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Abstract In this phase I dose-escalation trial, we assess the maximum tolerated dose (MTD) of Bermekimab in combination with Nanoliposomal Irinotecan (Nal-Iri) and 5-Fluorouracil/Folinic Acid (5-FU/FA). Secondarily, we investigate effects on weight, lean body mass, quality-of-life, the gut microbiome composition, inflammatory biomarkers, progression-free survival, and overall survival. This was a single-arm, open-label adaptive Bayesian dose-escalation study of Bermekimab combined with Nal-Iri and 5FU/FA in patients with advanced or locally advanced PDAC who failed gemcitabine-based chemotherapy. 22 patients enrolled between 2017 and 2019. 3 of 21 patients experienced dose-limiting toxicities attributable to the chemotherapy backbone. 58% (10/17) of patients exhibited weight stability. Physical performance status was preserved among all subjects. Patients reported improvements in quality-of-life metrics via QLQ-PAN26 questioner (−3.6, p = 0.18) and functional well-being (1.78, p = 0.02). Subjects exhibited a decrease in inflammatory cytokines, notably, vascular endothelial growth factor (−0.86, p = 0.017) with Bermekimab. Bermekimab treatment was associated with an increased abundance of gut health-promoting bacterial genera Akkermansia, with 3.82 Log2-fold change from baseline. In sum, Bermekimab is safe to be used in conjunction with Nal-Iri and 5-FU/FA chemotherapy. This benign toxicological profile warrants further Phase I/II investigation of Bermekimab in combinatorial strategies, and the impact of anti-IL-1α antibodies on the gut microbiome. Clinical trials registration: NCT03207724 05/07/2017.

Abstract Colonoscopy and endoscopic ultrasound play pivotal roles in the assessment of rectal diseases, especially rectal cancer and inflammatory bowel diseases. Optical coherence tomography (OCT) offers a superior depth resolution, which is a critical factor for individualizing the therapeutic concept and evaluating the therapy response. We developed two distinct rectoscope prototypes, which were integrated into a 1300 nm MHz-OCT system constructed at our facility. The rapid rotation of the distal scanning probe at 40,000 revolutions per minute facilitates a 667 Hz OCT frame rate, enabling real-time endoscopic imaging of large areas. The performance of these OCT-rectoscopes was assessed in an ex vivo porcine colon and a post mortem human in-situ colon. The OCT-rectoscope consistently distinguished various layers of the intestinal wall, identified gut-associated lymphatic tissue, and visualized a rectal polyp during the imaging procedure with 3D-reconstruction in real time. Subsequent histological examination confirmed these findings. The body donor was preserved using an ethanol-glycerol-lysoformin-based technique for true-to-life tissue consistency. We could demonstrate that the novel MHZ-OCT-rectoscope effectively discriminates rectal wall layers and crucial tissue characteristics in a post mortem human colon in-situ. This real-time-3D-OCT holds promise as a valuable future diagnostic tool for assessing disease state and therapy response on-site in rectal diseases.

Abstract Biofilms are resistant to many traditional antibiotics, which has led to search for new antimicrobials from different and unique sources. To harness the potential of aquatic microbial resources, we analyzed the meta-omics datasets of microalgae-bacteria communities and mined them for potential antimicrobial and quorum quenching enzymes. One of the most interesting candidates (Dlh3), a dienelactone hydrolase, is a α/β-protein with predicted eight α-helices and eight β-sheets. When it was applied to one of the major fish pathogens, Edwardsiella anguillarum, the biofilm development was reproducibly inhibited by up to 54.5%. The transcriptome dataset in presence of Dlh3 showed an upregulation in functions related to self-defense like active genes for export mechanisms and transport systems. The most interesting point regarding the biotechnological potential for aquaculture applications of Dlh3 are clear evidence of biofilm inhibition and that health and division of a relevant fish cell model (CHSE-214) was not impaired by the enzyme.

Abstract SARS-CoV-2 subunit vaccines continue to be the focus of intense clinical development worldwide. Protein antigens in these vaccines most commonly consist of the spike ectodomain fused to a heterologous trimerization sequence, designed to mimic the compact, prefusion conformation of the spike on the virus surface. Since 2020, we have produced dozens of such constructs in CHO cells, consisting of spike variants with different mutations fused to different trimerization sequences. This set of constructs displayed notable conformational heterogeneity, with two distinct trimer species consistently detected by analytical size exclusion chromatography. A recent report showed that spike ectodomain fusion constructs can adopt an alternative trimer conformation consisting of loosely associated ectodomain protomers. Here, we applied multiple biophysical and immunological techniques to demonstrate that this alternative conformation is formed to a significant extent by several SARS-CoV-2 variant spike proteins. We have also examined the influence of temperature and pH, which can induce inter-conversion of the two forms. The substantial structural differences between these trimer types may impact their performance as vaccine antigens.

Abstract The present study aimed at investigating the influence of personality on both anticipatory stress vulnerability and the effectiveness of coping strategies in an occupational stressful context. Following assessment of individual personality traits (Big Five Inventory), 147 volunteers were exposed to the anticipation of a stressful event. Anxiety and cardiac reactivity were assessed as markers of vulnerability to anticipatory stress. Participants were then randomly assigned to three groups and subjected to a 5-min intervention: relaxation breathing, relaxation breathing combined with cardiac biofeedback, and control. The effectiveness of coping interventions was determined through the cardiac coherence score achieved during the intervention. Higher neuroticism was associated with higher anticipatory stress vulnerability, whereas higher conscientiousness and extraversion were related to lower anticipatory stress vulnerability. Relaxation breathing and biofeedback coping interventions contributed to improve the cardiac coherence in all participants, albeit with greater effectiveness in individuals presenting higher score of openness to experience. The present findings demonstrated that personality traits are related to both anticipatory stress vulnerability and effectiveness of coping interventions. These results bring new insights into practical guidelines for stress prevention by considering personality traits. Specific practical applications for health professionals, who are likely to manage stressful situations daily, are discussed.

Abstract Clusterin (CLU) is one of the most significant genetic risk factors for late onset Alzheimer’s disease (AD). However, the mechanisms by which CLU contributes to AD development and pathogenesis remain unclear. Studies have demonstrated that the trafficking and localisation of glycosylated CLU proteins is altered by CLU-AD mutations and amyloid-β (Aβ), which may contribute to AD pathogenesis. However, the roles of non-glycosylated and glycosylated CLU proteins in mediating Aβ toxicity have not been studied in human neurons. iPSCs with altered CLU trafficking were generated following the removal of CLU exon 2 by CRISPR/Cas9 gene editing. Neurons were generated from control (CTR) and exon 2 −/− edited iPSCs and were incubated with aggregated Aβ peptides. Aβ induced changes in cell death and neurite length were quantified to determine if altered CLU protein trafficking influenced neuronal sensitivity to Aβ. Finally, RNA-Seq analysis was performed to identify key transcriptomic differences between CLU exon 2 −/− and CTR neurons. The removal of CLU exon 2, and the endoplasmic reticulum (ER)-signal peptide located within, abolished the presence of glycosylated CLU and increased the abundance of intracellular, non-glycosylated CLU. While non-glycosylated CLU levels were unaltered by Aβ25–35 treatment, the trafficking of glycosylated CLU was altered in control but not exon 2 −/− neurons. The latter also displayed partial protection against Aβ-induced cell death and neurite retraction. Transcriptome analysis identified downregulation of multiple extracellular matrix (ECM) related genes in exon 2 −/− neurons, potentially contributing to their reduced sensitivity to Aβ toxicity. This study identifies a crucial role of glycosylated CLU in facilitating Aβ toxicity in human neurons. The loss of these proteins reduced both, cell death and neurite damage, two key consequences of Aβ toxicity identified in the AD brain. Strikingly, transcriptomic differences between exon 2 −/− and control neurons were small, but a significant and consistent downregulation of ECM genes and pathways was identified in exon 2 −/− neurons. This may contribute to the reduced sensitivity of these neurons to Aβ, providing new mechanistic insights into Aβ pathologies and therapeutic targets for AD.

Abstract Targeted pharmacologic activation of antigen-specific (AgS) T cells may bypass limitations inherent in current T cell-based cancer therapies. We describe two immunotherapeutics platforms for selective delivery of costimulatory ligands and peptide-HLA (pHLA) to AgS T cells. We engineered and deployed on these platforms an affinity-attenuated variant of interleukin-2, which selectively expands oligoclonal and polyfunctional AgS T cells in vitro and synergizes with CD80 signals for superior proliferation versus peptide stimulation.

Abstract Rapid mapping of event landslides is crucial to identify the areas affected by damages as well as for effective disaster response. Traditionally, such maps are generated with visual interpretation of remote sensing imagery (manned/unmanned airborne systems or spaceborne sensors) and/or using pixel-based and object-based methods exploiting data-intensive machine learning algorithms. Recent works have explored the use of convolutional neural networks (CNN), a deep learning algorithm, for mapping landslides from remote sensing data. These methods follow a standard supervised learning workflow that involves training a model using a landslide inventory covering a relatively small area. The trained model is then used to predict landslides in the surrounding regions. Here, we propose a new strategy, i.e., a progressive CNN training relying on combined inventories to build a generalized model that can be applied directly to a new, unexplored area. We first prove the effectiveness of CNNs by training and validating on event landslides inventories in four regions after earthquakes and/or extreme meteorological events. Next, we use the trained CNNs to map landslides triggered by new events spread across different geographic regions. We found that CNNs trained on a combination of inventories have a better generalization performance, with a bias towards high precision and low recall scores. In our tests, the combined training model achieved the highest (Matthews correlation coefficient) MCC score of 0.69 when mapping landslides in new unseen regions. The mapping was done on images from different optical sensors, resampled to a spatial resolution of 6 m, 10 m, and 30 m. Despite a slightly reduced performance, the main advantage of combined training is to overcome the requirement of a local inventory for training a new deep learning model. This implementation can facilitate automated pipelines providing fast response for the generation of landslide maps in the post-disaster phase. In this study, the study areas were selected from seismically active zones with a high hydrological hazard distribution and vegetation coverage. Hence, future works should also include regions from less vegetated geographic locations.

Abstract Finding early disease markers using non-invasive and widely available methods is essential to develop a successful therapy for Alzheimer’s Disease. Few studies to date have examined urine, the most readily available biofluid. Here we report the largest study to date using comprehensive metabolic phenotyping platforms (NMR spectroscopy and UHPLC-MS) to probe the urinary metabolome in-depth in people with Alzheimer’s Disease and Mild Cognitive Impairment. Feature reduction was performed using metabolomic Quantitative Trait Loci, resulting in the list of metabolites associated with the genetic variants. This approach helps accuracy in identification of disease states and provides a route to a plausible mechanistic link to pathological processes. Using these mQTLs we built a Random Forests model, which not only correctly discriminates between people with Alzheimer’s Disease and age-matched controls, but also between individuals with Mild Cognitive Impairment who were later diagnosed with Alzheimer’s Disease and those who were not. Further annotation of top-ranking metabolic features nominated by the trained model revealed the involvement of cholesterol-derived metabolites and small-molecules that were linked to Alzheimer’s pathology in previous studies.

Abstract We use multitemporal analyses based on Synthetic Aperture Radar differential interferometry (DInSAR) to study the slope adjacent to the large Punatsangchhu-I hydropower plant, a concrete gravity dam under construction in Bhutan since 2009. Several slope failures affected the site since 2013, probably as a consequence of toe undercutting of a previously unrecognised active landslide. Our results indicate that downslope displacement, likely related to the natural instability, was already visible in 2007 on various sectors of the entire valley flank. Moreover, the area with active displacements impinging on the dam site has continuously increased in size since 2007 and into 2018, even though stabilization measures have been implemented since 2013. Stabilisation measures currently only focus on a small portion of the slope, however, the unstable area is larger than previously evaluated. Highly damaged rock is present across many areas of the entire valley flank, indicating that the volumes involved may be orders of magnitude higher than the area on which stabilisation efforts have been concentrated after the 2013 failure. The results highlight that satellite-based DInSAR could be systematically used to support decision making processes in the different phases of a complex hydropower project, from the feasibility study, to the dam site selection and construction phase.

Abstract Learning disabilities that affect about 10% of human population are linked to atypical neurodevelopment, but predominantly treated by behavioural interventions. Behavioural interventions alone have shown little efficacy, indicating limited success in modulating neuroplasticity, especially in brains with neural atypicalities. Even in healthy adults, weeks of cognitive training alone led to inconsistent generalisable training gains, or “transfer effects” to non-trained materials. Meanwhile, transcranial random noise stimulation (tRNS), a painless and more direct neuromodulation method was shown to further promote cognitive training and transfer effects in healthy adults without harmful effects. It is unknown whether tRNS on the atypically developing brain might promote greater learning and transfer outcomes than training alone. Here, we show that tRNS over the bilateral dorsolateral prefrontal cortices (dlPFCs) improved learning and performance of children with mathematical learning disabilities (MLD) during arithmetic training compared to those who received sham (placebo) tRNS. Training gains correlated positively with improvement on a standardized mathematical diagnostic test, and this effect was strengthened by tRNS. These findings mirror those in healthy adults, and encourage replications using larger cohorts. Overall, this study offers insights into the concept of combining tRNS and cognitive training for improving learning and cognition of children with learning disabilities.