Induction of cancer neoantigens facilitates development of clinically relevant models for the study of pancreatic cancer immunobiology

Neoantigen burden and CD8 T cell infiltrate are associated with clinical outcome in pancreatic ductal adenocarcinoma (PDAC). A shortcoming of many genetic models of PDAC is the lack of neoantigen burden and limited T cell infiltrate. The goal of the present study was to develop clinically relevant models of PDAC by inducing cancer neoantigens in KP2, a cell line derived from the KPC model of PDAC. KP2 was treated with oxaliplatin and olaparib (OXPARPi), and a resistant cell line was subsequently cloned to generate multiple genetically distinct cell lines (KP2-OXPARPi clones). Clones A and E are sensitive to immune checkpoint inhibition (ICI), exhibit relatively high T cell infiltration, and have significant upregulation of genes involved in antigen presentation, T cell differentiation, and chemokine signaling pathways. Clone B is resistant to ICI and is similar to the parental KP2 cell line in terms of relatively low T cell infiltration and no upregulation of genes involved in the pathways noted above. Tumor/normal exome sequencing and in silico neoantigen prediction confirms successful generation of cancer neoantigens in the KP2-OXPARPi clones and the relative lack of cancer neoantigens in the parental KP2 cell line. Neoantigen vaccine experiments demonstrate that a subset of candidate neoantigens are immunogenic and neoantigen synthetic long peptide vaccines can restrain Clone E tumor growth. Compared to existing models, the KP2-OXPARPi clones better capture the diverse immunobiology of human PDAC and may serve as models for future investigations in cancer immunotherapies and strategies targeting cancer neoantigens in PDAC

Outcomes of operations performed by attending surgeons after overnight trauma shifts

Background: To date, work-hour restrictions have not been imposed on attending surgeons in the United States. The purpose of this study was to investigate the impact of working an overnight trauma shift on outcomes of general surgery operations performed the next day by the post-call attending physician. Study Design: Consecutive patients over a 3.5-year period undergoing elective general surgical procedures were reviewed. Procedures were limited to hernia repairs (inguinal and ventral), cholecystectomies, and intestinal operations. Any operations that were performed the day after the attending surgeon had taken an overnight trauma shift were considered post-call (PC) cases; all other cases were considered nonpost-call (NP). Outcomes from the PC operations were compared with those from the NP operations. Results: There were 869 patients identified; 132 operations were performed PC and 737 were NP. The majority of operations included hernia repairs (46%), followed by cholecystectomies (35%), and intestinal procedures (19%). Overall, the PC operations did not differ from the NP operations with respect to complication rate (13.7% vs 13.5%, p = 0.93) or readmission within 30 days (5% vs 6%, p = 0.84). Additionally, multivariable logistic regression failed to identify an association between PC operations and the development of adverse outcomes. Follow-up was obtained for an average of 3 months. Conclusions: Performance of general surgery operations the day after an overnight in-hospital trauma shift did not affect complication rates or readmission rates. At this time, there is no compelling evidence to mandate work-hour restrictions for attending general surgeons. © 2013 by the American College of Surgeons

In silico epitope prediction analyses highlight the potential for distracting antigen immunodominance with allogeneic cancer vaccines

Allogeneic cancer vaccines are designed to induce antitumor immune responses with the goal of impacting tumor growth. Typical allogeneic cancer vaccines are produced by expansion of established cancer cell lines, transfection with vectors encoding immunostimulatory cytokines, and lethal irradiation. More than 100 clinical trials have investigated the clinical benefit of allogeneic cancer vaccines in various cancer types. Results show limited therapeutic benefit in clinical trials and currently there are no FDA approved allogeneic cancer vaccines. We used recently developed bioinformatics tools including the pVAC-seq suite of software tools to analyze DNA/RNA sequencing data from the TCGA to examine the repertoire of antigens presented by a typical allogeneic cancer vaccine, and to simulate allogeneic cancer vaccine clinical trials. Specifically, for each simulated clinical trial we modeled the repertoire of antigens presented by allogeneic cancer vaccines consisting of three hypothetical cancer cell lines to 30 patients with the same cancer type. Simulations were repeated ten times for each cancer type. Each tumor sample in the vaccine and the vaccine recipient was subjected to HLA typing, differential expression analyses for tumor associated antigens (TAAs), germline variant calling, and neoantigen prediction. These analyses provided a robust, quantitative comparison between potentially beneficial TAAs and neoantigens versus distracting antigens present in the allogeneic cancer vaccines. We observe that distracting antigens greatly outnumber shared TAAs and neoantigens, providing one potential explanation for the lack of observed responses to allogeneic cancer vaccines. This analysis provides additional rationale for the redirection of efforts towards a personalized cancer vaccine approach

Corrigendum to : prevention of adverse drug reactions in hospitalized older patients with multi-morbidity and polypharmacy : the SENATOR* randomized controlled clinical trial

When this paper was first published, there were errors in Figure 1 and Table 3. These errors have now been corrected online. In Figure 1, the text that read “No data available/lost to follow-up n = 56” should have read “No data available/lost to follow-up n = 40”. In Table 3, the text reading “Mortality (all-cause) within 30 days of randomization” should have read “Mortality (all-cause) within 12 weeks of randomization”. The authors wish to emphasize that these data presentation errors are minor and do not in any way alter the statistical results or conclusions of the published paper

Inducible Priming Phosphorylation Promotes Ligand-independent Degradation of the IFNAR1 Chain of Type I Interferon Receptor*

Phosphorylation-dependent ubiquitination and ensuing down-regulation and lysosomal degradation of the interferon α/β receptor chain 1 (IFNAR1) of the receptor for Type I interferons play important roles in limiting the cellular responses to these cytokines. These events could be stimulated either by the ligands (in a Janus kinase-dependent manner) or by unfolded protein response (UPR) inducers including viral infection (in a manner dependent on the activity of pancreatic endoplasmic reticulum kinase). Both ligand-dependent and -independent pathways converge on phosphorylation of Ser535 within the IFNAR1 degron leading to recruitment of β-Trcp E3 ubiquitin ligase and concomitant ubiquitination and degradation. Casein kinase 1α (CK1α) was shown to directly phosphorylate Ser535 within the ligand-independent pathway. Yet given the constitutive activity of CK1α, it remained unclear how this pathway is stimulated by UPR. Here we report that induction of UPR promotes the phosphorylation of a proximal residue, Ser532, in a pancreatic endoplasmic reticulum kinase-dependent manner. This serine serves as a priming site that promotes subsequent phosphorylation of IFNAR1 within its degron by CK1α. These events play an important role in regulating ubiquitination and degradation of IFNAR1 as well as the extent of Type I interferon signaling