The T cell differentiation landscape is shaped by tumour mutations in lung cancer

Tumour mutational burden (TMB) predicts immunotherapy outcome in non-small cell lung cancer (NSCLC), consistent with immune recognition of tumour neoantigens. However, persistent antigen exposure is detrimental for T cell function. How TMB affects CD4 and CD8 T cell differentiation in untreated tumours and whether this affects patient outcomes is unknown. Here, we paired high-dimensional flow cytometry, exome, single-cell and bulk RNA sequencing from patients with resected, untreated NSCLC to examine these relationships. TMB was associated with compartment-wide T cell differentiation skewing, characterized by loss of TCF7-expressing progenitor-like CD4 T cells, and an increased abundance of dysfunctional CD8 and CD4 T cell subsets with strong phenotypic and transcriptional similarity to neoantigen-reactive CD8 T cells. A gene signature of redistribution from progenitor-like to dysfunctional states was associated with poor survival in lung and other cancer cohorts. Single-cell characterization of these populations informs potential strategies for therapeutic manipulation in NSCLC

Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade

As tumors grow, they acquire mutations, some of which create neoantigens that influence the response of patients to immune checkpoint inhibitors. We explored the impact of neoantigen intratumor heterogeneity (ITH) on antitumor immunity. Through integrated analysis of ITH and neoantigen burden, we demonstrate a relationship between clonal neoantigen burden and overall survival in primary lung adenocarcinomas. CD8(+) tumor-infiltrating lymphocytes reactive to clonal neoantigens were identified in early-stage non–small cell lung cancer and expressed high levels of PD-1. Sensitivity to PD-1 and CTLA-4 blockade in patients with advanced NSCLC and melanoma was enhanced in tumors enriched for clonal neoantigens. T cells recognizing clonal neoantigens were detectable in patients with durable clinical benefit. Cytotoxic chemotherapy–induced subclonal neoantigens, contributing to an increased mutational load, were enriched in certain poor responders. These data suggest that neoantigen heterogeneity may influence immune surveillance and support therapeutic developments targeting clonal neoantigens

Normative values of eccentric hip abduction strength in novice runners:an equation adjusting for age and gender

PURPOSE: Low eccentric strength of the hip abductors, might increase the risk of patellofemoral pain syndrome and iliotibial band syndrome in runners. No normative values for maximal eccentric hip abduction strength have been established. Therefore the purpose of this study was to establish normative values of maximal eccentric hip abduction strength in novice runners. METHODS: Novice healthy runners (n = 831) were recruited through advertisements at a hospital and a university. Maximal eccentric hip abduction strength was measured with a hand–held dynamometer. The demographic variables associated with maximal eccentric hip abduction strength from a univariate analysis were included in a multivariate linear regression model. Based on the results from the regression model, a regression equation for normative hip abduction strength is presented. RESULTS: A significant difference in maximal eccentric hip abduction strength was found between males and females: 1.62 ± 0.38 Nm/kg (SD) for males versus 1.41 ± 0.33 Nm/kg (SD) for females (p < 0.001). Age was associated with maximal eccentric hip abduction strength: per one year increase in age a ‐0.0045 ± 0.0013 Nm/kg (SD) decrease in strength was found, p < 0.001. Normative values were identified using a regression equation adjusting for age and gender. Based on this, the equation to calculate normative values for relative eccentric hip abduction strength became: (1.600 + (age * ‐0.005) + (gender (1 = male / 0 = female) * 0.215) ± 1 or 2 * 0.354) Nm/kg. CONCLUSION: Normative values for maximal eccentric hip abduction strength in novice runners can be calculated by taking into account the differences in strength across genders and the decline in strength that occurs with increasing age. Age and gender were associated with maximal eccentric hip abduction strength in novice runners, and these variables should be taken into account when evaluating eccentric hip abduction strength in this group of athletes. LEVEL OF EVIDENCE: 2

Nephrogenic Systemic Fibrosis: A Survey of Nephrologists' Perceptions and Practices

Background and objectives: Nephrogenic systemic fibrosis (NSF) is a disorder that can affect patients with renal dysfunction exposed to a gadolinium-based contrast agent (GBCA). Given the unique role nephrologists play in caring for patients at risk to develop NSF, this study surveyed their perceptions and practices regarding NSF