Merkel cell carcinoma (MCC) is often caused by persistent expression of Merkel cell polyomavirus (MCPyV) T-antigen (T-Ag). These non-self proteins comprise about 400 amino acids (AAs). Clinical responses to immune checkpoint inhibitors, seen in about half of patients, may relate to T-Ag-specific T cells. Strategies to increase CD8+ T-cell number, breadth, or function could augment checkpoint inhibition, but vaccines to augment immunity must avoid delivery of oncogenic T-antigen domains. We probed MCC tumor-infiltrating lymphocytes (TILs) with an artificial antigen-presenting cell (aAPC) system and confirmed T-Ag recognition with synthetic peptides, HLA-peptide tetramers, and dendritic cells (DCs). TILs from 9 of 12 (75%) subjects contained CD8+ T cells recognizing 1-8 MCPyV epitopes per person. selleck compound Analysis of 16 MCPyV CD8+ TIL epitopes and prior TIL data indicated that 97% of MCPyV+ MCC patients had HLA alleles with the genetic potential that restrict CD8+ T-cell responses to MCPyV T-Ag. The LT AA 70-110 region was epitope-rich, whereas the oncogenic domains of T-Ag were not commonly recognized. Specific recognition of T-Ag-expressing DCs was documented. Recovery of MCPyV oncoprotein-specific CD8+ TILs from most tumors indicated that antigen indifference was unlikely to be a major cause of checkpoint inhibition failure. The myriad of epitopes restricted by diverse HLA alleles indicate that vaccination can be a rational component of immunotherapy if tumor immune suppression can be overcome, and the oncogenic regions of T-Ag can be modified without impacting immunogenicity. Copyright ©2020, American Association for Cancer Research.Fluctuations in serum creatinine (SCr) during hospitalization may provide additional prognostic value beyond baseline renal function. This study aimed to identify groups of patients with distinct creatinine trajectories over hospital stay and assess them in terms of clinical characteristics and short-term mortality. This retrospective study included 35 853 unique adult admissions to a tertiary referral center between January 2012 and January 2016 with at least three SCr measurements within the first 9 days of stay. Individual SCr courses were determined using linear regression or linear-splines model and grouped into clusters. SCr trajectories were described as median SCr courses within clusters. Almost half of the patients presented with changing, mainly declining SCr concentration during hospitalization. In comparison to patients with an increase in SCr, those with a significant decline were younger, more often admitted via the emergency department, more often required a higher level of care, had fewer comorbidities and the more pronounced the fall in SCr, the greater the observed difference. Regardless of baseline renal function, an increase in SCr was related to the highest in-hospital mortality risk among compared clusters. Also, patients with normal renal function at admission followed by decreasing SCr were at higher risk of inpatient death, but lower 90-day postdischarge mortality than patients with a stable SCr. Acute changes in inpatient SCr convey important prognostic information and can only be interpreted by looking at their evolution over time. Recognizing underlying causes and providing adequate care is crucial for improving adverse prognosis. © American Federation for Medical Research 2020. No commercial re-use. See rights and permissions. Published by BMJ.Case summaryA 10-year-old boy presented with severe progressive generalised weakness on a background of 3 days of diarrhoea and vomiting. Vital signs were normal. Peripheral neurological examination revealed grade 1-2 power in all limbs, hypotonia and hyporeflexia. Sensation was fully intact. Cranial nerve examination and speech were normal. The ECG (figure 1) and initial venous blood gas (figure 2) are shown.edpract;archdischild-2019-318286v1/F1F1F1Figure 1ECG.edpract;archdischild-2019-318286v1/F2F2F2Figure 2Venous blood gas. QUESTION 1 What abnormalities are present on the ECG?Peaked T waves, prolonged PR segment and loss of P waves?Shortening of the QT interval and Osborn waves (J waves)?T wave flattening/inversion, prominent U waves and long QU interval?Prolonged QT interval with multiple atrial and ventricular ectopics? QUESTION 2 How would you manage this patient's hypokalaemia? QUESTION 3 What is the likely diagnosis?Conversion disorder.Myasthenia gravis.Periodic paralysis.Guillain-Barré syndrome.Botulism. QUESTION 4 What interventions can be considered for long-term treatment of this condition?Answers can be found on page 2. © Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.Isoforms of protein kinase B (also known as AKT) play important roles in mediating insulin and growth factor signals. Previous studies have suggested that the AKT2 isoform is critical for insulin regulated glucose metabolism while the role of the AKT1 isoform remains less clear. This study focuses on the effects of AKT1 on the adaptive response of pancreatic β-cells. Using a mouse model with inducible β-cell specific deletion of Akt1 gene (βA1KO mice), we showed that AKT1 is involved in high fat diet (HFD) induced growth and survival of β-cells but is unnecessary for them to maintain a population in the absence of metabolic stress. When unchallenged, βA1KO mice presented the same metabolic profile and β-cell phenotype as the control mice with intact Akt1 genes. When metabolic stress was induced by HFD, β-cells in control mice with intact Akt1 proliferated as a compensatory mechanism for metabolic overload. Similar effects were not observed in βA1KO mice. We further demonstrated that AKT1 protein deficiency caused ER stress and potentiated β-cells to undergo apoptosis. Our results revealed that AKT1 protein loss led to induction of eIF2a signaling and ER stress markers under normal chow fed condition, indicating chronic low-level ER stress. Together, these data established a role of AKT1 as a growth and survival factor for adaptive β -cell response and suggest that ER stress induction may be responsible for this effect of AKT1. Copyright © 2020 American Society for Microbiology.