A chemokine network of T cell exhaustion and metabolic reprogramming in renal cell carcinoma

Renal cell carcinoma (RCC) is frequently infiltrated by immune cells, a process which is governed by chemokines. CD8+ T cells in the RCC tumor microenvironment (TME) may be exhausted which most likely influence therapy response and survival. The aim of this study was to evaluate chemokine-driven T cell recruitment, T cell exhaustion in the RCC TME, as well as metabolic processes leading to their functional anergy in RCC. Eight publicly available bulk RCC transcriptome collectives (n=1819) and a single cell RNAseq dataset (n=12) were analyzed. Immunodeconvolution, semi-supervised clustering, gene set variation analysis and Monte Carlo-based modeling of metabolic reaction activity were employed. Among 28 chemokine genes available, CXCL9/10/11/CXCR3, CXCL13/CXCR5 and XCL1/XCR1 mRNA expression were significantly increased in RCC compared to normal kidney tissue and also strongly associated with tumor-infiltrating effector memory and central memory CD8+ T cells in all investigated collectives. M1 TAMs, T cells, NK cells as well as tumor cells were identified as the major sources of these chemokines, whereas T cells, B cells and dendritic cells were found to predominantly express the cognate receptors. The cluster of RCCs characterized by high chemokine expression and high CD8+ T cell infiltration displayed a strong activation of IFN/JAK/STAT signaling with elevated expression of multiple T cell exhaustion-associated transcripts. Chemokinehigh RCCs were characterized by metabolic reprogramming, in particular by downregulated OXPHOS and increased IDO1-mediated tryptophan degradation. None of the investigated chemokine genes was significantly associated with survival or response to immunotherapy. We propose a chemokine network that mediates CD8+ T cell recruitment and identify T cell exhaustion, altered energy metabolism and high IDO1 activity as key mechanisms of their suppression. Concomitant targeting of exhaustion pathways and metabolism may pose an effective approach to RCC therapy

Ведение беременных с преэклампсией в женской консультации

ЖЕНЩИНЫ БЕРЕМЕННЫЕБЕРЕМЕННОСТЬБЕРЕМЕННОСТИ ОСЛОЖНЕНИЯГИПЕРТЕНЗИЯ, ВЫЗВАННАЯ БЕРЕМЕННОСТЬЮ /ПРОФПРЕЭКЛАМПСИЯГЕСТОЗЖЕНСКИЕ КОНСУЛЬТАЦИ

The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the ipilimumab network

Background: Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE) in up to 64% of patients. Treatment algorithms for the management of common ipilimumab-induced AEs have lead to a reduction of morbidity, e.g. due to bowel perforations. However, the spectrum of less common AEs is expanding as ipilimumab is increasingly applied. Stringent recognition and management of AEs will reduce drug-induced morbidity and costs, and thus, positively impact the cost-benefit ratio of the drug. To facilitate timely identification and adequate management data on rare AEs were analyzed at 19 skin cancer centers. Methods and Findings: Patient files (n = 752) were screened for rare ipilimumab-associated AEs. A total of 120 AEs, some of which were life-threatening or even fatal, were reported and summarized by organ system describing the most instructive cases in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS), granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patientś delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment. Conclusion: The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects

Identification of ICF categories relevant for nursing in the situation of acute and early post-acute rehabilitation

<p>Abstract</p> <p>Background</p> <p>The recovery of patients after an acute episode of illness or injury depends both on adequate medical treatment and on the early identification of needs for rehabilitation care. The process of early beginning rehabilitation requires efficient communication both between health professionals and the patient in order to effectively address all rehabilitation goals. The currently used nursing taxonomies, however, are not intended for interdisciplinary use and thus may not contribute to efficient rehabilitation management and an optimal patient outcome. The ICF might be the missing link in this communication process. The objective of this study was to identify the categories of the International Classification of Functioning, Disability and Health (ICF) categories relevant for nursing care in the situation of acute and early post-acute rehabilitation.</p> <p>Methods</p> <p>First, in a consensus process, "Leistungserfassung in der Pflege" (LEP) nursing interventions relevant for the situation of acute and early post-acute rehabilitation were selected. Second, in an integrated two-step linking process, two nursing experts derived goals of LEP nursing interventions from their practical knowledge and selected corresponding ICF categories most relevant for patients in acute and post-acute rehabilitation (ICF Core Sets).</p> <p>Results</p> <p>Eighty-seven percent of ICF Core Set categories could be linked to goals of at least one nursing intervention variable of LEP. The ICF categories most frequently linked with LEP nursing interventions were respiration functions, experience of self and time functions and focusing attention. Thirteen percent of ICF Core Set categories could not be linked with LEP nursing interventions. The LEP nursing interventions which were linked with the highest number of different ICF-categories of all were "therapeutic intervention", "patient-nurse communication/information giving" and "mobilising".</p> <p>Conclusion</p> <p>The ICF Core Sets for the acute hospital and early post-acute rehabilitation facilities are highly relevant for rehabilitation nursing. Linking nursing interventions with ICF Core Set categories is a feasible way to analyse nursing. Using the ICF Core Sets to describe goals of nursing interventions both facilitates inter-professional communication and respects patient's needs. The ICF may thus be a useful framework to set nursing intervention goals.</p