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     

Do vascular surgery patients need a cardiology work-up? A review of pre-operative cardiac clearance guidelines in vascular surgery.

OBJECTIVES: to outline the appropriate pre-operative cardiac work-up for patients who are scheduled for major peripheral vascular surgery. DESIGN: review of the literature. MATERIALS AND METHODS: a review of the literature focusing on studies that have correlated the pre-operative cardiac work-up patients receive to the cardiac morbidity and mortality following vascular surgery. Only studies with level A evidence were included. RESULTS: peri-operative beta blockade has been shown to decrease cardiac complications after vascular surgery in all risk groups. Non-invasive cardiac testing is only necessary for patients in the intermediate/high risk group. Coronary revascularization should only be considered after a positive non-invasive cardiac test. CONCLUSIONS: patients must be risk stratified pre-operatively based on history and physical examination. Low risk patients should receive peri-operative beta blockade only with no further non-invasive testing. On the other hand, intermediate and high risk patients should undergo non-invasive cardiac testing before going to the operating room.     

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.     

Is there relationship between serum uric acid levels and lower urinary tract symptoms,prostate volume,and PSA in men without cancer? A prospective population-based study

There are conflicting results about uric acid (UA) effect on the prostate. We investigated the relationship between UA and PSA, free PSA, prostate volume and international prostate symptoms score (IPSS) in benign prostate hyperplasia (BPH). This study was conducted in BPH men without cancer who were referred for annual health workup (N = 910) from 2017 to 2020. The mean ages were 67.28 ± 9.2 years. UA was positively related to IPSS and PSA (r = 0.210, p = .023 and r = 0.156, p = .041 respectively) and also negatively related to free/total PSA ratio (r = −0.332, p = .01) but not related to prostate volume (r = 0.036, p = .696). After adjustment for age, BMI and prostate volume, there were significant relationships between hyperuricaemia and PSA, free/total PSA ratio, and IPSS (95% CI: 0.254–1.645, OR = 0.647, p = .039; 95% CI: 0.076–0.899, OR = 0.270, p = .033 and 95% CI: 1.011–3.386, OR = 1.851, p = .038 respectively). These results should be considered during the general assessment of the patients with BPH. The findings raise the possible hypothesis of relationship between serum UA with IPSS and PSA which should be investigated by future studies.     

Cardiovascular Effects of Medical Marijuana: A Systematic Review

Utilization of marijuana as a medicinal agent is becoming increasingly popular, and so far, 25 states have legalized it for medical purposes. However, there is emerging evidence that marijuana use can result in cardiovascular side effects, such as rhythm abnormalities, syncope/dizziness, and myocardial infarction, among others. Further, there are currently no stringent national standards or approval processes, like Food and Drug Administration (FDA) evaluation, in place to assess medical marijuana products. This review includes the largest up-to-date pooled population of patients with exposure to marijuana and reported cardiovascular effects. Although purported as benign by many seeking to advance the use of marijuana as an adjunctive medical therapy across the country, marijuana is associated with its own set of cardiovascular risks and deserves further definitive study and the same level of scrutiny we apply in research of all other types of medications. When used as a medicinal agent, marijuana should be regarded accordingly, and both clinical providers and patients must be aware of potential adverse effects associated with its use for early recognition and management.