Molecular Mechanisms of Cutaneous Immune-Related Adverse Events (irAEs) Induced by Immune Checkpoint Inhibitors.

Over the past few decades, immune checkpoint inhibitors (ICIs) have emerged as promising therapeutic options for the treatment of various cancers. These novel treatments effectively target key mediators of immune checkpoint pathways. Currently, ICIs primarily consist of monoclonal antibodies that specifically block cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death 1 (PD-1), programmed cell death-ligand 1 (PD-L1), and lymphocyte activation gene 3 protein (LAG-3). Despite the notable efficacy of ICIs in cancer treatment, they can also trigger immune-related adverse events (irAEs), which present as autoimmune-like or inflammatory conditions. IrAEs have the potential to affect multiple organ systems, with cutaneous toxicities being the most commonly observed. Although cutaneous irAEs are typically of low-grade severity and can usually be managed effectively, there are cases where severe irAEs can become life-threatening. Therefore, early recognition and a comprehensive understanding of the mechanisms underlying cutaneous irAEs are crucial for improving clinical outcomes in cancer patients. However, the precise pathogenesis of cutaneous irAEs remains unclear. This review focuses on the skin manifestations induced by ICIs, the prognosis related to cutaneous irAEs, and the exploration of potential mechanisms involved in cutaneous irAEs.

Influence of Configuration on Stress Distribution of Pulmonary Monocusp Leaflet.

PURPOSE: For the relief of right ventricular outflow tract obstruction in operative treatment of tetralogy of Fallot and other complex congenital heart diseases, transannular monocusp patch operations are often necessary to prevent right ventricular pressure overload and reduce pulmonary regurgitation. However, long-term durability of a monocusp leaflet is unsatisfactory, its failure is believed to be related to mechanical stress, whose distribution is primarily affected by geometric configurations. Therefore, the influence of several geometrical parameters on stress distribution of leaflet is investigated. METHODS: Five parameters affecting leaflet configuration were established: angle between free edge of the leaflet and vessel wall, angle formed by the two end points of free edge, length of the free edge of the leaflet, height of the leaflet, and shape of elliptic conical surface constituting the leaflet surface. The first four parameters were fixed, and two factors were defined to describe the last parameter. Seven models with different values of these factors were analyzed using finite element method at the pressure of the pulmonary artery loaded on the leaflet. RESULTS: The peak stresses of all models occurred at end points of the free edge of the leaflet (tear high-risk regions). The middle of leaflet had the greatest stress gradient and produced tissue wrinkling; this area could be the risk region of calcification. Both factors were noted to influence the stress distribution, and one of the factors could also relieve the wrinkling. CONCLUSIONS: The leaflet of model (1.2_min) had the most even stress distribution and lowest peak principal stress, which was the optimal choice among all the models.

Systematic review of anaesthetic medication for ERCP based on a network meta-analysis.

AIMS: We performed a systematic review of various anaesthetic medications for endoscopic retrograde cholangiopancreatography (ERCP) and aimed to make a comprehensive comparison based on a network meta-analysis. METHODS: We searched globally recognized electronic databases, including PubMed, Cochrane Central and EMBASE, to retrieve relevant randomized controlled trials (RCTs) of anaesthetic medications for ERCP. Network meta-analysis was conducted by evaluating the procedure time, adverse effects and drug requirements. The cumulative probability P value was utilized to rank the medications under examination. RESULTS: Seventeen RCTs that examined 1877 patients were included in this research. Under good convergence and efficiency, data analysis was performed using a consistency model. For the comparison of procedure times, we found that a combination of dexmedetomidine and ketamine (P = 0.19) or propofol plus pethidine (P = 0.18) seemed to be the two best medications for reducing procedure time. Additionally, midazolam combined with dexmedetomidine plus pethidine seemed to be the safest application for ERCP (P = 0.36). Propofol plus alfentanil also exhibited a good safety value (P = 0.28). For evaluation of drug requirements, the whole network connection could not be established; thus, comparisons in two subgroups were conducted. The results showed that midazolam combined with dexmedetomidine plus pethidine (P = 0.41) and propofol plus refentanil (P = 0.94) were superior to others in decreasing drug requirements. CONCLUSIONS: Based on the objective results and our conclusions, we deemed that a combination of midazolam and dexmedetomidine was recommended, and propofol plus opioids also revealed great clinical value. However, we are still expecting more clinical research in the future.

Transit peptide design and plastid import regulation.

Import of most nuclear encoded proteins into plastids is directed by an N-terminal transit peptide. Early studies suggested that transit peptides are interchangeable between precursor proteins. However, emerging evidence shows that different transit peptides contain different motifs specifying their preference for certain plastid types or ages. In this opinion article, we propose a 'multi-selection and multi-order' (M&M) model for transit peptide design, describing each transit peptide as an assembly of motifs for interacting with selected translocon components. These interactions determine the preference of the precursor for a particular plastid type or age. Furthermore, the order of the motifs varies among transit peptides, explaining why no consensus sequences have been identified through linear sequence comparison of all transit peptides as one group.

Differential age-dependent import regulation by signal peptides.

Gene-specific, age-dependent regulations are common at the transcriptional and translational levels, while protein transport into organelles is generally thought to be constitutive. Here we report a new level of differential age-dependent regulation and show that chloroplast proteins are divided into three age-selective groups: group I proteins have a higher import efficiency into younger chloroplasts, import of group II proteins is nearly independent of chloroplast age, and group III proteins are preferentially imported into older chloroplasts. The age-selective signal is located within the transit peptide of each protein. A group III protein with its transit peptide replaced by a group I transit peptide failed to complement its own mutation. Two consecutive positive charges define the necessary motif in group III signals for older chloroplast preference. We further show that different members of a gene family often belong to different age-selective groups because of sequence differences in their transit peptides. These results indicate that organelle-targeting signal peptides are part of cells' differential age-dependent regulation networks. The sequence diversity of some organelle-targeting peptides is not a result of the lack of selection pressure but has evolved to mediate regulation.

Tic21 is an essential translocon component for protein translocation across the chloroplast inner envelope membrane.

An Arabidopsis thaliana mutant defective in chloroplast protein import was isolated and the mutant locus, cia5, identified by map-based cloning. CIA5 is a 21-kD integral membrane protein in the chloroplast inner envelope membrane with four predicted transmembrane domains, similar to another potential chloroplast inner membrane protein-conducting channel, At Tic20, and the mitochondrial inner membrane counterparts Tim17, Tim22, and Tim23. cia5 null mutants were albino and accumulated unprocessed precursor proteins. cia5 mutant chloroplasts were normal in targeting and binding of precursors to the chloroplast surface but were defective in protein translocation across the inner envelope membrane. Expression levels of CIA5 were comparable to those of major translocon components, such as At Tic110 and At Toc75, except during germination, at which stage At Tic20 was expressed at its highest level. A double mutant of cia5 At tic20-I had the same phenotype as the At tic20-I single mutant, suggesting that CIA5 and At Tic20 function similarly in chloroplast biogenesis, with At Tic20 functioning earlier in development. We renamed CIA5 as Arabidopsis Tic21 (At Tic21) and propose that it functions as part of the inner membrane protein-conducting channel and may be more important for later stages of leaf development.