GIV/Girdin is a central hub for profibrogenic signalling networks during liver fibrosis.

Progressive liver fibrosis is characterized by the deposition of collagen by activated hepatic stellate cells (HSCs). Activation of HSCs is a multiple receptor-driven process in which profibrotic signals are enhanced and antifibrotic pathways are suppressed. Here we report the discovery of a signalling platform comprising G protein subunit, Gαi and GIV, its guanine exchange factor (GEF), which serves as a central hub within the fibrogenic signalling network initiated by diverse classes of receptors. GIV is expressed in the liver after fibrogenic injury and is required for HSC activation. Once expressed, GIV enhances the profibrotic (PI3K-Akt-FoxO1 and TGFβ-SMAD) and inhibits the antifibrotic (cAMP-PKA-pCREB) pathways to skew the signalling network in favour of fibrosis, all via activation of Gαi. We also provide evidence that GIV may serve as a biomarker for progression of fibrosis after liver injury and a therapeutic target for arresting and/or reversing HSC activation during liver fibrosis

Molecular interactions between homeodomain proteins

During embryogenesis, patterning is one of the key processes by which the body plan of the embryo becomes established. Patterning of the A-P axis is accomplished by the products of the Hox gene family. In mammals, there are 39 genes in the Hox family that have been grouped into four clusters (A-D) by virtue of their chromosome location. Cross-species studies have confirmed the conservation of the Hox genes during evolution. In vivo, the products of the Hox genes function as transcription factors. The genes have a highly conserved sequence called the homeobox, which translates into a 60 amino acid homeodomain. The homeodomain is a DNA-binding domain made up of three alpha helices and an N-terminal arm which precedes helix 1. Since most HOX homeodomains bind a common core sequence (TAAT), the mechanism by which these proteins achieve specificity in target gene regulation was unknown for some years. This was resolved by the identification of extradenticle (exd). Genetic analysis of zygotic and maternal effect mutations of exd demonstrated that it is a required cofactor for the Drosophila Hox gene products. Examination of exd mutations showed posterior and anterior transformations with alteration in segmental identities. These transformations were similar to those caused by Hox genes. Further analysis of the Hox and exd mutations in vivo, substantiated by in vitro biochemical evidence showed that exd acts in concert with homeotic gene products by cooperatively binding DNA. The mammalian homologue of exd is PBX. PBX functions analogously to its Drosophila counterpart by modulating the DNA-binding specificity of HOX proteins. In mammals, PBX interacts with members of the first 10 paralog group HOX proteins. A second cofactor, MEIS with a high degree of homology to PBX was identified very recently. Both PBX and MEIS belong to the three amino acid loop extension (TALE) family of homeodomain proteins. The homeodomain of these proteins differ from the HOX homeodomains in

The immune microenvironment in patients with mismatch‐repair‐proficient oligometastatic colorectal cancer exposed to chemotherapy: the randomized MIROX GERCOR cohort study

International audienceIn the era of immune checkpoint inhibitors, understanding the metastatic microenvironment of proficient mismatch repair/microsatellite stable (pMMR/MSS) colorectal cancer (CRC) is of paramount importance to both prognostication and the development of more effective novel therapies. In this study, primary and paired metastasis tissue samples were collected from patients with resectable metastatic CRC treated with adjuvant FOLFOX or peri-operative chemotherapy in the MIROX phase III prospective study. In total, 74 cancer tissues were stained for CD3, CD8, Forkhead box protein 3 (FOXP3), Programmed cell Death protein-1(PD-1, invasive front, stromal, intra-epithelial compartments) and Programmed Death-Ligand 1 (PD-L1, tumor, immune cells). The immune profiling of primary CRC had a limited value to predict the immune context of paired metastases for all markers but CD3+. The expression of CD8 and PD-L1 was higher in metastases after neoadjuvant FOLFOX. In metastases, both CD3 T cells at the invasive front and PD-L1 expressions on immune cells were predictive of better disease-free survival. These results show that the effect of FOLFOX on modifying the immune microenvironment in resected CRC metastases and measurement of PD-L1 expression and tumor-infiltrating CD8 T cells in pMMR/MSS metastatic tissue samples could improve treatment strategies of metastatic CRC patients

Supplementary Table S1 from Immune Marker Spatial Distribution and Clinical Outcome after PD-1 Blockade in Mismatch Repair–deficient, Advanced Colorectal Carcinomas

Supplementary Table S1. Significant features in the univariable analysis for prediction of progression-free survival.</p

Supplementary Table S2 from Immune Marker Spatial Distribution and Clinical Outcome after PD-1 Blockade in Mismatch Repair–deficient, Advanced Colorectal Carcinomas

Supplementary Table S2. Significant features in the univariable analysis for prediction of tumor response.</p