Sugihara, Takaaki

AbstractBackground & AimsGlycogenic hepatopathy (GH) in type 1 diabetes‐mellitus (T1DM) is characterized by hepatomegaly and perturbations of liver chemistries (LC) that have not been well studied. Furthermore, misdiagnosis with other hepatic complications of T1DM, such as nonalcoholic fatty liver disease, has been described. We perform a systematic review of biopsy‐proven GH reports in T1DM patients to identify LC patterns.MethodsA systematic review identified reports of biopsy‐proven GH in patients with T1DM. We excluded GH with other liver diseases, Mauriac syndrome, or GH without T1DM. Two reviewers screened and extracted studies and assessed their methodological quality. LC elevation magnitude, AST‐to‐ALT ratio, R‐ratio to designate hepatocellular, cholestatic or mixed pattern of hepatic injury, and evolution of transaminases after glycemic control were analyzed.ResultsA total of 192 patients were included, with median age of 20 years, 73% adults, 66% females, median duration of T1DM before diagnosis 10 years, median adult body mass index 21 kg/m2, median HbA1c 12%, at least one episode of diabetic ketoacidosis 70%, and hepatomegaly 92%. ALT and AST showed moderate‐to‐severe elevation in 78% and 76%, respectively, AST/ALT >1 in 71% and hepatocellular to mixed pattern of hepatic injury in 81%. Transaminase improvement with glycemic control was the rule, regardless of other factors in multilinear regression analysis.ConclusionGH tends to have AST‐predominant elevation with a median of 13 times the upper normal limit and R‐ratio >2, which may distinguish it from other etiologies of AST‐predominant LC elevation, and in the appropriate clinical context, may obviate invasive tests.

Abstract The Hippo pathway effector, Yes-associated protein (YAP), is a transcriptional coactivator implicated in cholangiocarcinoma (CCA) pathogenesis. YAP is known to be regulated by a serine/threonine kinase relay module (MST1/2–LATS1/2) culminating in phosphorylation of YAP at Serine 127 and cytoplasmic sequestration. However, YAP also undergoes tyrosine phosphorylation, and the role of tyrosine phosphorylation in YAP regulation remains unclear. Herein, YAP regulation by tyrosine phosphorylation was examined in human and mouse CCA cells, as well as patient-derived xenograft (PDX) models. YAP was phosphorylated on tyrosine 357 (Y357) in CCA cell lines and PDX models. SRC family kinase (SFK) inhibition with dasatinib resulted in loss of YAPY357 phosphorylation, promoted its translocation from the nucleus to the cytoplasm, and reduced YAP target gene expression, including cell lines expressing a LATS1/2-resistant YAP mutant in which all serine residues were mutated to alanine. Consistent with these observations, precluding YAPY357 phosphorylation by site-directed mutagenesis (YAPY357F) excluded YAP from the nucleus. Targeted siRNA experiments identified LCK as the SFK that most potently mediated YAPY357 phosphorylation. Likewise, inducible CRISPR/Cas9-targeted LCK deletion decreased YAPY357 phosphorylation and its nuclear localization. The importance of LCK in CCA biology was demonstrated by clinical observations suggesting LCK expression levels were associated with early tumor recurrence following resection of CCA. Finally, dasatinib displayed therapeutic efficacy in PDX models. Mol Cancer Res; 16(10); 1556–67. ©2018 AACR.

Objective Peribiliary cysts are usually benign, although severe complications and mortality may occur, and they may be confounded with other diseases. No classification delineating their different characteristics exists. Design We performed a systematic review of the frequency and clinical manifestations of peribiliary cysts. Two reviewers identified studies after searching multiple databases on 2 August 2017. Results These cysts were prevalent in cirrhosis (9%). A total of 135 patients were reported in 72 papers with sufficient clinical data (10 countries, 65% from Japan, median age 63 years (range: 4–88), and 80% were males). Symptoms were present in 70%. Misdiagnosis occurred in 40%, and 33% underwent therapeutic misadventures. Cysts were solitary in 10%. Obstructive features and cholangitis were observed in 36% and 12.5%, respectively. Cysts progression was observed in 37.5% over a median of 18 months. Mortality was 24%, mostly due to cirrhosis. A classification framework is proposed, wherein type I includes hepatic, type II extrahepatic and type III mixed hepatic and extrahepatic cysts, each having distinct features. Specifically, type II was more frequent in females, solitary, without cirrhosis, presenting with obstructive jaundice, more difficult to diagnose and required more surgical interventions (all p<0.05). Conclusion Although rarely studied in the literature, peribiliary cysts were frequent in studies designed to evaluate their prevalence, and were mostly asymptomatic. Inaccurate diagnosis, therapeutic misadventures, cysts progression and cysts-related complications are frequent. In a novel classification framework based on location, extrahepatic peribiliary cysts have distinct characteristics and require a special approach for diagnosis and management.

AbstractThe Hippo pathway effector YAP is implicated in the pathogenesis of cholangiocarcinoma (CCA). The Hippo pathway relies on signaling cross talk for its regulation. Given the importance of platelet derived growth factor receptor (PDGFR) signaling in CCA biology, our aim was to examine potential YAP regulation by PDGFR. We employed human and mouse CCA specimens and cell lines for these studies. Initially, we confirmed upregulation of PDGFRβ and PDGFR ligands in human and mouse CCA specimens and cell lines. YAP, a transcriptional co‐activator, was localized to the nucleus in human CCA specimens and a cell line, as well as patient derived xenografts (PDX). PDGFR pharmacologic inhibition led to a redistribution of YAP from the nucleus to cytosol and downregulation of YAP target genes in a human CCA cell line. siRNA silencing of PDGFR‐β similarly downregulated YAP target genes. YAP activation (nuclear localization and target gene expression) was regulated by Src family kinases (SFKs) downstream of PDGFR. SFK activity resulted in phosphorylation of YAP on tyrosine357 (YAPY357). The importance of YAPY357 phosphorylation in regulating YAP activation was confirmed utilizing the SB‐1 cell line, a mouse cell line expressing YAP S127A precluding canonical serine phosphorylation. PDGFR inhibition decreased cellular abundance of the survival protein Mcl‐1, a known YAP target gene, and accordingly increased cell death in CCA cells in vitro and in vivo. These preclinical data demonstrate that a PDGFR‐SFK cascade regulates YAP activation via tyrosine phosphorylation in CCA. Inhibiting this cascade may provide a viable therapeutic strategy for this human malignancy.