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     

Impact of sampling rate on statistical significance for single subject fMRI connectivity analysis

A typical time series in functional magnetic resonance imaging (fMRI) exhibits autocorrelation, that is, the samples of the time series are dependent. In addition, temporal filtering, one of the crucial steps in preprocessing of functional magnetic resonance images, induces its own autocorrelation. While performing connectivity analysis in fMRI, the impact of the autocorrelation is largely ignored. Recently, autocorrelation has been addressed by variance correction approaches, which are sensitive to the sampling rate. In this article, we aim to investigate the impact of the sampling rate on the variance correction approaches. Toward this end, we first derived a generalized expression for the variance of the sample Pearson correlation coefficient (SPCC) in terms of the sampling rate and the filter cutoff frequency, in addition to the autocorrelation and cross‐covariance functions of the time series. Through simulations, we illustrated the importance of the variance correction for a fixed sampling rate. Using the real resting state fMRI data sets, we demonstrated that the data sets with higher sampling rates were more prone to false positives, in agreement with the existing empirical reports. We further demonstrated with single subject results that for the data sets with higher sampling rates, the variance correction strategy restored the integrity of true connectivity.     

Rostral anterior cingulate cortex activity in the theta band predicts response to antidepressive medication.

During the last 10 years the knowledge about rostral anterior cingulate cortex (ACC) activity in major depression has substantially increased. Several groups have independently described a relationship between resting activity in this area and response to antidepressant treatment. We have recently confirmed a relationship between resting activity of rostral ACC activity and response in a group of 20 patients with major depression using resting theta activity. In this earlier study regions of interest (ROI) were defined in order to establish regional specificity. Differences between responders and nonresponders were only found in the ACC-ROI, but not in the posterior cingulate region. We have now reanalyzed our data using a whole brain voxelwise approach, in order not to miss any other relevant functional differences. In addition to major differences between responders and nonresponders in the rostral ACC, we have identified a nearby region in the midline orbito-frontal region.     

Tumor induction by ras and myc oncogenes in fetal and neonatal brain: modulating effects of developmental stage and retroviral dose

Introduction into fetal rat brain cells of a replication-defective retroviral vector harboring v-Ha-ras and v-gag-myc rapidly causes the induction of highly malignant undifferentiated neuroectodermal tumors following transplantation into the brains of syngeneic hosts [Wiestler, et al. (1992) Cancer Res. 52: 3760–3767]. In the present study, we have investigated the modulating effect of the developmental stage of neural target cells and of the dose of the retroviral vector used in the grafting experiments. Exposure of fetal cells from embryonic day (E)12 or E14 produced a 100% incidence of malignant neuroectodermal tumors which led to the death of recipient animals after a median latency period of 32 days. A 100-fold reduction of the virus dose from 2.062×10⁶ to 2.062×10⁴ focus-forming units/ml resulted in a lower tumor incidence of 25%. Of six neural grafts exposed to v-Ha-ras and v-myc at E16, only one showed evidence of tumorigenesis (low-grade astrocytoma and hemangioma). All other transplants were morphologically normal for observation periods of 26 weeks, indicating a marked loss of transforming activity of ras and myc in more advanced stages of brain development. In retrovirus-exposed donor cells which caused the development of neural tumors in recipient rats, malignant transformation was also evident during culture in vitro, usually after 9–12 days. Oncogene complementation was also studied in the newborn rat brain. After microinjection of the retroviral vector into the brain at postnatal day (P)0, P1 and P3, 5 out of 20 animals (25%) developed a total of seven brain tumors. Histopathologically, three of these neoplasms were malignant neuroectodermal tumors which, in contrast to those induced in fetal brain transplants showed evidence of focal glial and/or neuronal differentiation. In addition, we observed one oligodendroglioma, two hemangiomas and a malignant hemangioendothelioma. These data indicate that neural precursor cells and endothelia of the rat brain represent the major target cells for the complementary action of ras and myc and that the use of target cells from later developmental stages (E16 and postnatal) leads to the induction of both primitive and more differentiated neoplasms.These studies were supported by the Fonds zur Förderung der wissenschaftlichen Forschung in Österreich (Erwin Schrödinger fellowship, JO501-MED), by the Swiss National Science Foundation and by the Cancer League of the Kanton of Zürich     

Relationships of plasma viscosity, coagulation and fibrinolysis to coronary risk factors and angina

Plasma viscosity, molecular markers of activated coagulation and fibrinolysis (fibrinopeptides A and B beta 15-42), coagulation factors (fibrinogen and factor VII) and antiplasmins were measured in 529 men aged 35-54 years and related to new angina pectoris (n = 117) and to coronary risk factors in controls without angina (n = 412). Five major risk factors (cigarette-smoking, blood pressure, cholesterol, triglyceride and body mass index) were each associated with increases in plasma viscosity, coagulation factors, and imbalance of coagulation over fibrinolysis (increased ratio of fibrinopeptide A/fibrinopeptide B beta 15-42). Increased viscosity and fibrinogen in smokers were partly reversed in ex-smokers, but the imbalance of coagulation and fibrinolysis persisted. Cholesterol and triglyceride were also associated with increased antiplasmin activity. In men with angina, only fibrinogen was elevated compared to controls. We suggest that increased plasma viscosity and an imbalance of coagulation over fibrinolysis may be mechanisms by which known risk factors promote arterial thrombosis, but are not present in stable angina.     

Thiamin status of incarcerated and nonincarcerated adolescent males: dietary intake and thiamin pyrophosphate response

We measured thiamin status in 137 incarcerated and 42 nonincarcerated adolescent males by use of both dietary intake data and a standard biochemical assay, thiamin pyrophosphate (TPP) response. Average thiamin intake of the total group was greater than 120% of the age-specific recommended dietary allowance (RDA). Ninety-two percent of incarcerated subjects and 93% of nonincarcerated subjects were consuming greater than or equal to 70% of RDA. Although average daily thiamin intake of nonincarcerated subjects was significantly higher than that of incarcerated subjects, both groups appeared to be at minimal risk for marginal thiamin status. Comparison of TPP response values indicated that there was no significant difference between groups. However, approximately 24% of the total population appeared to have less than adequate RBC thiamin on the basis of current standards for TPP response. Neither dietary intake nor reported previous alcohol intake was correlated with TPP response. These discrepant findings raise questions about the usefulness of the TPP response as the sole indicator of marginal thiamin status.