between courtesy stigma and anxiety symptoms was different in the high (1 standard deviation (SD) above the mean, b = 0.258, standard error (SE) = 0.056, t = 4.567, P &lt; 0.001) and low (1 SD below the mean, b = 0.470, SE = 0.053, t = 8.870, P &lt; 0.001) groups of general self-efficacy. In addition, the association between courtesy stigma and depressive symptoms was also different in the high (1 SD above the mean, b = 0.241, SE = 0.056, t = 4.268, P &lt; 0.001) and low (1 SD below the mean, b = 0.469, SE = 0.053, t = 8.844, P &lt; 0.001) groups of general self-efficacy.ConclusionsGeneral self-efficacy could moderate the impact of courtesy stigma on anxiety and depressive symptoms. Therefore, among parents of children with ASD who experienced high courtesy stigma, enhancing general self-efficacy could be an effective strategy to reduce anxiety and depressive symptoms in this population.