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     

Heterogeneity in amount of growth factors secreted by platelets in platelet-rich plasma samples from alopecia patients

Platelet α-granules release growth factors (GFs) that promote healing and tissue regeneration. Platelet-rich plasma (PRP) is shown to be beneficial in treating alopecia, and however, clinical response can be inconsistent. Due to several fold enrichment of platelets secreting large quantities of GFs following PRP injections, heterogeneity in amounts of GFs secreted by platelets may contribute to inconsistent clinical responses. Herein, we evaluated factors that could potentially contribute to heterogeneous secretion of GFs by platelets. We measured platelet secretion of transforming growth factor beta1 (TGFβ1), platelet-derived growth factor (PDGF-BB), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF2) in aliquots of de-identified PRP samples from female patients undergoing therapy in the hair disease clinic. Although secretion of GFs by platelets was comparable in PRP samples of patients with non-cicatricial and cicatricial alopecia, a Shapiro-Wilk test for normal distribution indicated significant variability across all patient samples. The amount of GF secreted by platelets was comparable when PRP prepared from two FDA-cleared devices with distinct techniques were compared. We provide evidence of platelets secreting heterogeneous amounts of GFs within each sample as high and low secretion of random factors could be simultaneously detected. These results suggest inherent heterogeneity in secretion of GFs by platelets in patient samples that are not influenced by the device used to prepare PRP. Since some GFs could have antagonistic effects on hair growth, a balance between amounts of growth promoting and inhibiting factors may be crucial in determining clinical response to PRP therapy.     

MRI技术对高原人群颅脑脱髓鞘疾病回顾性研究

目的研究高原地区,脱髓鞘疾病与中老年人疾病等因素的关系。方法对我院所有接受过磁共振头部扫描的病人进行评估,确诊出40位脱髓鞘疾病患者,并对大脑7个部位的脱髓鞘疾病按严重性分4级打分,统计临床数据,最后运用统计学方法分析其相关性。结果在40例患者中,出现在大脑半球、放射冠、半卵圆中心和脑室前后角的脑白质损伤频率最多,分别占总量的50%、67.5%、77.5%和87.5%。脑白质损伤患者的平均年龄为47.1岁,这比世界其他地区都有明显的提前。男性患者将近是女性患者的3倍(29∶11)。年龄、慢性高原红细胞增多症、收缩压、脑梗塞与脑白质损伤正相关(P<0.05)。结论对于高海拔地区,有效控制高原心血管疾病的发生对于减少颅脑脱髓鞘疾病的发生具有重要意义。     

Vaccine-associated paralytic poliomyelitis in a patient with MHC class II deficiency.

Vaccine-associated paralytic poliomyelitis (VAPP) is a rare complication of oral polio vaccine. We describe a fatal case of VAPP in an 8-month-old boy with Major Histocompatibility Class II deficiency. The isolated poliovirus was a Sabin type 2-type 1 recombinant that showed 1.4% VP1 divergence from Sabin type 2.     

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.     

Nonpancreatic Pancreatic Panniculitis: An Incidental Finding in Individuals without Pancreatic Disease? A Case Series and Review of the Literature

Pancreatic panniculitis occurs in up to three percent of all patients with pancreatic disease. This cutaneous eruption, as implied by the name, is almost exclusively encountered in the context of pancreatic disorders, such as pancreatitis or pancreatic carcinoma. We report three cases in which histopathologic examination demonstrated hallmarks of pancreatic panniculitis occurring in patients without any history or evidence of pancreatic disorder. These nonpancreatic pancreatic panniculitis eruptions might be underreported in the literature.     

Localized Bullous Pemphigoid Following Orthopedic Surgery

Bullous pemphigoid is an autoimmune condition whereby the immune system forms antibodies that target the skin, resulting in the formation of blisters in a generalized and symmetric pattern. Localized bullous pemphigoid can occur in special circumstances. Here, we describe two patients that developed localized bullous pemphigoid in one lower extremity following orthopedic surgery. We propose that underlying edema following orthopedic surgery is a potential trigger for localized bullous pemphigoid.