Predictions versus high-throughput experiments in T-cell epitope discovery: competition or synergy?

Prediction methods as well as experimental methods for T-cell epitope discovery have developed significantly in recent years. High-throughput experimental methods have made it possible to perform full-length protein scans for epitopes restricted to a limited number of MHC alleles. The high costs and limitations regarding the number of proteins and MHC alleles that are feasibly handled by such experimental methods have made in silico prediction models of high interest. MHC binding prediction methods are today of a very high quality and can predict MHC binding peptides with high accuracy. This is possible for a large range of MHC alleles and relevant length of binding peptides. The predictions can easily be performed for complete proteomes of any size. Prediction methods are still, however, dependent on good experimental methods for validation, and should merely be used as a guide for rational epitope discovery. We expect prediction methods as well as experimental validation methods to continue to develop and that we will soon see clinical trials of products whose development has been guided by prediction methods

Antigen Processing and Remodeling of the Endosomal Pathway: Requirements for Antigen Cross-Presentation

Cross-presentation of endocytosed antigen as peptide/class I major histocompatibility complex complexes plays a central role in the elicitation of CD8+ T cell clones that mediate anti-viral and anti-tumor immune responses. While it has been clear that there are specific subsets of professional antigen presenting cells capable of antigen cross-presentation, identification of mechanisms involved is still ongoing. Especially amongst dendritic cells (DC), there are specialized subsets that are highly proficient at antigen cross-presentation. We here present a focused survey on the cell biological processes in the endosomal pathway that support antigen cross-presentation. This review highlights DC-intrinsic mechanisms that facilitate the cross-presentation of endocytosed antigen, including receptor-mediated uptake, maturation-induced endosomal sorting of membrane proteins, dynamic remodeling of endosomal structures and cell surface-directed endosomal trafficking. We will conclude with the description of pathogen-induced deviation of endosomal processing, and discuss how immune evasion strategies pertaining endosomal trafficking may preclude antigen cross-presentation

An Efficient Index for Reachability Queries in Public Transport Networks

Computing path queries such as the shortest path in public transport networks is challenging because the path costs between nodes change over time. A reachability query from a node at a given start time on such a network retrieves all points of interest (POIs) that are reachable within a given cost budget. Reachability queries are essential building blocks in many applications, for example, group recommendations, ranking spatial queries, or geomarketing. We propose an efficient solution for reachability queries in public transport networks. Currently, there are two options to solve reachability queries. (1) Execute a modified version of Dijkstra’s algorithm that supports time-dependent edge traversal costs; this solution is slow since it must expand edge by edge and does not use an index. (2) Issue a separate path query for each single POI, i.e., a single reachability query requires answering many path queries. None of these solutions scales to large networks with many POIs. We propose a novel and lightweight reachability index. The key idea is to partition the network into cells. Then, in contrast to other approaches, we expand the network cell by cell. Empirical evaluations on synthetic and real-world networks confirm the efficiency and the effectiveness of our index-based reachability query solution

Solid-state esophageal pressure sensor for the estimation of pleural pressure:a bench and first-in-human validation study

Background: Advanced respiratory monitoring through the measurement of esophageal pressure (Pes) as a surrogate of pleural pressure helps guiding mechanical ventilation in ICU patients. Pes measurement with an esophageal balloon catheter, the current clinical reference standard, needs complex calibrations and a multitude of factors influence its reliability. Solid-state pressure sensors might be able to overcome these limitations. Objectives: To evaluate the accuracy of a new solid-state Pes transducer (Pessolid). We hypothesized that measurements are non-inferior to those obtained with a properly calibrated balloon catheter (Pesbal).Methods:Absolute and relative solid-state sensor Pes measurements were compared to a reference pressure in a 5-day bench setup, and to simultaneously placed balloon catheters in 15 spontaneously breathing healthy volunteers and in 16 mechanically ventilated ICU patients. Bland–Altman analysis was performed using mixed effects modelling with bootstrapping to estimate bias and upper and lower limits of agreement (LoA) and their confidence intervals. Results: Bench study: Solid-state pressure transducers had a positive bias (Psolid – Pref) of around 1 cmH2O for the absolute minimal and maximum pressures, and no bias for pressure swings. Healthy volunteers: the solid-state transducer revealed a bias (i.e., Pessolid – Pesbal) [upper LoA; lower LoA] of 1.59 [8.21; − 5.02], − 2.32 [4.27; − 8.92] and 3.91 [11.04; − 3.23] cmH2O for end-expiratory, end-inspiratory and ΔPes values, respectively. ICU patients: the solid-state transducer showed a bias (Pessolid–Pesbal) [upper LoA; lower LoA] during controlled/assisted ventilation of: − 0.15 [1.41; − 1.72]/− 0.19 [5.23; − 5.62], 0.32 [3.45; − 2.82]/− 0.54 [4.81; − 5.90] and 0.47 [3.90; − 2.96]/0.35 [4.01; − 3.31] cmH2O for end-expiratory, end-inspiratory and ΔPes values, respectively. LoA were ≤ 2cmH2O for static measurements on controlled ventilation. Conclusions: The novel solid-state pressure transducer showed good accuracy on the bench, in healthy volunteers and in ventilated ICU-patients. This could contribute to the implementation of Pes as advanced respiratory monitoring technique. Trial registration: Clinicaltrials.gov identifier: NCT05817968 (patient study). Registered on 18 April 2023.</p

Post-intrathecal chemotherapy-related paraplegia syndrome in hematological cancer patients: A systematic review

BACKGROUND: Intrathecal (IT) chemotherapy is essential in treating hematological malignancies, but it can lead to ascending paraplegia, a condition that currently lacks clear management guidelines. METHODS: We conducted a systematic review, analyzing 1219 studies and 116 patients, adhering to PRISMA guidelines for individual patient data. The study, registered under PROSPERO (CRD42022362121), focused on the onset, diagnostic approaches, and therapeutic interventions associated with this complication, and management strategies to tackle the ascending paraplegia. RESULTS: Paraplegia typically manifests approximately 10 days after chemotherapy, irrespective of injection frequency. In 95% of cases, paralysis stabilizes around the umbilical region, although some patients progress to upper limb involvement and respiratory compromise. Despite various diagnostic methods, consistent inflammatory markers in blood or cerebrospinal fluid are lacking, with approximately 60% of patients showing normal magnetic resonance imaging results at presentation. Misdiagnoses often include transverse myelitis, Guillain-Barré syndrome, and autoimmune radiculitis. Common treatments such as corticosteroids and intravenous immunoglobulins show limited effectiveness. CONCLUSION: Our review delineates the clinical entity of ascending paraplegia following IT chemotherapy, aiming to increase clinician awareness and provide prognostic insight. We introduce the term post-IT paraplegia syndrome to facilitate accurate diagnosis and optimize treatment strategies for affected patients

Developmental changes in mesenteric artery reactivity in embryonic and newly hatched chicks

At birth, the intestine becomes the sole site for nutrient absorption requiring a dramatic increase in blood flow. The vascular changes accompanying this transition have been partly characterized in mammals. We investigated, using wire myography, the developmental changes in chick mesenteric artery (MA) reactivity. Rings of the MA from 15-day (E15) and 19-day (E19) chicken embryos (total incubation 21 days) as well as non-fed 0–3-h-old (NH3h) and first-fed 1-day-old (NH1d) newly hatched chicks contracted in response to KCl, norepinephrine (NE), U46619, and endothelin (ET)-1 and relaxed in response to acetylcholine (ACh), sodium nitroprusside (SNP), and forskolin indicating the presence of electro- and pharmaco-mechanical coupling as well as cGMP- and cAMP-mediated relaxation. In ovo development and transition to ex ovo life was accompanied by alterations in the response of the MAs, but a different developmental trajectory was observed for each reactivity pathway tested. Thus, the contractile efficacy of KCl underwent a linear increase (E15 < E19 < NH3h < NH1d). The efficacy of NE and U46619 increased in ovo, but not ex ovo (E15 < E19 = NH3h = NH1d) and the efficacy of ET-1 peaked at E19 (E15 < E19 > NH3h = NH1d). The relaxations elicited by ACh (endothelium-dependent), SNP, and forskolin did not undergo significant developmental changes. In conclusion, the ability of chick MAs to constrict in response to pharmacological stimuli increases during the embryonic period, but no dramatic changes are induced by hatching or the first feeding. Maturation of vasodilator mechanisms precedes that of vasoconstrictor mechanisms. Alterations of the delicate balance between vasoconstrictors and vasodilators may play an important role in perinatal intestinal diseases