Although liver transplantation (LT) yields survival benefit for patients with acute-on-chronic liver failure grade 3 (ACLF-3), knowledge gaps remain regarding risk factors for post-LT mortality. We retrospectively reviewed data from 10 centers in the United States and Canada for patients transplanted between 2018 and 2019 and who required care in the intensive care unit prior to LT. ACLF was identified using the European Association for the Study of the Liver-Chronic Liver Failure (EASL-CLIF) criteria. A total of 318 patients were studied, of whom 106 (33.3%) had no ACLF, 61 (19.1%) had ACLF-1, 74 (23.2%) had ACLF-2, and 77 (24.2%) had ACLF-3 at transplantation. Survival probability 1 year after LT was significantly higher in patients without ACLF (94.3%) compared with patients with ACLF (87.3%; P = 0.02), but similar between ACLF-1 (88.5%), ACLF-2 (87.8%), and ACLF-3 (85.7%; P = 0.26). Recipients with ACLF-3 and circulatory failure (n = 29) had similar 1-year post-LT survival (82.3%) compared with patients with ACLF-3 without circulatory failure (89.6%; P = 0.32), including those requiring multiple vasopressors. For patients transplanted with ACLF-3 including respiratory failure (n = 20), there was a trend toward significantly lower post-LT survival (P = 0.07) among those with respiratory failure (74.1%) compared with those without (91.0%). The presence of portal vein thrombosis (PVT) at LT for patients with ACLF-3 (n = 15), however, yielded significantly lower survival (91.9% versus 57.1%; P < 0.001). Multivariable logistic regression analysis revealed that PVT was significantly associated with post-LT mortality within 1 year (odds ratio, 7.3; 95% confidence interval, 1.9-28.3). No correlation was found between survival after LT and the location or extent of PVT, presence of transjugular intrahepatic portosystemic shunt, or anticoagulation. LT in patients with ACLF-3 requiring vasopressors yields excellent 1-year survival. LT should be approached cautiously among candidates with ACLF-3 and PVT.
Crosstalk between different receptor tyrosine kinases (RTKs) is thought to drive oncogenic signaling and allow therapeutic escape. EGFR and RON are two such RTKs from different subfamilies, which engage in crosstalk through unknown mechanisms. We combined high-resolution imaging with biochemical and mutational studies to ask how EGFR and RON communicate. EGF stimulation promotes EGFR-dependent phosphorylation of RON, but ligand stimulation of RON does not trigger EGFR phosphorylation – arguing that crosstalk is unidirectional. Nanoscale imaging reveals association of EGFR and RON in common plasma membrane microdomains. Two-color single particle tracking captured formation of complexes between RON and EGF-bound EGFR. Our results further show that RON is a substrate for EGFR kinase, and that transactivation of RON requires formation of a signaling competent EGFR dimer. These results support a role for direct EGFR/RON interactions in propagating crosstalk, such that EGF-stimulated EGFR phosphorylates RON to activate RON-directed signaling.
Systemic sclerosis (SSc) is a heterogenous, multisystem autoimmune disease defined by fibrosis and classified by extent of skin and organ involvement with varying clinical manifestations, progression rates, morbidity, and mortality. This heterogeneity complicates diagnosis, as well as epidemiological estimates. Globally, in areas of higher incidence, such as North America, SSc affects approximately 14 to 21 per million per year. 1 Higher rates are seen in middle-aged women, but there is relatively poorer prognosis in men and African Americans. 1,2 To date, there exists a paucity of literature on SSc and liver involvement. PaTHOPHYsiOlOGYSSc is thought to be caused by an environmental insult activating genetic predisposition through epigenetic modifications to initiate a cascade of autoimmune inflammation via both innate and adaptive systems resulting in vascular dysfunction and, ultimately, fibrosis of the skin and internal organs (Fig. 1). 1,3,4 Numerous gene variants have been implicated in SSc, and first-degree family members exhibit a relative risk ratio of 13 for development. 1 However, exact SSc pathogenesis remains unclear.Pathology of the gastrointestinal (GI) lumens is postulated to initiate with neuroimmunological damage through autoantibodies or adrenergic overdrive. 5 Autoimmunity, such as through anti-mitochondrial antibodies (AMAs) or PDC-E2, a T cell mitochondrial target, is a common driver of cholangiocyte activation and dysfunction as seen in primary biliary cholangitis (PBC), the most common hepatic pathology in SSc. 4,6 As with other end-organ fibrosis in SSc, it is thought that progressive endothelial dysfunction and microvascular damage result in reduced vascular capacity, causing hypoxic damage to terminal tissues. Both pathological pathways result in cyclic inflammatory crosstalk, including overproduction of a key fibrosis regulator, transforming growth factorβ (TGFβ), resulting in fibrosis
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