An immune risk score predicts progression-free survival of melanoma patients in South China receiving anti-PD-1 inhibitor therapy-a retrospective cohort study examining 66 circulating immune cell subsets.

Introduction: Immune checkpoint blockade inhibitor (ICI) therapy offers significant survival benefits for malignant melanoma. However, some patients were observed to be in disease progression after the first few treatment cycles. As such, it is urgent to find convenient and accessible indicators that assess whether patients can benefit from ICI therapy. Methods: In the training cohort, flow cytometry was used to determine the absolute values of 66 immune cell subsets in the peripheral blood of melanoma patients (n=29) before treatment with anti-PD-1 inhibitors. The least absolute shrinkage and selection operator (LASSO) Cox regression model was followed for the efficacy of each subset in predicting progression-free survival. Then we validated the performance of the selected model in validation cohorts (n=20), and developed a nomogram for clinical use. Results: A prognostic immune risk score composed of CD1c+ dendritic cells and three subsets of T cells (CD8+CD28+, CD3+TCRab+HLA-DR+, CD3+TCRgd+HLA-DR+) with a higher prognostic power than individual features (AUC = 0.825). Using this model, patients in the training cohort were divided into high- and low-risk groups with significant differences in mean progression-free survival (3.6 vs. 12.3 months), including disease control rate (41.2% vs. 91.7%), and objective response rate (17.6% vs. 41.6%). Integrating four-immune cell-subset based classifiers and three clinicopathologic risk factors can help to predict which patients might benefit from anti-PD-1 antibody inhibitors and remind potential non-responders to pursue effective treatment options in a timely way. Conclusions: The prognostic immune risk score including the innate immune and adaptive immune cell populations could provide an accurate prediction efficacy in malignant melanoma patients with ICI therapy.

RBM20-Mediated Pre-mRNA Splicing Has Muscle-Specificity and Differential Hormonal Responses between Muscles and in Muscle Cell Cultures.

Pre-mRNA splicing plays an important role in muscle function and diseases. The RNA binding motif 20 (RBM20) is a splicing factor that is predominantly expressed in muscle tissues and primarily regulates pre-mRNA splicing of Ttn, encoding a giant muscle protein titin that is responsible for muscle function and diseases. RBM20-mediated Ttn splicing has been mostly studied in heart muscle, but not in skeletal muscle. In this study, we investigated splicing specificity in different muscle types in Rbm20 knockout rats and hormonal effects on RBM20-mediated splicing both in cellulo and in vivo studies. The results revealed that RBM20 is differentially expressed across muscles and RBM20-mediated splicing is muscle-type specific. In the presence of RBM20, Ttn splicing responds to hormones in a muscle-type dependent manner, while in the absence of RBM20, Ttn splicing is not affected by hormones. In differentiated and undifferentiated C2C12 cells, RBM20-mediated splicing in response to hormonal effects is mainly through genomic signaling pathway. The knowledge gained from this study may help further understand muscle-specific gene splicing in response to hormone stimuli in different muscle types.

Protein Expression of Angiotensin-Converting Enzyme 2 (ACE2) is Upregulated in Brains with Alzheimer's Disease.

Alzheimer's disease is a chronic neurodegenerative disorder and represents the main cause of dementia globally. Currently, the world is suffering from the coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a virus that uses angiotensin-converting enzyme 2 (ACE2) as a receptor to enter the host cells. In COVID-19, neurological manifestations have been reported to occur. The present study demonstrates that the protein expression level of ACE2 is upregulated in the brain of patients with Alzheimer's disease. The increased ACE2 expression is not age-dependent, suggesting the direct relationship between Alzheimer's disease and ACE2 expression. Oxidative stress has been implicated in the pathogenesis of Alzheimer's disease, and brains with the disease examined in this study also exhibited higher carbonylated proteins, as well as an increased thiol oxidation state of peroxiredoxin 6 (Prx6). A moderate positive correlation was found between the increased ACE2 protein expression and oxidative stress in brains with Alzheimer's disease. In summary, the present study reveals the relationships between Alzheimer's disease and ACE2, the receptor for SARS-CoV-2. These results suggest the importance of carefully monitoring patients with both Alzheimer's disease and COVID-19 in order to identify higher viral loads in the brain and long-term adverse neurological consequences.

Maternal Overnutrition During Gestation in Sheep Alters Autophagy Associated Pathways in Offspring Heart.

Poor maternal nutrition during gestation can negatively affect offspring growth, development, and health pre- and post-natally. Overfeeding during gestation or maternal obesity (MO) results in altered metabolism and imbalanced endocrine hormones in animals and humans which will have long-lasting and detrimental effects on offspring growth and health. In this study, we examined the effects of overnutrition during gestation on autophagy associated pathways in offspring heart muscles at two gestational and one early postnatal time point (n = 5 for treated and untreated male and female heart respectively at each time point). Two-way ANOVA was used to analyze the interaction between treatment and sex at each time point. Our results revealed significant interactions of maternal diet by developmental stages for offspring autophagy signaling. Overfeeding did not affect the autophagy signaling at mid-gestation day 90 (GD90) in both male and female offspring while the inflammatory cytokines were increased in GD90 MO male offsrping; however, overfeeding during gestation significantly increased autophagy signaling, but not inflammation level at a later developmental stage (GD135 and day 1 after birth) in both males and females. We also identified a sexual dimorphic response in which female progeny were more profoundly influenced by maternal diet than male progeny regardless of developmental stages. We also determined the cortisol concentrations in male and female hearts at three developmental stages. We did not observe cortisol changes between males and females or between overfeeding and control groups. Our exploratory studies imply that MO alters autophagy associated pathways in both male and female at later developmental stages with more profound effects in female. This finding need be confirmed with larger sample numbers in the future. Our results suggest that targeting on autophagy pathway could be a strategy for correction of adverse effects in offspring of over-fed ewes.

Life Course Impact of Glucocorticoids During Pregnancy on Muscle Development and Function.

Maternal stress, such as maternal obesity, can induce severe gestational disease and hormonal disorder which may disrupt fetal organ maturation and further cause endangered early or future health in offspring. During fetal development, glucocorticoids are essential for the maturation of organ systems. For instance, in clinical applications, glucocorticoids are commonly utilized to pregnant women with the risk of preterm delivery to reduce mortality of the newborns. However, exposure of excessive glucocorticoids at embryonic and fetal developmental stages can cause diseases such as cardiovascular disease and muscle atrophy in adulthood. Effects of excessive glucocorticoids on human health are well-recognized and extensively studied. Nonetheless, effects of these hormones on farm animal growth and development, particularly on prenatal muscle development, and postnatal growth, did not attract much attention until the last decade. Here, we provided a short review of the recent progress relating to the effect of glucocorticoids on prenatal skeletal muscle development and postnatal muscle growth as well as heart muscle development and cardiovascular disease during life course.

Angiotensin-converting enzyme 2 (ACE2) is upregulated in Alzheimer's disease brain.

Alzheimer's disease is a chronic neurodegenerative disorder and represents the main cause of dementia. Currently, the world is suffering from the pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that uses angiotensin-converting enzyme 2 (ACE2) as a receptor to enter the host cells. In COVID-19, neurological manifestations have been reported to occur. The present study demonstrates that the protein expression level of ACE2 is upregulated in the brain of Alzheimer's disease patients. The increased ACE2 expression is not age-dependent, suggesting the direct relationship between Alzheimer's disease and the ACE2 expression. Oxidative stress has been implicated in the pathogenesis of Alzheimer's disease, and Alzheimer's disease brains examined in this study also exhibited higher carbonylated proteins as well as increased thiol oxidation state of peroxiredoxin 6 (Prx6). The positive correlation was found between the increased ACE2 protein expression and oxidative stress in Alzheimer's disease brain. Thus, the present study reveals the relationships between Alzheimer's disease and ACE2, the receptor for SARS-CoV-2. These results warrant monitoring Alzheimer's disease patients with COVID-19 carefully for the possible higher viral load in the brain and long-term adverse neurological consequences.