Search Results (30)

Background and Objectives: The pulmonary artery pulsatility index (PAPi) is an emerging marker of right ventricular (RV) injury but has not been well investigated in acute pulmonary embolism (PE) or chronic thromboembolic pulmonary hypertension (CTEPH). We aimed to investigate its discriminatory capabilities and ability to detect therapeutic effects in acute PE and CTEPH. Materials and Methods: This was a secondary analysis of data from both experimental studies of autologous PE and human studies of acute PE and CTEPH. PAPi was calculated and compared in (1) PE versus sham and (2) before and after interventions aimed at reducing RV afterload in PE and CTEPH. The correlations between PAPi, cardiac output, and RV to pulmonary artery coupling were investigated. Results: PAPi did not differ between animals with acute PE versus sham, nor was it affected by clot burden (p = 0.673) or at a 30-day follow-up (p = 0.242). Pulmonary vasodilatation with oxygen was associated with a reduction in PAPi (4.9 [3.7–7.8] vs. 4.0 [3.2–5.6], p = 0.016), whereas positive inotropes increased PAPi in the experimental PE. In humans, PAPi did not change consistently with interventions. Balloon pulmonary angioplasty did not significantly increase PAPi (6.5 [4.3–10.7] vs. 9.8 [6.8–14.2], p = 0.1) in patients with CTEPH, and a non-significant reduction in PAPi (4.3 ± 1.6 vs. 3.3 ± 1.2, p = 0.074) was observed in patients with acute PE who received sildenafil. PAPi did not correlate well with cardiac output or measures of RV to pulmonary artery coupling in either species. Conclusions: PAPi did not detect acute, experimental PE or changes as a result of therapeutic interventions in patients with hemodynamically stable acute PE or CTEPH. However, it did change with pharmacological interventions in the experimental PE. Further research should establish its utility in detecting and monitoring RV injury in different clinical phenotypes of acute PE and CTEPH. Full article

Background: During the initial steps of green biorefining aimed at protein recovery, endogenous proteins and enzymes, along with, e.g., phytochemical constituents, are decompartmentalized into a green juice. This creates a highly dynamic environment prone to a plethora of reactions including oxidative protein modification and deterioration. Obtaining a fundamental understanding of the enzymes capable of exerting antioxidant activity ex vivo could help mitigate these reactions for improved product quality. Methods: In this study, we investigated perennial ryegrass (Lolium perenne var. Abosan 1), one of the most widely used turf and forage grasses, as a model system. Using size exclusion chromatography, we fractionated the green juice to investigate in vitro antioxidant properties and coupled this with quantitative bottom-up proteomics, GO-term analysis, and fraction-based enrichment. Results: Our findings revealed that several enzymes, such as superoxide dismutase and peroxiredoxin proteoforms, already known for their involvement in in vivo oxidative protection, are enriched in fractions displaying increased in vitro antioxidant activity, indicating retained activity ex vivo. Moreover, this study provides the most detailed characterization of the L. perenne proteome today and delivers new insights into protein-level partitioning during wet fractionation. Conclusions: Ultimately, this work contributes to a better understanding of the first steps of green biorefining and provides the basis for process optimization. Full article

Circulating tumor DNA (ctDNA) is a promising cancer biomarker, but accurately detecting tumor mutations in cell-free DNA (cfDNA) is challenging due to their low frequency and sequencing errors. Our study benchmarked Mutect2, VarScan2, shearwater, and DREAMS-vc using deep targeted sequencing of cfDNA with Unique Molecular Identifiers (UMIs) from 111 colorectal cancer patients. Performance was assessed at both the mutation level (distinguish tumor variants from errors) and the sample level (detect if an individual has cancer). Additionally, we investigated the effects of various UMI grouping and consensus strategies. The shearwater-AND variant calling method demonstrated the highest precision in detecting tumor-derived mutations from plasma, and reached the highest ROC-AUC of 0.984 for sample classification in tumor-informed cfDNA analyses. DREAMS-vc exhibited the highest ROC-AUC of 0.808 for sample classification in tumor-agnostic studies. We also found that sequencing depth differences in PBMCs could lead to false positives, particularly with VarScan2 and Mutect2, which was addressed by downsampling to equivalent mean depths. Additionally, network-based UMI grouping methods outperformed those using identical UMIs when all reads were retained. Our findings emphasize that the optimal variant caller depends on the study context—whether focused on mutation or sample classification, and whether conducted under tumor-informed or tumor-agnostic conditions. Full article

Movement-related cortical potential (MRCP) is observed in EEG recordings prior to a voluntary movement. It has been used for e.g., quantifying motor learning and for brain-computer interfacing (BCIs). The MRCP amplitude is affected by various factors, but the effect of caffeine is underexplored. The aim of this study was to investigate if a cup of coffee with 85 mg caffeine modulated the MRCP amplitude and the classification of MRCPs versus idle activity, which estimates BCI performance. Twenty-six healthy participants performed 2 × 100 ankle dorsiflexion separated by a 10-min break before a cup of coffee was consumed, followed by another 100 movements. EEG was recorded during the movements and divided into epochs, which were averaged to extract three average MRCPs that were compared. Also, idle activity epochs were extracted. Features were extracted from the epochs and classified using random forest analysis. The MRCP amplitude did not change after consuming caffeine. There was a slight increase of two percentage points in the classification accuracy after consuming caffeine. In conclusion, a cup of coffee with 85 mg caffeine does not affect the MRCP amplitude, and improves MRCP-based BCI performance slightly. The findings suggest that drinking coffee is only a minor confounder in MRCP-related studies. Full article

Circulating tumor DNA (ctDNA) is a promising biomarker, reflecting the presence of tumor cells. Sequencing-based detection of ctDNA at low tumor fractions is challenging due to the crude error rate of sequencing. To mitigate this challenge, we developed ultra-deep mutation-integrated sequencing (UMIseq), a fixed-panel deep targeted sequencing approach, which is universally applicable to all colorectal cancer (CRC) patients. UMIseq features UMI-mediated error correction, the exclusion of mutations related to clonal hematopoiesis, a panel of normal samples for error modeling, and signal integration from single-nucleotide variations, insertions, deletions, and phased mutations. UMIseq was trained and independently validated on pre-operative (pre-OP) plasma from CRC patients (n = 364) and healthy individuals (n = 61). UMIseq displayed an area under the curve surpassing 0.95 for allele frequencies (AFs) down to 0.05%. In the training cohort, the pre-OP detection rate reached 80% at 95% specificity, while it was 70% in the validation cohort. UMIseq enabled the detection of AFs down to 0.004%. To assess the potential for detection of residual disease, 26 post-operative plasma samples from stage III CRC patients were analyzed. From this we found that the detection of ctDNA was associated with recurrence. In conclusion, UMIseq demonstrated robust performance with high sensitivity and specificity, enabling the detection of ctDNA at low allele frequencies. Full article

Philadelphia chromosome-negative chronic myeloproliferative neoplasms (MPNs) arise due to acquired somatic driver mutations in stem cells and develop over 10–30 years from the earliest cancer stages (essential thrombocythemia, polycythemia vera) towards the advanced myelofibrosis stage with bone marrow failure. The JAK2V617F mutation is the most prevalent driver mutation. Chronic inflammation is considered to be a major pathogenetic player, both as a trigger of MPN development and as a driver of disease progression. Chronic inflammation in MPNs is characterized by persistent connective tissue remodeling, which leads to organ dysfunction and ultimately, organ failure, due to excessive accumulation of extracellular matrix (ECM). Considering that MPNs are acquired clonal stem cell diseases developing in an inflammatory microenvironment in which the hematopoietic cell populations are progressively replaced by stromal proliferation—“a wound that never heals”—we herein aim to provide a comprehensive review of previous promising research in the field of circulating ECM fragments in the diagnosis, treatment and monitoring of MPNs. We address the rationales and highlight new perspectives for the use of circulating ECM protein fragments as biologically plausible, noninvasive disease markers in the management of MPNs. Full article

Objective: Circulating tumor DNA (ctDNA) is a candidate biomarker of cancer with practice-changing potential in the detection of both early and residual disease. Disease stage and tumor size affect the probability of ctDNA detection, whereas little is known about the influence of other tumor characteristics on ctDNA detection. This study investigates the impact of tumor cell whole-genome doubling (WGD) on the detection of ctDNA in plasma collected preoperatively from newly diagnosed colorectal cancer (CRC) patients. Methods: WGD was estimated from copy numbers derived from whole-exome sequencing (WES) data of matched tumor and normal DNA from 833 Danish CRC patients. To explore if tumor WGD status impacts ctDNA detection, we applied tumor-informed ctDNA analysis to preoperative plasma samples from all patients. Results: Patients with WGD+ tumors had 53% increased odds of being ctDNA positive (OR = 1.53, 95%CI: 1.12–2.09). After stratification for UICC stage, the association persisted for Stage I (OR = 2.44, 95%CI: 1.22–5.03) and Stage II (OR = 1.76, 95%CI: 1.11–2.81) but not for Stage III (OR = 0.83, 95%CI: 0.44–1.53) patients. Conclusion: The presence of WGD significantly increases the probability of detecting ctDNA, particularly for early-stage disease. In patients with more advanced disease, the benefit of WGD on ctDNA detection is less pronounced, consistent with increased DNA shedding from these tumors, making ctDNA detection less dependent on the amount of ctDNA released per tumor cell. Full article

The discovery of new inorganic magnesium electrolytes may act as a foundation for the rational design of novel types of solid-state batteries. Here we investigated a new type of organic-inorganic metal hydride, isopropylamine magnesium borohydride, Mg(BH₄)₂∙(CH₃)₂CHNH₂, with hydrophobic domains in the solid state, which appear to promote fast Mg²⁺ ionic conductivity. A new synthetic strategy was designed by combination of solvent-based methods and mechanochemistry. The orthorhombic structure of Mg(BH₄)₂∙(CH₃)₂CHNH₂ was solved ab initio by the Rietveld refinement of synchrotron X-ray powder diffraction data and density functional theory (DFT) structural optimization in space group I2₁2₁2₁ (unit cell, a = 9.8019(1) Å, b = 12.1799(2) Å and c = 17.3386(2) Å). The DFT calculations reveal that the three-dimensional structure may be stabilized by weak dispersive interactions between apolar moieties and that these may be disordered. Nanoparticles and heat treatment (at T > 56 °C) produce a highly conductive composite, σ(Mg²⁺) = 2.86 × 10⁻⁷, and 2.85 × 10⁻⁵ S cm⁻¹ at −10 and 40 °C, respectively, with a low activation energy, E_a = 0.65 eV. Nanoparticles stabilize the partially eutectic molten state and prevent recrystallization even at low temperatures and provide a high mechanical stability of the composite. Full article

The lockdown of society arising out of COVID-19 can be viewed as a microscope exposing the existential conditions and challenges of young people’s lives and their manner of dealing with crises. This study employs a qualitative research methodology using semi-structured interviews of 19 young people, aged 16–17 years, after the second COVID-19 lockdown in Denmark, March 2021. An analytical strategy was applied using reflexive methodology taking concepts from Søren Kierkegaard, Martin Buber, and Martin Heidegger to interpret the participants’ experiences of existential themes important to them, such as identity. Drawing on Kierkegaard’s idea of different “interpretive spheres” of life, we suggest that crisis revealed a disruption of the young peoples’ performance-oriented approach to life that made it possible to reflect and relate to themselves through aesthetic, ethical and self-transcending spheres. We suggest that the relationship to the other—as an ethical obligation, as an affective Being-with, and as something bigger than themselves—is crucial to the ways in which young people handle and relate to existential challenges and the experience of being and becoming themselves. The findings contribute to education and well-being, pointing out mental challenges among young people and stressing an existential focus as a priority in educational practice. Full article

Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are associated with an impaired autonomic nervous system and vagus nerve function. Electrical or physiological (deep breathing—DB) vagus nerve stimulation (VNS) could be a potential treatment approach, but no direct comparison has been made. In this study, the effect of transcutaneous auricular VNS (taVNS) and DB on vagal tone was compared in healthy participants and RA or SLE patients. The vagal tone was estimated using time-domain heart-rate variability (HRV) parameters. Forty-two healthy participants and 52 patients performed 30 min of DB and 30 min of taVNS on separate days. HRV was recorded before and immediately after each intervention. For the healthy participants, all HRV parameters increased after DB (SDNN + RMSSD: 21–46%), while one HRV parameter increased after taVNS (SDNN: 16%). For the patients, all HRV parameters increased after both DB (17–31%) and taVNS (18–25%), with no differences between the two types of VNS. DB was associated with the largest elevation of the HRV parameters in healthy participants, while both types of VNS led to elevated HRV parameters in the patients. The findings support a potential use of VNS as a new treatment approach, but the clinical effects need to be investigated in future studies. Full article

Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE) are associated with autonomic dysfunction, potentially through reduced vagus nerve tone. Vagus nerve stimulation has been proposed as an anti-inflammatory treatment, and it can be performed through deep breathing (DB) exercises. In this study, the dose-response relationship between DB exercises and heart rate variability (HRV) was investigated in healthy participants and reliability across days in patients with RA and SLE. On three separate days, 41 healthy participants performed DB for: 5, 15, or 30 min. On two separate days, 52 RA or SLE patients performed DB with the dose associated with the highest HRV increase in healthy participants. The HRV was estimated from ECG-recordings recorded prior and post the DB exercises. Increases in dose led to larger HRV-responses. Thirty minutes led to the largest HRV-response. In the RA and SLE patients, this dose increased the HRV-parameters consistently across the two days, indicating reliability. DB increases HRV in healthy participants and RA or SLE patients, which indicates stimulation of the vagus nerve. Of the tested durations, 30 min of DB was the optimal period of stimulation. A potential anti-inflammatory effect of DB exercises should be investigated in future studies. Full article

Background: Patients undergoing lung transplantation (LTx) experience a rapid decline in glomerular filtration rate (GFR) in the acute postoperative period. However, no prospective longitudinal studies directly comparing the performance of equations for estimating GFR in this patient population currently exist. Methods: In total, 32 patients undergoing LTx met the study criteria. At pre-LTx and 1-, 3-, and 12-weeks post-LTx, GFR was determined by ⁵¹Cr-EDTA and by equations for estimating GFR based on plasma (P)-Creatinine, P-Cystatin C, or a combination of both. Results: Measured GFR declined from 98.0 mL/min/1.73 m² at pre-LTx to 54.1 mL/min/1.73 m² at 12-weeks post-LTx. Equations based on P-Creatinine underestimated GFR decline after LTx, whereas equations based on P-Cystatin C overestimated this decline. Overall, the 2021 CKD-EPI combination equation had the lowest bias and highest precision at both pre-LTx and post-LTx. Conclusions: Caution must be applied when interpreting renal function based on equations for estimating GFR in the acute postoperative period following LTx. Simplified methods for measuring GFR may allow for more widespread use of measured GFR in this vulnerable patient population. Full article

Diagnosis of acute kidney injury (AKI) based on plasma creatinine often lags behind actual changes in renal function. Here, we investigated early detection of AKI using the plasma soluble urokinase plasminogen activator receptor (suPAR) and neutrophil gelatinase-sssociated lipocalin (NGAL) and observed the impact of early detection on prescribing recommendations for renally-eliminated medications. This study is a secondary analysis of data from the DISABLMENT cohort on acutely admitted older (≥65 years) medical patients (n = 339). Presence of AKI according to kidney disease: improving global outcomes (KDIGO) criteria was identified from inclusion to 48 h after inclusion. Discriminatory power of suPAR and NGAL was determined by receiver-operating characteristic (ROC). Selected medications that are contraindicated in AKI were identified in Renbase^®. A total of 33 (9.7%) patients developed AKI. Discriminatory power for suPAR and NGAL was 0.69 and 0.78, respectively, at a cutoff of 4.26 ng/mL and 139.5 ng/mL, respectively. The interaction of suPAR and NGAL yielded a discriminatory power of 0.80, which was significantly higher than for suPAR alone (p = 0.0059). Among patients with AKI, 22 (60.6%) used at least one medication that should be avoided in AKI. Overall, suPAR and NGAL levels were independently associated with incident AKI and their combination yielded excellent discriminatory power for risk determination of AKI. Full article

Antitumor activity of immune checkpoint blocking antibodies against programmed death 1 (PD-1) in basal cell carcinoma (BCC) has been described. IO103 is a peptide vaccine against the major PD-1 ligand PD-L1. A phase IIa study of vaccination with IO103 and Montanide adjuvant was conducted in patients with resectable BCC (NCT03714529). Vaccinations were given six times every 2 weeks (q2w), followed by three vaccines q4w in responders. Primary endpoints were clinical responses of target tumors, change in target tumor size and immune responses to the vaccine. Secondary endpoint was safety. One tumor per patient was designated target tumor and biopsied twice during the course of vaccination. Synchronous non-target BCCs were not biopsied during vaccinations. Ten patients were vaccinated (six patients received six vaccinations and four patients received nine vaccinations). A partial response (PR) was seen in two target tumors. Two complete responses (CR) and one PR were observed in eight non-target tumors in four patients. No tumors progressed. Related adverse events were grade 1 and reversible. Immune responses against IO103 were induced in blood samples from nine of ten and skin-infiltrating lymphocytes from five of the nine patients. The regressions seen in non-target tumors suggest that IO103 may be effective against a subtype of BCC. Full article

The RAS mutations are the most frequently occurring somatic mutations in humans, and several studies have established that T cells from patients with RAS-mutant cancer recognize and kill RAS-mutant cells. Enhancing the T cell response via therapeutic cancer vaccination against mutant RAS results in a clinical benefit to patients; thus, T cells specific to RAS mutations are effective at battling cancer. As the theory of cancer immuno-editing indicates that healthy donors may clear malignantly transformed cells via immune-mediated killing, and since T cells have been shown to recognize RAS-mutant cancer cells, we investigated whether healthy donors harbor T-cell responses specific to mutant RAS. We identified strong and frequent responses against several epitopes derived from the RAS codon 12 and codon 13 mutations. Some healthy donors demonstrated a response to several mutant epitopes, and some, but not all, exhibited cross-reactivity to the wild-type RAS epitope. In addition, several T cell responses were identified against mutant RAS epitopes in healthy donors directly ex vivo. Clones against mutant RAS epitopes were established from healthy donors, and several of these clones did not cross-react with the wild-type epitope. Finally, CD45RO⁺ memory T cells from healthy donors demonstrated a strong response to several mutant RAS epitopes. Taken together, these data suggest that the immune system in healthy donors spontaneously clears malignantly transformed RAS-mutant cells, and the immune system consequently generates T-cell memory against the mutations. Full article