GC has received grants, research support or is coinvestigator in clinical trials by Bristol-Myers-Squibb, Celgene, Boehringer Ingelheim, Roche, Tigen Pharma, Iovance and Kite. GC has received honoraria for consultations or presentations by Roche, Genentech, BMS, AstraZeneca, Sanofi-Aventis, Nextcure and GeneosTx. GC has patents in the domain of antibodies and vaccines targeting the tumor vasculature as well as technologies related to T-cell expansion and engineering for T-cell therapy. GC receives royalties from the University of Pennsylvania. FH reports grants from Prostate Cancer Foundation, Bristol-Myers-Squibb, Accuray Inc, Bioprotect, and non-financial support from Roche ImFlame cooperative group, European Organization for Research and Treatment of Cancer (EORTC) chairman Gynecology Cancer Group. FH has received honoraria for consultations from

Acute myeloid leukemia (AML) is a molecularly and clinically heterogeneous hematological malignancy. Although immunotherapy may be an attractive modality to exploit in patients with AML, the ability to predict the groups of patients and the types of cancer that will respond to immune targeting remains limited. This study dissected the complexity of the immune architecture of AML at high resolution and assessed its influence on therapeutic response. Using 442 primary bone marrow samples from three independent cohorts of children and adults with AML, we defined immune-infiltrated and immune-depleted disease classes and revealed critical differences in immune gene expression across age groups and molecular disease subtypes. Interferon (IFN)–γ–related mRNA profiles were predictive for both chemotherapy resistance and response of primary refractory/relapsed AML to flotetuzumab immunotherapy. Our compendium of microenvironmental gene and protein profiles provides insights into the immuno-biology of AML and could inform the delivery of personalized immunotherapies to IFN-γ–dominant AML subtypes.

K63-linked ubiquitination of GPCRs mediated by the NEDD4-2 E3 ubiquitin ligase regulates recruitment of a TAB1–TAB2 complex on endosomes and stimulates p38 MAPK through a noncanonical pathway, which is critical for endothelial barrier disruption.

No abstract

NAFLD occurred in 8.2% of the IBD population. NAFLD patients were older and had a later onset of IBD disease. IBD patients develop NAFLD with fewer metabolic risk factors than non-IBD NAFLD patients. It is also less common among patients who received anti-TNF-α therapy.

Intestinal decontamination with rifaximin may prevent SBP in cirrhotic patients with ascites. Prospective randomized controlled trials are needed to confirm this finding.

No abstract

Protease-activated receptor-1 (PAR1) is a G-protein-coupled receptor (GPCR) for the coagulant protease thrombin. Similar to other GPCRs, PAR1 is promiscuous and couples to multiple heterotrimeric G-protein subtypes in the same cell and promotes diverse cellular responses. The molecular mechanism by which activation of a given GPCR with the same ligand permits coupling to multiple G-protein subtypes is unclear. Here, we report that N-linked glycosylation of PAR1 at extracellular loop 2 (ECL2) controls G12/13 versus Gq coupling specificity in response to thrombin stimulation. A PAR1 mutant deficient in glycosylation at ECL2 was more effective at stimulating Gq-mediated phosphoinositide signaling compared with glycosylated wildtype receptor. In contrast, wildtype PAR1 displayed a greater efficacy at G12/13-dependent RhoA activation compared with mutant receptor lacking glycosylation at ECL2. Endogenous PAR1 rendered deficient in glycosylation using tunicamycin, a glycoprotein synthesis inhibitor, also exhibited increased PI signaling and diminished RhoA activation opposite to native receptor. Remarkably, PAR1 wildtype and glycosylation-deficient mutant were equally effective at coupling to Gi and β-arrestin-1. Consistent with preferential G12/13 coupling, thrombin-stimulated PAR1 wildtype strongly induced RhoA-mediated stress fiber formation compared with mutant receptor. In striking contrast, glycosylation-deficient PAR1 was more effective at increasing cellular proliferation, associated with Gq signaling, than wildtype receptor. These studies suggest that N-linked glycosylation at ECL2 contributes to the stabilization of an active PAR1 state that preferentially couples to G12/13 versus Gq and defines a previously unidentified function for N-linked glycosylation of GPCRs in regulating G-protein signaling bias.