Propionyl-CoA carboxylase subunit B regulates anti-tumor T cells in a pancreatic cancer mouse model.

Most human pancreatic ductal adenocarcinoma (PDAC) are not infiltrated with cytotoxic T cells and are highly resistant to immunotherapy. Over 90% of PDAC have oncogenic KRAS mutations, and phosphoinositide 3-kinases (PI3Ks) are direct effectors of KRAS. Our previous study demonstrated that ablation of Pik3ca in KPC (KrasG12D; Trp53R172H; Pdx1-Cre) pancreatic cancer cells induced host T cells to infiltrate and completely eliminate the tumors in a syngeneic orthotopic implantation mouse model. Now, we show that implantation of Pik3ca-/- KPC (named αKO) cancer cells induces clonal expansion of cytotoxic T cells infiltrating the pancreatic tumors. To identify potential molecules that can regulate the activity of these anti-tumor T cells, we conducted an in vivo genome-wide gene-deletion screen using αKO cells implanted in the mouse pancreas. The result shows that deletion of propionyl-CoA carboxylase subunit B gene (Pccb) in αKO cells (named p-αKO) leads to immune evasion, tumor progression and death of host mice. Surprisingly, p-αKO tumors are still infiltrated with clonally expanded CD8+ T cells but they are inactive against tumor cells. However, blockade of PD-L1/PD1 interaction reactivated these clonally expanded T cells infiltrating p-αKO tumors, leading to slower tumor progression and improve survival of host mice. These results indicate that Pccb can modulate the activity of cytotoxic T cells infiltrating some pancreatic cancers and this understanding may lead to improvement in immunotherapy for this difficult-to-treat cancer.

Postoperative acute respiratory distress syndrome in patients with previous exposure to bleomycin.

OBJECTIVE: To determine the incidence and risk factors for postoperative acute respiratory distress syndrome (ARDS) in a large cohort of bleomycin-exposed patients undergoing surgery with general endotracheal anesthesia. PATIENTS AND METHODS: From a Mayo Clinic cancer registry, we identified patients who had received systemic bleomycin and then underwent a major surgical procedure that required more than 1 hour of general anesthesia from January 1, 2000, through August 30, 2012. Heart, lung, and liver transplantations were excluded. Postoperative ARDS (within 7 days after surgery) was defined according to the Berlin criteria. RESULTS: We identified 316 patients who underwent 541 major surgical procedures. Only 7 patients met the criteria for postoperative ARDS; all were white men, and 6 were current or former smokers. On univariate analysis, we observed an increased risk of postoperative ARDS in patients who were current or former smokers. Furthermore, significantly greater crystalloid and colloid administration was found in patients with postoperative ARDS. We also observed a trend toward longer surgical duration and red blood cell transfusion in patients with postoperative ARDS, although this finding was not significant. Intraoperative fraction of inspired oxygen was not associated with postoperative ARDS. In bleomycin-exposed patients, the incidence of postoperative ARDS after major surgery with general anesthesia is approximately 1.3% (95% CI, 0.6%-2.6%). For first major procedures after bleomycin therapy, the incidence is 1.9% (95% CI, 0.9%-4.1%). CONCLUSION: The risk of postoperative ARDS in patients exposed to systemic bleomycin appears to be lower than expected. Smoking status may be an important factor that modifies the risk of postoperative ARDS in these patients.

Reward modulates attention independently of action value in posterior parietal cortex.

While numerous studies have explored the mechanisms of reward-based decisions (the choice of action based on expected gain), few have asked how reward influences attention (the selection of information relevant for a decision). Here we show that a powerful determinant of attentional priority is the association between a stimulus and an appetitive reward. A peripheral cue heralded the delivery of reward or no reward (these cues are termed herein RC+ and RC-, respectively); to experience the predicted outcome, monkeys made a saccade to a target that appeared unpredictably at the same or opposite location relative to the cue. Although the RC had no operant associations (did not specify the required saccade), they automatically biased attention, such that an RC+ attracted attention and an RC- repelled attention from its location. Neurons in the lateral intraparietal area (LIP) encoded these attentional biases, maintaining sustained excitation at the location of an RC+ and inhibition at the location of an RC-. Contrary to the hypothesis that LIP encodes action value, neurons did not encode the expected reward of the saccade. Moreover, at odds with an adaptive decision process, the cue-evoked biases interfered with the required saccade, and these biases increased rather than abating with training. After prolonged training, valence selectivity appeared at shorter latencies and automatically transferred to a novel task context, suggesting that training produced visual plasticity. The results suggest that reward predictors gain automatic attentional priority regardless of their operant associations, and this valence-specific priority is encoded in LIP independently of the expected reward of an action.