Checkpoint-blocker-induced autoimmunity is associated with favourable outcome in metastatic melanoma and distinct T-cell expression profiles

Background Immune checkpoint blockers (ICBs) activate CD8⁺ T cells, eliciting both anti-cancer activity and immune-related adverse events (irAEs). The relationship of irAEs with baseline parameters and clinical outcome is unclear.Methods Retrospective evaluation of irAEs on survival was performed across primary (N = 144) and secondary (N = 211) independent cohorts of patients with metastatic melanoma receiving single agent (pembrolizumab/nivolumab—sICB) or combination (nivolumab and ipilimumab—cICB) checkpoint blockade. RNA from pre-treatment and post-treatment CD8⁺ T cells was sequenced and differential gene expression according to irAE development assessed.Results 58.3% of patients developed early irAEs and this was associated with longer progression-free (PFS) and overall survival (OS) across both cohorts (log-rank test, OS: P < 0.0001). Median survival for patients without irAEs was 16.6 months (95% CI: 10.9–33.4) versus not-reached (P = 2.8 × 10⁻⁶). Pre-treatment monocyte and neutrophil counts, but not BMI, were additional predictors of clinical outcome. Differential expression of numerous gene pathway members was observed in CD8⁺ T cells according to irAE development, and patients not developing irAEs demonstrating upregulated CXCR1 pre- and post-treatment.Conclusions Early irAE development post-ICB is associated with favourable survival in MM. Development of irAEs is coupled to expression of numerous gene pathways, suggesting irAE development in-part reflects baseline immune activation.Subject terms: Immunotherapy, Melanoma     

Postnatal development of intrinsic GABAergic rhythms in mouse hippocampus

The local circuitry of the mammalian limbic cortices, including the hippocampus, is capable of generating spontaneous rhythmic activities of 0.5-4 Hz when isolated in vitro. These rhythmic activities are mediated by synchronous inhibitory postsynaptic potentials in pyramidal neurons as the result of repeated discharges of inhibitory interneurons. As such, they are thought to represent an intrinsic inhibitory rhythm. It is unknown at present whether such a rhythm occurs in the immature rodent hippocampus and, if so, the postnatal time window in which it develops. We explored these issues using our recently developed whole mouse hippocampal isolate preparation in vitro. We found that spontaneous rhythmic field potentials started to emerge in mouse hippocampal isolates around postnatal day 10, stabilized after postnatal day 15 and persisted into adulthood. In postnatal days 11-14 mouse hippocampi, the properties of these rhythmic potentials were in keeping with a CA3-driven, IPSP-based intrinsic network activity. The lack of spontaneous field rhythm in neonatal (postnatal days 2-7) hippocampi cannot be attributed to the excitatory activities mediated by gamma-aminobutyric acid type A (GABA-A) receptors, as chloride-dependent hyperpolarizing inhibitory postsynaptic potentials were detectable in neonatal pyramidal neurons at voltages near resting potentials and pharmacological antagonisms of GABA-A receptors produced robust epileptiform discharges in neonatal hippocampi. High frequency afferent stimulation or applications of 4-aminopyridine at low micromolar concentrations failed to induce persistent field rhythm in neonatal hippocampi, suggesting that an overall weak glutamatergic drive is not the sole causing factor. We suggest that the inhibitory postsynaptic potential-based spontaneous rhythmic field potentials develop in a discrete time window during the second postnatal week in the mouse hippocampus due to a fine-tuning in the structure and function of CA3 recurrent circuitry and associated GABAergic inhibitory interneurons.     

Apoptosis of murine neonatal T cells

Recent evidence supports the idea that T cells in neonatal animals are developmentally mature in their capacity to mount protective helper and cytotoxic responses. Nonetheless, neonates fall prey to infections which have little effect on adults and they often fail to mount mature responses to environmental, experimental, or vaccine antigens. To reconcile these observations, it may be important to consider the potential role of apoptosis in neonatal immune responses. In adults, apoptosis is well established as a centrally important process in the homeostasis of cellular immune responses. Activated T cells deprived of IL-2 undergo cytokine withdrawal-induced apoptosis. Previously activated T cells can also be triggered by secondary stimulation to undergo activation induced apoptosis. This review summarizes our current state of knowledge of apoptosis of murine neonatal T cells and discusses the possible impact(s) of this apoptosis on neonatal immune responses in vivo.     

Suicidal Behaviors Among Ukrainian College Students: the Role of Substance Use,Religion, and Depression

Early adulthood is a critical life period associated with increased suicide risk. The present study used a sample of students from ten Ukrainian public universities (N = 1005). Participants were 17 to 24 years of age (M = 19.19, SD = 1.99). The prevalence of lifetime suicidal ideation was 26.13% and 5.45% of participants reported a lifetime suicide attempt. Participants were more likely to report higher lifetime suicidal ideation if they had higher rates of alcohol and marijuana use, have met a clinical cutoff point for depression and were older, females, and not affiliated with any religion. The lifetime suicide attempt was associated with clinical levels of depression, increased marijuana use, and non-religious affiliation. These results suggest that mental health, alcohol and cannabis use can increase the risk of suicidality while religious affiliation might be an important protective mechanism for Ukrainian young adults at risk for suicidal behaviors.

     

The effect of insulin and glucagon on splanchnic oxygen consumption

The purpose of these experiments was to measure the influence of insulin and glucagon on the splanchnic oxygen consumption. Two experiments were performed. METHODS: In one experiment, the influence of hyperinsulinaemia was investigated in six healthy subjects, who were studied during a euglycaemic hyperinsulinaemic clamp. In another experiment, the influence of glucagon was investigated in seven healthy subjects, who were studied twice during a pancreatic islet clamp with either supplementation of insulin and glucagon, or of insulin alone. In both situations the measurements were performed during euglycaemia. Splanchnic oxygen consumption and net substrate balances were studied by the arterio-hepatic venous catheterisation technique and measurement of splanchnic blood flow in all experiments. RESULTS: During the euglycaemic hyperinsulinaemic clamp, the splanchnic blood flow increased significantly and the splanchnic oxygen consumption decreased by about 20%, while the net splanchnic glucose output reversed to a net uptake. In the pancreatic islet clamp experiments there was a significant difference between the net splanchnic glucose outputs whether glucagon and insulin or only insulin was supplemented. In spite of this, the splanchnic oxygen consumption decreased by about 20% in both situations, i.e. independent of glucagon supplementation. In both experiments there was a pronounced inhibition of lipolysis, which led to decreased fatty acids availability to the liver. This resulted in a concomitant decrease in hepatic ketone body formation. This decrease could account for about 30% of the decrease in splanchnic oxygen consumption. CONCLUSION: The reduction in splanchnic oxygen consumption can be explained by decreased ketogenesis, decreased protein synthesis and changes in splanchnic fuel selection, while changes in the rate of gluconeogenesis does not seem to play a significant role.     

Fatty acid composition of ovule in kutum (Rutilus frisii kutum Komensky, 1901)

Fatty acid composition of ovules (ovulated oocytes) from kutum (Rutilus frisii kutum) was investigated to assess their relationship to gonad biological characteristics, larval size, fertilization, and hatching success. Forty-eight kutum were captured in the wild during the spawning season. Results revealed an inverse relationship between linoleic acid (18:2n-6) and ovule weight (P?<?0.05). Arachidonic acid (20:4n-6) and eicosapentaenoic acid (20:5n-3) contents showed a direct correlation with the number of ovules per gram (P?<?0.05); the latter had an inverse relationship with the ratio of surface to volume (P?<?0.01). There was a direct and significant correlation between docosahexaenoic acid (22:6n-3) and ovule weight (P?<?0.05). High unsaturated fatty acid levels indicated a direct relationship with egg and yolk diameters and also an inverse correlation with ovule surface to volume ratio (P?<?0.l05). Direct relationships were found between polyunsaturated fatty acids and the diameter of egg and yolk as well as the ratio of surface to volume (P?<?0.05). There was a direct correlation between saturated fatty acid content and the number of eggs (per gram) (P?<?0.01). Total lipid and weight of newly hatched larvae represented a direct relationship (P?<?0.05). Despite living in brackish water and migrating to fresh water during the reproductive season, kutum exhibited greater similarity in ovule fatty acid composition to saltwater fish than species in fresh water. Moreover, with respect to biological characteristics, this species shows more significant relationships with n-3 fatty acids than with n-6 fatty acids.