bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Stroboscopic Vision on Depth Jump Motor Control: A Biomechanical Analysis
Authors: Harrison Kenneth D. , Dakin Christopher J. , Beethe Anne Z. , Louder Talin
Published: March 2024

Researchers commonly use the ‘free-fall’ paradigm to investigate motor control during landing impacts, particularly in drop landings and depth jumps (DJ). While recent studies have focused on the impact of vision on landing motor control, previous research fully removed continuous visual input, limiting ecological validity. The aim of this investigation was to evaluate the effects of stroboscopic vision on depth jump (DJ) motor control. Ground reaction forces (GRF) and lower-extremity surface electromyography (EMG) were collected for 20 young adults (11 male; 9 female) performing six depth jumps (0.51 m drop height) in each of two visual conditions (full vision vs. 3 Hz stroboscopic vision). Muscle activation magnitude was estimated from EMG signals using root-mean-square amplitudes (RMS) over specific time intervals (150 ms pre-impact; 30–60 ms, 60–85 ms, and 85–120 ms post-impact). The main effects of and interactions between vision and trial number were assessed using two-way within-subjects repeated measures analyses of variance. Peak GRF was 6.4% greater, on average, for DJs performed with stroboscopic vision compared to full vision (p = 0.042). Tibialis anterior RMS EMG during the 60–85 ms post-impact time interval was 14.1% lower for DJs performed with stroboscopic vision (p = 0.020). Vastus lateralis RMS EMG during the 85–120 ms post-impact time interval was 11.8% lower for DJs performed with stroboscopic vision (p = 0.017). Stroboscopic vision altered DJ landing mechanics and lower-extremity muscle activation. The observed increase in peak GRF and reduction in RMS EMG of the tibialis anterior and vastus lateralis post-landing may signify a higher magnitude of lower-extremity musculotendinous stiffness developed pre-landing. The results indicate measurable sensorimotor disruption for DJs performed with stroboscopic vision, warranting further research and supporting the potential use of stroboscopic vision as a sensorimotor training aid in exercise and rehabilitation. Stroboscopic vision could induce beneficial adaptations in multisensory integration, applicable to restoring sensorimotor function after injury and preventing injuries in populations experiencing landing impacts at night (e.g., military personnel).
Engineering a Dual Specificity γδ T-Cell Receptor for Cancer Immunotherapy
Authors: Davies David M. , Pugliese Giuseppe , Parente Pereira Ana C. , Whilding Lynsey M. , Larcombe-Young Daniel , Maher John
Published: March 2024

γδ T-cells provide immune surveillance against cancer, straddling both innate and adaptive immunity. G115 is a clonal γδ T-cell receptor (TCR) of the Vγ9Vδ2 subtype which can confer responsiveness to phosphoantigens (PAgs) when genetically introduced into conventional αβ T-cells. Cancer immunotherapy using γδ TCR-engineered T-cells is currently under clinical evaluation. In this study, we sought to broaden the cancer specificity of the G115 γδ TCR by insertion of a tumour-binding peptide into the complementarity-determining region (CDR) three regions of the TCR δ2 chain. Peptides were selected from the foot and mouth disease virus A20 peptide which binds with high affinity and selectivity to αvβ6, an epithelial-selective integrin that is expressed by a range of solid tumours. Insertion of an A20-derived 12mer peptide achieved the best results, enabling the resulting G115 + A12 T-cells to kill both PAg and αvβ6-expressing tumour cells. Cytolytic activity of G115 + A12 T-cells against PAg-presenting K562 target cells was enhanced compared to G115 control cells, in keeping with the critical role of CDR3 δ2 length for optimal PAg recognition. Activation was accompanied by interferon (IFN)-γ release in the presence of either target antigen, providing a novel dual-specificity approach for cancer immunotherapy.
Ammoniagenic Action of Valproate without Signs of Hepatic Dysfunction in Rats: Possible Causes and Supporting Evidence
Authors: Alilova Gubidat , Tikhonova Lyudmila , Montoliu Carmina , Kosenko Elena
Published: March 2024

(1) Background: Valproic acid (VPA) is one of the frequently prescribed antiepileptic drugs and is generally considered well tolerated. However, VPA neurologic adverse effects in the absence of liver failure are fairly common, suggesting that in the mechanism for the development of VPA-induced encephalopathy, much more is involved than merely the exposure to hyperammonemia (HA) caused by liver insufficiency to perform detoxification. Taking into account the importance of the relationship between an impaired brain energy metabolism and elevated ammonia production, and based on the ability of VPA to interfere with neuronal oxidative pathways, the current study intended to investigate a potential regional ammoniagenic effect of VPA on rats’ brains by determining activities of the enzymes responsible for ammonia production and neutralization. (2) Methods: Rats received a single intraperitoneal injection of VPA (50, 100, 250, 500 mg/kg). Plasma, the neocortex, the cerebellum, and the hippocampus were collected at 30 min after injection. The levels of ammonia, urea, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were measured in blood plasma. The activities of glutaminase and glutamate dehydrogenase (GDH) in mitochondria and the activities of AMP deaminase (AMPD), adenosine deaminase (ADA), and glutamine synthetase (GS) in cytosolic fractions isolated from rat brain regions were measured. Ammonia, ALT, and AST values were determined in the mitochondrial and cytosolic fractions. (3) Results: Multi-dose VPA treatment did not significantly affect the plasma levels of ammonia and urea or the ALT and AST liver enzymes. Significant dose-independent increases in the accumulation of ammonia were found only in the cytosol from the cerebellum and there was a strong correlation between the ammonia level and the ADA activity in this brain structure. A significant decrease in the AMPD and AST activities was observed, while the ALT activity was unaffected. Only the highest VPA dose (500 mg/kg) was associated with significantly less activity of GS compared to the control in all studied brain structures. In the mitochondria of all studied brain structures, VPA caused a dose-independent increases in ammonia levels, a high concentration of which was strongly and positively correlated with the increased GDH and ALT activity, while glutaminase activity remained unchanged, and AST activity significantly decreased compared to the control in all studied brain structures. (4) Conclusions: This study highlights the rat brain region-specific ammoniagenic effects of VPA, which may manifest themselves in the absence of hyperammonemia. Further research should analyze how the responsiveness of the different brain regions may vary in VPA-treated animals that exhibit compromised energy metabolism, leading to increased ammoniagenesis.
Epitope Mapping of Japanese Encephalitis Virus Neutralizing Antibodies by Native Mass Spectrometry and Hydrogen/Deuterium Exchange
Authors: Adhikari Jagat , Heffernan James , Edeling Melissa , Fernandez Estefania , Jethva Prashant N. , Diamond Michael S. , Fremont Daved H. , Gross Michael L.
Published: March 2024

Japanese encephalitis virus (JEV) remains a global public health concern due to its epidemiological distribution and the existence of multiple strains. Neutralizing antibodies against this infection have shown efficacy in in vivo studies. Thus, elucidation of the epitopes of neutralizing antibodies can aid in the design and development of effective vaccines against different strains of JEV. Here, we describe a combination of native mass spectrometry (native-MS) and hydrogen/deuterium exchange mass spectrometry (HDX-MS) to complete screening of eight mouse monoclonal antibodies (MAbs) against JEV E-DIII to identify epitope regions. Native-MS was used as a first pass to identify the antibodies that formed a complex with the target antigen, and it revealed that seven of the eight monoclonal antibodies underwent binding. Native mass spectra of a MAb (JEV-27) known to be non-binding showed broad native-MS peaks and poor signal, suggesting the protein is a mixture or that there are impurities in the sample. We followed native-MS with HDX-MS to locate the binding sites for several of the complex-forming antibodies. This combination of two mass spectrometry-based approaches should be generally applicable and particularly suitable for screening of antigen–antibody and other protein–protein interactions when other traditional approaches give unclear results or are difficult, unavailable, or need to be validated.
Role of Polyunsaturated Fatty Acids (PUFAs) and Eicosanoids on Dry Eye Symptoms and Signs
Authors: Mangwani-Mordani Simran , Prislovsky Amanda , Stephenson Daniel , Chalfant Charles E. , Galor Anat , Mandal Nawajes
Published: March 2024

Polyunsaturated fatty acids (PUFAs) generate pro- and anti-inflammatory eicosanoids via three different metabolic pathways. This study profiled tear PUFAs and their metabolites and examined the relationships with dry eye (DE) and meibomian gland dysfunction (MGD) symptoms and signs. A total of 40 individuals with normal eyelids and corneal anatomies were prospectively recruited. The symptoms and signs of DE and MGD were assessed, and tear samples (from the right eye) were analyzed by mass spectrometry. Mann–Whitney U tests assessed differences between medians; Spearman tests assessed correlations between continuous variables; and linear regression models assessed the impact of potential confounders. The median age was 63 years; 95% were male; 30% were White; and 85% were non-Hispanic. The symptoms of DE/MGD were not correlated with tear PUFAs and eicosanoids. DE signs (i.e., tear break-up time (TBUT) and Schirmer’s) negatively correlated with anti-inflammatory eicosanoids (11,12-dihydroxyeicosatrienoic acid (11,12 DHET) and 14,15-dihydroxyicosatrienoic acid (14,15, DHET)). Corneal staining positively correlated with the anti-inflammatory PUFA, docosahexaenoic acid (DHA). MGD signs significantly associated with the pro-inflammatory eicosanoid 15-hydroxyeicosatetranoic acid (15-HETE) and DHA. Several relationships remained significant when potential confounders were considered. DE/MGD signs relate more to tear PUFAs and eicosanoids than symptoms. Understanding the impact of PUFA-related metabolic pathways in DE/MGD may provide targets for new therapeutic interventions.
Postweaning Development Influences Endogenous VPAC1 Modulation of LTP Induced by Theta-Burst Stimulation: A Link to Maturation of the Hippocampal GABAergic System
Authors: Gil Marta , Caulino-Rocha Ana , Bento Marta , Rodrigues Nádia C. , Silva-Cruz Armando , Ribeiro Joaquim A. , Cunha-Reis Diana
Published: March 2024

Long-term potentiation (LTP) induced by theta-burst stimulation (TBS) undergoes postweaning developmental changes partially linked to GABAergic circuit maturation. Endogenous vasoactive intestinal peptide (VIP) acting on its VPAC1 receptor strongly influences LTP induced by theta-burst stimulation (TBS), an effect dependent on GABAergic transmission. Although VPAC1 receptor levels are developmentally regulated during embryogenesis, their variation along postweaning development is unknown, as is the VPAC1 modulation of LTP or its relation to hippocampal GABAergic circuit maturation. As such, we investigated how VPAC1 modulation of LTP adjusts from weaning to adulthood along with GABAergic circuit maturation. As described, LTP induced by mild TBS (5 bursts, 4 pulses delivered at 100 Hz) was increasingly greater from weaning to adulthood. The influence of the VPAC1 receptor antagonist PG 97-269 (100 nM) on TBS-induced LTP was much larger in juvenile (3-week-old) than in young adult (6–7-week-old) or adult (12-week-old) rats. This effect was not associated with a developmental decrease in synaptic VPAC1 receptor levels. However, an increase in pre and post-synaptic GABAergic synaptic markers suggests an increase in the number of GABAergic synaptic contacts that is more prominent than the one observed in glutamatergic connections during this period. Conversely, endogenous VPAC2 receptor activation did not significantly influence TBS-induced LTP. VPAC2 receptor levels enhance pronouncedly during postweaning development, but not at synaptic sites. Given the involvement of VIP interneurons in several aspects of hippocampal-dependent learning, neurodevelopmental disorders, and epilepsy, this could provide important insights into the role of VIP modulation of hippocampal synaptic plasticity during normal and altered brain development potentially contributing to epileptogenesis.
Inhibition of Granule Cell Dispersion and Seizure Development by Astrocyte Elevated Gene-1 in a Mouse Model of Temporal Lobe Epilepsy
Authors: Leem Eunju , Kim Sehwan , Sharma Chanchal , Nam Youngpyo , Kim Tae Yeon , Shin Minsang , Lee Seok-Geun , Kim Jaekwang , Kim Sang Ryong
Published: March 2024

Although granule cell dispersion (GCD) in the hippocampus is known to be an important feature associated with epileptic seizures in temporal lobe epilepsy (TLE), the endogenous molecules that regulate GCD are largely unknown. In the present study, we have examined whether there is any change in AEG-1 expression in the hippocampus of a kainic acid (KA)-induced mouse model of TLE. In addition, we have investigated whether the modulation of astrocyte elevated gene-1 (AEG-1) expression in the dentate gyrus (DG) by intracranial injection of adeno-associated virus 1 (AAV1) influences pathological phenotypes such as GCD formation and seizure susceptibility in a KA-treated mouse. We have identified that the protein expression of AEG-1 is upregulated in the DG of a KA-induced mouse model of TLE. We further demonstrated that AEG-1 upregulation by AAV1 delivery in the DG-induced anticonvulsant activities such as the delay of seizure onset and inhibition of spontaneous recurrent seizures (SRS) through GCD suppression in the mouse model of TLE, while the inhibition of AEG-1 expression increased susceptibility to seizures. The present observations suggest that AEG-1 is a potent regulator of GCD formation and seizure development associated with TLE, and the significant induction of AEG-1 in the DG may have therapeutic potential against epilepsy.
Evaluation of the Prognostic Impact of SP263-Evaluated PD-L1 Expression in Patients with Stage III Non-Small Cell Lung Cancer (NSLC) Treated with Radio-Chemotherapy
Authors: Wagner Jan Nicolai , Roeper Julia , Heukamp Lukas , Falk Markus , Willborn Kay , Griesinger Frank
Published: March 2024

Background: The PACIFIC study showed that after radio-chemotherapy, patients with NSCLC derived a benefit in PFS and OS when treated with durvalumab. This effect was limited to patients with a PD-L1 expression of >1%, partly because the outcome in the observational control arm was surprisingly favorable. Thus, it could be speculated that a lack of PD-L1 expression confers a favorable outcome for patients with stage III NSCLC. Methods: Clinical data, PD-L1 expression, predictive blood markers, and the outcomes of 99 homogeneously treated patients with stage III NSCLC were retrospectively captured. Statistical analyses using the log rank test were performed. Results: The median OS of patients with an expression of PD-L1 < 1% was 20 months (CI 10.5–29.5) and the median OS of patients with an expression of PD-L1 ≥ 1% was 28 months (CI 16.5–39.2) (p = 0.734). The median PFS of patients with an expression of PD-L1 < 1% was 9 months (CI 6.3–11.6) and the median PFS of patients with an expression of PD-L1 ≥ 1% was 12 months (CI 9.8–14.2) (p = 0.112). Conclusions: The assumption that the lack of PD-L1 expression represents a favorable prognostic factor after radio-chemotherapy vs. PD-L1 expression > 1% was not confirmed.
Comparing ANOVA and PowerShap Feature Selection Methods via Shapley Additive Explanations of Models of Mental Workload Built with the Theta and Alpha EEG Band Ratios
Authors: Raufi Bujar , Longo Luca
Published: March 2024

Background: Creating models to differentiate self-reported mental workload perceptions is challenging and requires machine learning to identify features from EEG signals. EEG band ratios quantify human activity, but limited research on mental workload assessment exists. This study evaluates the use of theta-to-alpha and alpha-to-theta EEG band ratio features to distinguish human self-reported perceptions of mental workload. Methods: In this study, EEG data from 48 participants were analyzed while engaged in resting and task-intensive activities. Multiple mental workload indices were developed using different EEG channel clusters and band ratios. ANOVA’s F-score and PowerSHAP were used to extract the statistical features. At the same time, models were built and tested using techniques such as Logistic Regression, Gradient Boosting, and Random Forest. These models were then explained using Shapley Additive Explanations. Results: Based on the results, using PowerSHAP to select features led to improved model performance, exhibiting an accuracy exceeding 90% across three mental workload indexes. In contrast, statistical techniques for model building indicated poorer results across all mental workload indexes. Moreover, using Shapley values to evaluate feature contributions to the model output, it was noted that features rated low in importance by both ANOVA F-score and PowerSHAP measures played the most substantial role in determining the model output. Conclusions: Using models with Shapley values can reduce data complexity and improve the training of better discriminative models for perceived human mental workload. However, the outcomes can sometimes be unclear due to variations in the significance of features during the selection process and their actual impact on the model output.
Customizable Nichrome Wire Heaters for Molecular Diagnostic Applications
Authors: Lim Juhee , Han Won , Thang Le Tran Huy , Lee Yong Wook , Shin Joong Ho
Published: March 2024

Accurate sample heating is vital for nucleic acid extraction and amplification, requiring a sophisticated thermal cycling process in nucleic acid detection. Traditional molecular detection systems with heating capability are bulky, expensive, and primarily designed for lab settings. Consequently, their use is limited where lab systems are unavailable. This study introduces a technique for performing the heating process required in molecular diagnostics applicable for point-of-care testing (POCT), by presenting a method for crafting customized heaters using freely patterned nichrome (NiCr) wire. This technique, fabricating heaters by arranging protrusions on a carbon black-polydimethylsiloxane (PDMS) cast and patterning NiCr wire, utilizes cost-effective materials and is not constrained by shape, thereby enabling customized fabrication in both two-dimensional (2D) and three-dimensional (3D). To illustrate its versatility and practicality, a 2D heater with three temperature zones was developed for a portable device capable of automatic thermocycling for polymerase chain reaction (PCR) to detect Escherichia coli (E. coli) O157:H7 pathogen DNA. Furthermore, the detection of the same pathogen was demonstrated using a customized 3D heater surrounding a microtube for loop-mediated isothermal amplification (LAMP). Successful DNA amplification using the proposed heater suggests that the heating technique introduced in this study can be effectively applied to POCT.
A Narrative Review of Current and Emerging Trends in the Treatment of Alcohol Use Disorder
Authors: Celik Muhammet , Gold Mark S. , Fuehrlein Brian
Published: March 2024

Alcohol use disorder (AUD) is a significant contributor to morbidity and mortality in the United States. It contributes to over 140,000 annual deaths, to over 200 related diseases and health conditions globally, and accounts for 5.1% of the global disease burden. Despite its substantial impact, AUD remains undertreated, marked by a scarcity of approved medications. This paper explores the current treatment landscape and novel strategies for both alcohol withdrawal syndrome and AUD. Promising results, including the use of psychedelics alongside psychotherapy, noninvasive neural-circuit-based interventions, phosphodiesterase-4 inhibitors, and GLP-1 receptor agonists, have emerged from recent studies. While these advancements show potential, further research is crucial for a comprehensive understanding of their effectiveness. The clear shortage of approved medications and other treatment modalities underscores the pressing need for ongoing research.
Exploring Immunological Effects and Novel Immune Adjuvants in Immunotherapy for Salivary Gland Cancers
Authors: Sato Ryosuke , Yamaki Hidekiyo , Komatsuda Hiroki , Wakisaka Risa , Inoue Takahiro , Kumai Takumi , Takahara Miki
Published: March 2024

Salivary gland cancer (SGC) is rare and comprises over 20 histological subtypes. Recently, clinical experience regarding immunotherapies for SGCs has been accumulating, yet their efficacy remains controversial. Understanding the tumor microenvironment (TME), including the expression of immune checkpoint molecules in SGC, is crucial to optimizing immunotherapy. In this review, we demonstrate that high-grade mucoepidermoid carcinoma and salivary duct carcinoma generally exhibit immune-hot TME with high immune cell infiltration, frequent genetic mutations, and robust immune checkpoint molecule expression. In contrast, adenoid cystic carcinomas exhibit an immune-cold TME. While the reported efficacy of immune checkpoint inhibitors (ICIs) for SGCs is generally poor, several studies showed promising clinical efficacy of ICIs, with an objective response rate ranging from 20.0–33.3%, indicating that ICIs might be beneficial for a specific population of SGC. Molecule-targeted therapies including anti-human epidermal growth factor receptor 2 and anti-androgen receptor therapies have shown promising clinical efficacy against SGC. Recent evidence indicates that these molecules could be targets for antigen-specific immunotherapies including chimeric antigen receptor-T therapy and cancer vaccines. This review discusses the current understanding and future directions of immunotherapies for SGCs, including ongoing clinical trials.
Correction: Casili et al. Therapeutic Potential of BAY-117082, a Selective NLRP3 Inflammasome Inhibitor, on Metastatic Evolution in Human Oral Squamous Cell Carcinoma (OSCC). Cancers 2023, 15, 2796
Authors: Casili Giovanna , Scuderi Sarah Adriana , Lanza Marika , Filippone Alessia , Mannino Deborah , Giuffrida Raffaella , Colarossi Cristina , Mare Marzia , Capra Anna Paola , De Gaetano Federica , Portelli Marco , Militi Angela , Cuzzocrea Salvatore , Paterniti Irene , Esposito Emanuela
Published: March 2024

In the original publication [...]
Mutations in the Serine/Threonine Kinase BRAF: Oncogenic Drivers in Solid Tumors
Authors: Roa Paola , Bremer Nicole Virginia , Foglizzo Valentina , Cocco Emiliano
Published: March 2024

Since their discovery in 2002, BRAF mutations have been identified as clear drivers of oncogenesis in several cancer types. Currently, their incidence rate is nearly 7% of all solid tumors with BRAF V600E constituting approximately 90% of these diagnoses. In melanoma, thyroid cancer, and histiocytic neoplasms, BRAF hotspot mutations are found at a rate of about 50%, while in lung and colorectal cancers they range from 3% to 10% of reported cases. Though present in other malignancies such as breast and ovarian cancers, they constitute a small portion of diagnoses (<1%). Given their frequency along with advancements in screening technologies, various methods are used for the detection of BRAF-mutant cancers. Among these are targeted next-generation sequencing (NGS) on tumor tissue or circulating tumor DNA (ctDNA) and immunohistochemistry (IHC)-based assays. With advancements in detection technologies, several approaches to the treatment of BRAF-mutant cancers have been taken. In this review, we retrace the milestones that led to the clinical development of targeted therapies currently available for these tumors.
Longitudinal Assessment of Quality of Life in Nasopharyngeal Cancer Patients Treated with Intensity-Modulated Proton Therapy and Volumetric Modulated Arc Therapy at Different Time Points
Authors: Liao Kuan-Cho , Huang Yu-Jie , Tsai Wen-Ling , Lee Chien-Hung , Fang Fu-Min
Published: March 2024

Purpose: This retrospective cohort study aims to compare the quality of life (QoL) in patients with nasopharyngeal cancer (NPC) treated with intensity-modulated proton therapy (IMPT) versus volumetric modulated arc therapy (VMAT) at different time points. Materials and Methods: We conducted a longitudinal assessment of QoL on 287 newly diagnosed NPC patients (IMPT: 41 and VMAT: 246). We collected outcomes of global QoL, functional QoL, C30 symptoms, and HN35 symptoms from EORTC QLQ-C30 and QLQ-HN35 questionnaires at pre-radiotherapy, during radiotherapy (around 40 Gy), 3 months post radiotherapy, and 12-months post radiotherapy (RT). The generalized estimating equation was utilized to interpret the group effect, originating from inherent group differences; time effect, attributed to RT effects over time; and interaction of the group and time effect. Results: IMPT demonstrated superior mean dose reductions in 12 of the 16 organs at risk compared to VMAT, including a significant (>50%) reduction in the oral cavity and larynx. Both groups exhibited improved scores of global QoL, functional QoL, and C30 symptoms at 12 months post RT compared to the pre-RT status. Regarding global QoL and C30 symptoms, there was no interaction effect of group over time. In contrast, significant interaction effects were observed on functional QoL (p = 0.040) and HN35 symptoms (p = 0.004) during RT, where IMPT created an average of 7.5 points higher functional QoL and 10.7 points lower HN35 symptoms than VMAT. Conclusions: Compared to VMAT, dose reduction attributed to IMPT could translate into better functional QoL and HN35 symptoms, but the effect is time dependent and exclusively observed during the RT phase.
Proteomic Profiling of Cerebrospinal Fluid and Its Extracellular Vesicles from Extraventricular Drainage in Pediatric Pilocytic Astrocytoma, towards Precision Oncology
Authors: Spinelli Sonia , Kajana Xhuliana , Garbarino Andrea , Bartolucci Martina , Petretto Andrea , Pavanello Marco , Verrina Enrico , Candiano Giovanni , Panfoli Isabella , Bruschi Maurizio
Published: March 2024

Pediatric pilocytic astrocytoma (PA) is the most common brain tumor in children. Complete resection provides a favorable prognosis, except for unresectable PA forms. There is an incomplete understanding of the molecular and cellular pathogenesis of PA. Potential biomarkers for PA patients, especially the non-BRAF-mutated ones are needed. Cerebrospinal fluid (CSF) is a valuable source of brain tumor biomarkers. Extracellular vesicles (EVs), circulating in CSF, express valuable disease targets. These can be isolated from CSF from waste extraventricular drainage (EVD). We analyzed the proteome of EVD CSF from PA, congenital hydrocephalus (CH, non-tumor control), or medulloblastoma (MB, unrelated tumoral control) patients. A total of 3072 proteins were identified, 47.1%, 65.6%, and 86.2% of which were expressed in the unprocessed total and in its large-EV (LEV), and small-EV (SEV) fractions. Bioinformatics identified 50 statistically significant proteins in the comparison between PA and HC, and PA and MB patients, in the same fractions. Kinase enrichment analysis predicted five enriched kinases involved in signaling. Among these, only Cyclin-dependent kinase 2 (CDK2) kinase was overexpressed in PA samples. PLS-DA highlighted the inactive carboxypeptidase-like protein X2 (CPXM2) and aquaporin-4 (AQP4) as statistically significant in all the comparisons, with CPXM2 being overexpressed (validated by ELISA and Western blot) and AQP4 downregulated in PA. These proteins were considered the most promising potential biomarkers for discriminating among pilocytic astrocytoma and unrelated tumoral (MB) or non-tumoral conditions in all the fractions examined, and are proposed to be prospectively validated in the plasma for translational medicine applications.
T-Cell Subtypes and Immune Signatures in Cutaneous Immune-Related Adverse Events in Melanoma Patients under Immune Checkpoint Inhibitor Therapy
Authors: Absmaier-Kijak Magdalena , Iuliano Caterina , Kaesler Susanne , Biedermann Tilo , Posch Christian , Brockow Knut
Published: March 2024

Immune checkpoint inhibition (ICI) improves outcomes in melanoma patients, but associated T-cell activation frequently leads to immune-related cutaneous adverse events (cutAEs). To dynamically identify T-cell subtypes and immune signatures associated with cutAEs, a pilot study was performed in stage III-IV melanoma patients using blood samples for flow cytometry and cytokine analysis. Blood samples were taken from patients before initiation of ICI (naive), at the onset of a cutAE, and after 6 months of ICI treatment. Overall, 30 patients were treated either with anti-PD1 monotherapy or with anti-PD-1/anti-CTLA-4 combination therapy. Flow cytometry analysis of PBMCs showed that ICI induced an overall shift from a Th2 towards a Th1 profile. Twelve patients (40%) developed cutAEs, which were associated with increased Th22 cells and Th17 cells, supported by a tendency to have elevated Th17/Th22-associated cytokines such as IL-17A, IL-22 and IL-23 levels in the plasma. Cytokine signatures specific for urticaria and T-cell-mediated cutAEs were identified in the plasma of patients by a bead-based assay. IL-10 was elevated in non-responders and, interestingly, during cutAEs. In conclusion, we identified distinct immune signatures based on the Th17/Th22 pathway in cutAEs, both in PBMCs and plasma. In addition, our finding of upregulated IL-10 during cutAEs supports the notion of treating these patients early and adequately to avoid implications for the overall outcome.
Real-World Outcome of Treatment with Single-Agent Ibrutinib in Italian Patients with Chronic Lymphocytic Leukemia: Final Results of the EVIdeNCE Study
Authors: Mauro Francesca Romana , Scalzulli Potito Rosario , Scarfò Lydia , Minoia Carla , Murru Roberta , Sportoletti Paolo , Frigeri Ferdinando , Albano Francesco , Di Renzo Nicola , Sanna Alessandro , Laurenti Luca , Massaia Massimo , Cassin Ramona , Coscia Marta , Patti Caterina , Pennese Elsa , Tafuri Agostino , Chiarenza Annalisa , Galieni Piero , Perbellini Omar , Selleri Carmine , Califano Catello , Ferrara Felicetto , Cuneo Antonio , Murineddu Marco , Palumbo Gaetano , Scortechini Ilaria , Tedeschi Alessandra , Trentin Livio , Varettoni Marzia , Pane Fabrizio , Liberati Anna Marina , Merli Francesco , Morello Lucia , Musuraca Gerardo , Tani Monica , Ibatici Adalberto , Regazzoni Giulia , Di Candia Michele , Palma Maria , Arienti Danilo , Molica Stefano
Published: March 2024

Real-world data in clinical practice are needed to confirm the efficacy and safety that ibrutinib has demonstrated in clinical trials of patients with chronic lymphocytic leukemia (CLL). We described the real-world persistence rate, patterns of use, and clinical outcomes in 309 patients with CLL receiving single-agent ibrutinib in first line (1L, n = 118), 2L (n = 127) and ≥3L (n = 64) in the prospective, real-world, Italian EVIdeNCE study. After a median follow-up of 23.9 months, 29.8% of patients discontinued ibrutinib (1L: 24.6%, 2L: 29.9%, ≥3L: 39.1%), mainly owing to adverse events (AEs)/toxicity (14.2%). The most common AEs leading to discontinuation were infections (1L, ≥3L) and cardiac events (2L). The 2-year retention rate was 70.2% in the whole cohort (1L: 75.4%, 2L: 70.1%, ≥3L: 60.9%). The 2-year PFS and OS were, respectively, 85.4% and 91.7% in 1L, 80.0% and 86.2% in 2L, and 70.1% and 80.0% in ≥3L. Cardiovascular conditions did not impact patients’ clinical outcomes. The most common AEs were infections (30.7%), bleeding (12.9%), fatigue (10.0%), and neutropenia (9.7%), while grade 3–4 atrial fibrillation occurred in 3.9% of patients. No new safety signals were detected. These results strongly support ibrutinib as a valuable treatment option for CLL.
COVID-19 and the Heart: Lessons Learned and Future Research Directions
Authors: Lee Tetz , Omar Alaa , Bella Jonathan
Published: March 2024

It has become evident that acute COVID-19 infection can lead to cardiovascular complications. While the exact mechanisms by which COVID-19 affects the cardiovascular system have yet to be fully elucidated, several mechanisms have been proposed, including direct myocardial effects on the virus and systemic inflammation as an indirect result. The cardiovascular complications of COVID-19 have been characterized and described using noninvasive cardiac imaging. The impact of COVID-19 on the cardiovascular system extends beyond the acute phase of the infection and well beyond recovery or the convalescent period. However, the underlying mechanisms of post-viral long-COVID symptoms have yet to be elucidated. It is evident that COVID-19 has become endemic and is here to stay. Future studies are needed (1) to understand the long-term effects of the cardiovascular complications of COVID-19, future cardiovascular events and the impact of mutating variants on cardiovascular complications through data collection and analysis, (2) to identify the most important diagnostic criteria for prognosis of COVID-19 and to understand the disease mechanism through biomarkers and advanced cardiac imaging, including echocardiography and (3) to develop novel strategies to manage and treat these cardiovascular complications using the knowledge gained.
Hydrocracking of a HDPE/VGO Blend: Influence of Catalyst-to-Feed Ratio on Fuel Yield and Composition
Authors: Vela Francisco J. , Palos Roberto , Bilbao Javier , Arandes José M. , Gutiérrez Alazne
Published: March 2024

The effects that the catalyst-to-feed ratio have on the yields of products and composition of the naphtha and light cycle oil (LCO) fractions in the hydrocracking of a blend composed of high-density polyethylene (HDPE) and vacuum gasoil (VGO) using a PtPd/HY catalyst were assessed. The hydrocracking runs were carried out in a batch reactor fixing the following operation conditions: 420 °C, 80 bar, 120 min and an HDPE-to-VGO ratio of 0.2 gHDPE gVGO−1, varying the catalyst-to-feed mass ratio within the 0.05–0.1 gcatalyst gfeed−1 range. The obtained results exposed that a catalyst-to-feed mass ratio of 0.075 gcatalyst gfeed−1 provided the best results, since the conversion of the heavy cycle oil (HCO) fraction and of the HDPE offered quite high values (73.1 and 63.9%, respectively) without causing an excessive overcracking in the form of gas products (the yield of gases was of 25%). Moreover, an interesting yield of naphtha (37.0 wt%) with an RON within the commercial standards (92.5) was obtained. With regard to coke formation, not-so-developed structures were formed for a catalyst-to-feed mass ratio of 0.075 gcatalyst gfeed−1, easing their combustion and presumably extending the lifespan of the catalyst.
All but Small: miRNAs from Wharton’s Jelly-Mesenchymal Stromal Cell Small Extracellular Vesicles Rescue Premature White Matter Injury after Intranasal Administration
Authors: Tscherrig Vera , Steinfort Marel , Haesler Valérie , Surbek Daniel , Schoeberlein Andreina , Joerger-Messerli Marianne Simone
Published: March 2024

White matter injury (WMI) is a common neurological issue in premature-born neonates, often causing long-term disabilities. We recently demonstrated a key beneficial role of Wharton’s jelly mesenchymal stromal cell-derived small extracellular vesicles (WJ-MSC-sEVs) microRNAs (miRNAs) in WMI-related processes in vitro. Here, we studied the functions of WJ-MSC-sEV miRNAs in vivo using a preclinical rat model of premature WMI. Premature WMI was induced in rat pups through inflammation and hypoxia-ischemia. Small EVs were purified from the culture supernatant of human WJ-MSCs. The capacity of WJ-MSC-sEV-derived miRNAs to decrease microglia activation and promote oligodendrocyte maturation was evaluated by knocking down (k.d) DROSHA in WJ-MSCs, releasing sEVs containing significantly less mature miRNAs. Wharton’s jelly MSC-sEVs intranasally administrated 24 h upon injury reached the brain within 1 h, remained detectable for at least 24 h, significantly reduced microglial activation, and promoted oligodendrocyte maturation. The DROSHA k.d in WJ-MSCs lowered the therapeutic capabilities of sEVs in experimental premature WMI. Our results strongly indicate the relevance of miRNAs in the therapeutic abilities of WJ-MSC-sEVs in premature WMI in vivo, opening the path to clinical application.
Comparison of Minced Cartilage Implantation with Autologous Chondrocyte Transplantation in an In Vitro Inflammation Model
Authors: Ossendorff Robert , Grede Lisa , Scheidt Sebastian , Strauss Andreas C. , Burger Christof , Wirtz Dieter C. , Salzmann Gian M. , Schildberg Frank A.
Published: March 2024

The current gold standard to treat large cartilage defects is autologous chondrocyte transplantation (ACT). As a new surgical method of cartilage regeneration, minced cartilage implantation (MCI) is increasingly coming into focus. The aim of this study is to investigate the influence of chondrogenesis between isolated and cultured chondrocytes compared to cartilage chips in a standardized inflammation model with the proinflammatory cytokine TNFα. Articular chondrocytes from bovine cartilage were cultured according to the ACT method to passage 3 and transferred to spheroid culture. At the same time, cartilage was fragmented (<1 mm3) to produce cartilage chips. TNFα (20 ng/mL) was supplemented to simulate an inflammatory process. TNFα had a stronger influence on the passaged chondrocytes compared to the non-passaged ones, affecting gene expression profiles differently between isolated chondrocytes and cartilage chips. MCI showed less susceptibility to TNFα, with reduced IL-6 release and less impact on inflammation markers. Biochemical and histological analyses supported these findings, showing a greater negative influence of TNFα on the passaged pellet cultures compared to the unpassaged cells and MCI constructs. This study demonstrated the negative influence of TNFα on chondrogenesis in a chondrocyte spheroid culture and cartilage fragment model. Passaged chondrocytes are more sensitive to cytokine influences compared to non-passaged cells and chondrons. This suggests that MCI may have superior regeneration potential in osteoarthritic conditions compared to ACT. Further investigations are necessary for the translation of these findings into clinical practice.
Generation of Highly Functional Hepatocyte-like Organoids from Human Adipose-Derived Mesenchymal Stem Cells Cultured with Endothelial Cells
Authors: Chen Shuhai , Saito Yu , Waki Yuhei , Ikemoto Tetsuya , Teraoku Hiroki , Yamada Shinichiro , Morine Yuji , Shimada Mitsuo
Published: March 2024

Previously, we successfully established a highly functional, three-dimensional hepatocyte-like cell (3D-HLC) model from adipose-derived mesenchymal stem cells (ADSCs) via a three-step differentiation protocol. The aim of the present study was to investigate whether generating hepatocyte-like organoids (H-organoids) by adding endothelial cells further improved the liver-like functionality of 3D-HLCs and to assess H-organoids’ immunogenicity properties. Genes representing liver maturation and function were detected by quantitative reverse transcription–PCR analysis. The expression of hepatic maturation proteins was measured using immunofluorescence staining. Cytochrome P (CYP)450 metabolism activity and ammonia metabolism tests were used to assess liver function. H-organoids were successfully established by adding human umbilical vein endothelial cells at the beginning of the definitive endoderm stage in our 3D differentiation protocol. The gene expression of alpha-1 antitrypsin, carbamoyl–phosphate synthase 1, and apolipoprotein E, which represent liver maturation state and function, was higher in H-organoids than non-organoid 3D-HLCs. H-organoids possessed higher CYP3A4 metabolism activity and comparable ammonia metabolism capacity than 3D-HLCs. Moreover, although H-organoids expressed human leukocyte antigen class I, they expressed little human leukocyte antigen class II, cluster of differentiation (CD)40, CD80, CD86, and programmed cell death ligand 1, suggesting their immunogenicity properties were not significantly upregulated during differentiation from ADSCs. In conclusion, we successfully established an H-organoid model with higher liver-like functionality than previously established 3D-HLCs and comparable immunogenicity to ADSCs.
Eye Drop with Fas-Blocking Peptide Attenuates Age-Related Macular Degeneration
Authors: Yi Yujong , Pyun Seon-Hong , Kim Chae-Yeon , Yun Gyeongju , Kang Eunhwa , Heo Seoyoun , Ullah Irfan , Lee Sang-Kyung
Published: March 2024

Age-related macular degeneration (AMD), characterized by macular retinal degeneration, poses a significant health concern due to the lack of effective treatments for prevalent dry AMD. The progression of AMD is closely linked to reactive oxygen species and Fas signaling, emphasizing the need for targeted interventions. In this study, we utilized a NaIO3-induced retinal degeneration mouse model to assess the efficacy of Fas-blocking peptide (FBP). Intravitreal administration of FBP successfully suppressed Fas-mediated inflammation and apoptosis, effectively arresting AMD progression in mice. We developed a 6R-conjugated FBP (6R-FBP) for eye drop administration. 6R-FBP, administered as an eye drop, reached the retinal region, attenuating degeneration by modulating the expression of inflammatory cytokines and blocking Fas-mediated apoptosis in rodent and rabbit NaIO3-induced retinal degeneration models to address practical concerns. Intravitreal FBP and 6R-FBP eye drops effectively reduced retinal degeneration and improved retinal thickness in rodent and rabbit models. This study highlights the therapeutic potential of FBP, particularly 6R-FBP as an eye drop, in inhibiting Fas-mediated cell signaling and protecting against retinal cell death and inflammation in dry AMD. Future investigations should explore the translational prospects of this approach in primates with eye structures comparable to those of humans.
The Natural World in Western Thought
Authors: Jarwar Mazhar Ali , Dumontet Stefano , Pasquale Vincenzo
Published: March 2024

The Western approach to the natural world, considering “nature” as an object of scientific scrutiny and of exploitation for economic purposes, results in a separateness and subsequent alienation from nature. The overarching aim of this paper is to emphasize the limitations and consequences of this approach, including how nature is perceived, the value attributed to nature, and the substantial denial of cultural contributions from non-Western philosophical and scientific backgrounds. We also consider the Western attempt at balancing industrial and technological endeavors, aimed at preserving ecological equilibria. In this framework, we argue that the current ever-increasing concern about sustainability cannot be decoupled from the perception of nature and natural values, whether material, aesthetic, or spiritual. Therefore, modern sustainability challenges, mainly attributable to Western overexploitation of nature and natural resources, need to be considered in the context of the limited Western paradigms, which often leave the very definition of nature unanswered. We argue that efforts to ease the anthropogenic pressure on natural ecosystems, leading to their degradation, cannot be uniquely bounded by Western science and its technological appendices.
Profile of the Effectiveness Factor under Optimal Operating Conditions for the Conversion of Ortho-Xylene to Phthalic Anhydride in a Fixed-Bed Tubular Reactor
Authors: Carrasco-Venegas Luis Américo , Vásquez-Alvarez Elsa , González-Fernández José Vulfrano , Castañeda-Pérez Luz Genara , Medina-Collana Juan Taumaturgo , Palomino-Hernández Guido , Martínez-Hilario Daril Giovanni , Trujillo-Pérez Salvador Apolinar
Published: March 2024

The objective of this research is to find the effectiveness factor of the catalyst particles for the most favorable conditions of the phthalic anhydride production in a fixed bed reactor, with the aim of achieving the highest rate of phthalic anhydride production compared to other secondary products and analyzing the areas of lower effectiveness for the modification of the reactor design. Initially, the material and the energy balances in the catalytic bed are solved to obtain the concentration and temperature profiles based on the radius and length of the reactor, using polymath software(Polymath® v6.2 Software Minitab 19 Matlab 2019) with the data from literature. Once the profiles reproducibility was verified using the initial data (inlet temperature, pressure in the reactor, reactor wall temperature, reactor radius and mass flow rate) the experimental design 35 carry out, which generates 243 “experiments”, whose response variable (phthalic anhydride concentration) was obtained using Matlab. Subsequently, the variables were analyzed using the Minitab 18® that, through the response surface analysis method, allowed us to obtain the optimal values of the tested variables. Then, Subsequently, material and energy balances coupled with Fourier and Fick’s laws, along with the effectiveness factor equation, were applied, resulting in the generation of 9 coupled differential equations. Upon implementing the finite difference method, this yielded 90 nonlinear algebraic equations, which were solved using the Polymath software. A total of 78 particles were preselected based on their radial and axial positions to determine the effectiveness factor profile, with values ranging from 0.83 to near unity. The lower values correspond to the points with higher temperature, as evidenced by the calculations performed.
Utilizing Peripheral Nerve Blocks for Pain Management in Pediatric Patients during Embolization and Sclerotherapy for Vascular Malformations
Authors: Kocher Matthew , Evankovich Maria , Lavage Danielle R. , Yilmaz Sabri , Sadhasivam Senthilkumar , Visoiu Mihaela
Published: March 2024

Vascular anomalies are a diverse group of abnormal blood vessel developments that can occur at birth or shortly afterward. Embolization and sclerotherapy have been utilized as a treatment option for these malformations but may cause moderate-to-severe pain. This study aims to evaluate the utilization of peripheral nerve blocks in opioid consumption, pain scores, and length of stay. A retrospective chart review was conducted at the UPMC Children’s Hospital of Pittsburgh for all patients who underwent embolization and sclerotherapy between 2011 and 2020. Patient data were collected to compare opioid consumption, pain scores, and length of stay. In total, 854 procedures were performed on 347 patients. The morphine milligram equivalent per kilogram mean difference between groups was 0.9 (0.86, 0.95) with a p-value of <0.001. The pain score mean ratio was −1.17 (−2.2, −0.1) with a p-value of 0.027. The length of stay had an incident rate ratio of 0.94 (0.4, 2) and a p-value of 0.875. By decreasing opioid consumption and postoperative pain scores, peripheral nerve blocks may have utility in patients undergoing embolization and sclerotherapy while not clinically increasing the length of stay for patients. Their use should be individualized and carefully discussed with the interventional radiologist.