The Vehicle, Fall 1996

Vol. 38, No. 1 Table of Contents DarcyMichael Maypage 1 Time in TimeJoe Howardpage 2 Sestina for DyingAmy Haynespage 3 VioletsSandra Beauchamppage 5 Melody\u27s SongSandra Beauchamppage 7 A Spinning Top ContemplationThomas T. Brownpage 10 Lady of the NightShari Grierpage 13 The Difference Between a Hand and a Killing JarJason S. Loguepage 14 The Bat I KilledMichael Maypage 15 UntitledKimberly Mannypage 16 ReleaseKimberly Mannypage 17 Fountain in the RainEric Chisauskypage 18 War, the Old Fashioned WayCarmella Cosenzapage 19 AloneCarmella Cosenzapage 20 MotelMichael Maypage 21 UntitledAndrea Traxlerpage 22 UntitledMichael Maypage 23 From Across the CourtyardShannon Goodallpage 24 CommunionShannon Goodallpage 26 Please Come HomeKendall W. Baumannpage 27 UntitledMichael Maypage 29 Indefinite SacrificeAmanda Watsonpage 30 Recovery RoomAbby Kollerpage 31 Questioning FaithMichael Kawapage 31 MerulaMichael Maypage 32 Biographiespage 33https://thekeep.eiu.edu/vehicle/1066/thumbnail.jp

Metabolic rewiring induced by ranolazine improves melanoma responses to targeted therapy and immunotherapy

Resistance of melanoma to targeted therapy and immunotherapy is linked to metabolic rewiring. Here, we show that increased fatty acid oxidation (FAO) during prolonged BRAF inhibitor (BRAFi) treatment contributes to acquired therapy resistance in mice. Targeting FAO using the US Food and Drug Administration-approved and European Medicines Agency-approved anti-anginal drug ranolazine (RANO) delays tumour recurrence with acquired BRAFi resistance. Single-cell RNA-sequencing analysis reveals that RANO diminishes the abundance of the therapy-resistant NGFRhi neural crest stem cell subpopulation. Moreover, by rewiring the methionine salvage pathway, RANO enhances melanoma immunogenicity through increased antigen presentation and interferon signalling. Combination of RANO with anti-PD-L1 antibodies strongly improves survival by increasing antitumour immune responses. Altogether, we show that RANO increases the efficacy of targeted melanoma therapy through its effects on FAO and the methionine salvage pathway. Importantly, our study suggests that RANO could sensitize BRAFi-resistant tumours to immunotherapy. Since RANO has very mild side-effects, it might constitute a therapeutic option to improve the two main strategies currently used to treat metastatic melanoma

An immune dysfunction score for stratification of patients with acute infection based on whole-blood gene expression

Dysregulated host responses to infection can lead to organ dysfunction and sepsis, causing millions of global deaths each year. To alleviate this burden, improved prognostication and biomarkers of response are urgently needed. We investigated the use of whole-blood transcriptomics for stratification of patients with severe infection by integrating data from 3149 samples from patients with sepsis due to community-acquired pneumonia or fecal peritonitis admitted to intensive care and healthy individuals into a gene expression reference map. We used this map to derive a quantitative sepsis response signature (SRSq) score reflective of immune dysfunction and predictive of clinical outcomes, which can be estimated using a 7- or 12-gene signature. Last, we built a machine learning framework, SepstratifieR, to deploy SRSq in adult and pediatric bacterial and viral sepsis, H1N1 influenza, and COVID-19, demonstrating clinically relevant stratification across diseases and revealing some of the physiological alterations linking immune dysregulation to mortality. Our method enables early identification of individuals with dysfunctional immune profiles, bringing us closer to precision medicine in infection.peer-reviewe