Replicative senescence of human dermal fibroblasts affects structural and functional aspects of the Golgi apparatus

It is well recognized that the world population is ageing rapidly. Therefore, it is important to understand ageing processes at the cellular and molecular levels to predict the onset of age‐related diseases and prevent them. Recent research has focused on the identification of ageing biomarkers, including those associated with the properties of the Golgi apparatus. In this context, Golgi‐mediated glycosylation of proteins has been well characterized. Additionally, other studies show that the secretion of many compounds, including pro‐inflammatory cytokines and extracellular matrix–degrading enzymes, is modified during ageing, resulting in physical and functional skin degradation. Since the Golgi apparatus is a central organelle of the secretory pathway, we investigated its structural organization in senescent primary human dermal fibroblasts using confocal and electron microscopy. In addition, we monitored the expression of Golgi‐related genes in the same cells. Our data showed a marked alteration in the Golgi morphology during replicative senescence. In contrast to its small and compact structure in non‐senescent cells, the Golgi apparatus exhibited a large and expanded morphology in senescent fibroblasts. Our data also demonstrated that the expression of many genes related to Golgi structural integrity and function was significantly modified in senescent cells, suggesting a relationship between Golgi apparatus function and ageing.     

The effect of maternal antibodies on the cellular immune response after infant vaccination: A review

During the last few decades, maternal immunization as a strategy to protect young infants from infectious diseases has been increasingly recommended, yet some issues have emerged. Studies have shown that for several vaccines, such as live attenuated, toxoid and conjugated vaccines, high maternal antibody titers inhibit the infant’s humoral immune response after infant vaccination. However, it is not clear whether this decreased antibody titer has any clinical impact on the infant’s protection, as the cellular immune responses are often equally important in providing disease protection and may therefore compensate for diminished antibody levels. Reports describing the effect of maternal antibodies on the cellular immune response after infant vaccination are scarce, probably because such studies are expensive, labor intensive and utilize poorly standardized laboratory techniques. Therefore, this review aims to shed light on what is currently known about the cellular immune responses after infant vaccination in the presence of high (maternal) antibody titers both in animal and human studies. Overall, the findings suggest that maternally derived antibodies do not interfere with the cellular immune responses after infant vaccination. However, more research in humans is clearly needed, as most data originate from animal studies.     

New Zealand Emergency Medicine Network: A collaboration for acute care research in New Zealand

The specialty of emergency medicine in Australasia is coming of age. As part of this maturation there is a need for high‐quality evidence to inform practice. This article describes the development of the New Zealand Emergency Medicine Network, a collaboration of committed emergency care researchers who share the vision that New Zealand/Aotearoa will have a world‐leading, patient‐centred emergency care research network, which will improve emergency care for all, so that people coming to any ED in the country will have access to the same world‐class emergency care.     

The critical role of the inferior frontal cortex in establishing a prediction model for generating subsequent mismatch negativity (MMN): A TMS-EEG study

BackgroundThe prediction violation account of automatic or pre-attentive change detection assumed that the inferior frontal cortex (IFC) is involved in establishing a prediction model for detecting unexpected changes. Evidence supporting the IFC’s contribution to prediction model is mainly based on the Mismatch Negativity (MMN) to deviants violating predictions that are established based on the frequently presented standard events. However, deviant detection involves processes, such as events comparison, other than prediction model establishment.ObjectiveThe current study investigated the critical role of the IFC in establishing a prediction model during standards processing for subsequent deviant detection.MethodsTranscranial Magnetic Stimulation (TMS) was applied at the IFC to disrupt the processing of the initial 2 or 5 standards of a 3-, 6-, or 9-standard train, while the MMN responses to pitch deviant presented after the standard trains were recorded and compared.ResultsAn abolishment of MMN was only observed when TMS was delivered to the IFC at the initial 2 standards of the 3-standard train, but not at the initial 5 standards, or when TMS at the vertex or TMS sound recording was applied. The MMNs were also preserved when IFC TMS, vertex TMS, or TMS sound recording was applied at the initial 2 or 5 standards of longer trains.ConclusionThe IFC plays a critical role in processing the initial standards of a short standard train for subsequent deviant detection. This result is consistent with the prediction violation account that the IFC is important for establishing the prediction model.     

Immune Checkpoint Inhibitor Toxicities

Immune checkpoint inhibitors are molecules that increase the endogenous immune response against tumors. They have revolutionized the field of oncology. Since their initial approval for the treatment of advanced melanoma, their use has expanded to the treatment of several other advanced cancers. Unfortunately, immune checkpoint inhibitors have also been associated with the emergence of a new subset of autoimmune-like toxicities, known as immune-related adverse events. These toxicities differ depending on the agent, malignancy, and individual susceptibilities. Although the skin and colon are most commonly involved, any organ may be affected, including the liver, lungs, kidneys, and heart. Most of these toxicities are diagnosed by excluding other secondary infectious or inflammatory causes. Corticosteroids are commonly used for treatment of moderate and severe immune-related adverse events, although additional immunosuppressive therapy may occasionally be required. The occurrence of immune-related toxicities may require discontinuation of immunotherapy, depending on the specific toxicity and its severity. In this article, we provide a focused review to familiarize practicing clinicians with this important topic given that the use of immune checkpoint inhibitors continues to increase.     

Putting age-related task activation into large-scale brain networks: A meta-analysis of 114 fMRI studies on healthy aging

Normal aging is associated with cognitive decline and underlying brain dysfunction. Previous studies concentrated less on brain network changes at a systems level. Our goal was to examine these age-related changes of fMRI-derived activation with a common network parcellation of the human brain function, offering a systems-neuroscience perspective of healthy aging. We conducted a series of meta-analyses on a total of 114 studies that included 2035 older adults and 1845 young adults. Voxels showing significant age-related changes in activation were then overlaid onto seven commonly referenced neuronal networks. Older adults present moderate cognitive decline in behavioral performance during fMRI scanning, and hypo-activate the visual network and hyper-activate both the frontoparietal control and default mode networks. The degree of increased activation in frontoparietal network was associated with behavioral performance in older adults. Age-related changes in activation present different network patterns across cognitive domains. The systems neuroscience approach used here may be useful for elucidating the underlying network mechanisms of various brain plasticity processes during healthy aging.     

B细胞介导的体液免疫应答在肝移植急性排斥反应中的作用

目前，国内外肝移植学界对肝移植术后急性排斥反应(AR)的机制阐释为T细胞介导的细胞免疫应答，但为获得长期生存仍需长期乃至终身服用免疫抑制剂。即使如此，临床上AR仍时有发生，并导致相当一部分受者移植肝功能丧失，更重要的是受者术后还受到感染、肿瘤和其他一系列不良反应及沉重经济负担的影响。因此，为肝移植AR机制提出新的理论解释，更全面深入阐明肝移植免疫排斥反应的内在机制，进而依据新的机制研制出新型免疫抑制剂已势在必行。本文就B细胞介导的体液免疫应答在肝移植AR中的作用作一综述。     

Immunotherapy in Hodgkin and non-Hodgkin lymphoma: Innate,adaptive and targeted immunological strategies

Since the clinical introduction of anti-CD20 monoclonal antibodies into lymphoma treatment, immunologic approaches in lymphoma have made substantial progress. Advances in our understanding of tumor immunology have led to the development of strategies to overcome immunologic barriers responsible for an ineffective immune response. Specifically, therapeutic agents have been developed and tested against molecules that are responsible for T-cell exhaustion. The use of monoclonal antibodies against immune checkpoints in the adaptive immune system, such as programmed cell death-1 and cytotoxic T-lymphocyte-associated protein 4, has changed the landscape of cancer therapy including the treatment of lymphoma. This achievement has recently been accompanied by the development of novel immune checkpoint inhibitors targeting the innate immune system, including the CD47-SIRPα signaling pathway, and this approach has yielded promising results. To overcome impaired antigen presentation, antibody-based cytotoxic strategies, namely antibody-drug conjugates (polatuzumab vedotin and brentuximab vedotin) and bispecific T-cell or NK-cell engagers (blinatumomab, REGN1979, RG6206, and AFM13), have rapidly evolved with promising clinical activity. As additional tools become available for lymphoma treatment, formulation of safe, rational combination strategies to combine them with standard therapy will be of paramount importance. A successful approach to the treatment of lymphoma may require both an optimized anti-tumor immune response as well as effective depletion of malignant lymphoid cells.