Reactivation of T cell immunity by PD-1/PD-L1 immune checkpoint blockade has been shown to be a promising cancer therapeutic strategy. However, PD-L1 immunohistochemical readout is inconsistent with patient response, which presents a clinical challenge to stratify patients. Because PD-L1 is heavily glycosylated, we developed a method to resolve this by removing the glycan moieties from cell surface antigens via enzymatic digestion, a process termed sample deglycosylation. Notably, deglycosylation significantly improves anti-PD-L1 antibody binding affinity and signal intensity, resulting in more accurate PD-L1 quantification and prediction of clinical outcome. This proposed method of PD-L1 antigen retrieval may provide a practical and timely approach to reduce false-negative patient stratification for guiding anti-PD-1/PD-L1 therapy.

An analytic Schmidt transformation is used to create locally refined global model grids capable of efficient climate simulation with gridcell widths as small as 10 km in the GFDL High-Resolution Atmosphere Model (HiRAM). This method of grid stretching produces a grid that varies very gradually into the region of enhanced resolution without changing the topology of the model grid and does not require radical changes to the solver. AMIP integrations were carried out with two grids stretched to 10-km minimum gridcell width: one centered over East Asia and the western Pacific warm pool, and the other over the continental United States. Robust improvements to orographic precipitation, the diurnal cycle of warm-season continental precipitation, and tropical cyclone maximum intensity were found in the region of enhanced resolution, compared to 25-km uniform-resolution HiRAM. The variations in grid size were not found to create apparent grid artifacts, and in some measures the global-mean climate improved in the stretched-grid simulations. In the enhanced-resolution regions, the number of tropical cyclones was reduced, but the fraction of storms reaching hurricane intensity increased, compared to a uniform-resolution simulation. This behavior was also found in a stretched-grid perpetual-September aquaplanet simulation with 12-km resolution over a part of the tropics. Furthermore, the stretched-grid aquaplanet simulation was also largely free of grid artifacts except for an artificial Walker-type circulation, and simulated an ITCZ in its unrefined region more resembling that of higher-resolution aquaplanet simulations, implying that the unrefined region may also be improved in stretched-grid simulations. The improvements due to stretching are attributable to improved resolution as these stretched-grid simulations were sparingly tuned.

13Here we show that coupling a high-resolution one-column ocean model to an 14

Spontaneous bacterial empyema in cirrhotic patients is a high mortality complication. The independent factors related to poor outcome are high MELD-Na score, initial ICU admission and initial antibiotic treatment failure. High MELD-Na score may be a useful mortality predictor of SBE in cirrhotic patients.

SUMMARY Multiple mechanisms of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been identified in EGFR-mutant non-small cell lung cancer (NSCLC); however, recurrent resistance to EGFR TKIs due to the heterogeneous mechanisms underlying resistance within a single patient remains a major challenge in the clinic. Here, we report a role of nuclear protein kinase Cδ (PKCδ) as a common axis across multiple known TKI-resistance mechanisms. Specifically, we demonstrate that TKI-inactivated EGFR dimerizes with other membrane receptors implicated in TKI resistance to promote PKCδ nuclear translocation. Moreover, the level of nuclear PKCδ is associated with TKI response in patients. The combined inhibition of PKCδ and EGFR induces marked regression of resistant NSCLC tumors with EGFR mutations.