Patel, Tushar

AbstractCholangiocarcinoma (CCA) is an aggressive biliary tract malignancy with limited treatment options and low survival rates. Currently, there are no curative medical therapies for CCA. Recent advances have enhanced our understanding of the genetic basis of this disease, and elucidated therapeutically relevant targets. Therapeutic efforts in development are directed at several key pathways due to genetic aberrations including receptor tyrosine kinase pathways, mutant IDH enzymes, the PI3K-AKT-mTOR pathway, and chromatin remodeling networks. A highly desmoplastic, hypovascular stroma is characteristic of CCAs and recent work has highlighted the importance of targeting this pathway via stromal myofibroblast depletion. Future efforts should concentrate on combination therapies with action against the cancer cell and the surrounding tumor stroma. As the mutational landscape of CCA is being illuminated, molecular profiling of patient tumors will enable identification of specific mutations and the opportunity to offer directed, personalized treatment options.

AbstractIntrahepatic cholangiocarcinomas (iCCA) are primary intrahepatic malignancies originating from biliary epithelia. While both hepatocellular cancer and iCCA can present as mass lesions within the liver, these cancers are distinct in their morphology, etiology, pathology, natural history and response to therapy. There is a need for accurate and sensitive molecular markers for the diagnosis of iCCA. Recent advances in elucidating molecular and genetic characteristics of iCCA offer the potential of molecular‐based diagnosis of iCCA. Specific genetic mutations of IDH1/2, BAP1, p53, and KRAS, FGFR gene fusions and alterations in microRNA have all been described in iCCA. Although there are no accurate serum or biliary biomarkers currently available for diagnosis of iCCA, several potential candidates have been identified. Knowledge of specific genetic or molecular abnormalities offers potential for individualized approaches for the treatment of patients with iCCA in the future.

Abstract Hepatocellular cancer (HCC) is a highly treatment-refractory cancer and is also highly resistant to adverse cellular stress. Although cell behavior can be modulated by noncoding RNAs (ncRNA) within extracellular vesicles (EV), the contributions of long noncoding RNAs (lncRNAs) are largely unknown. To this end, the involvement and functional roles of lncRNAs contained within EVs during chemotherapeutic stress in human HCC were determined. Expression profiling identified a subset of lncRNAs that were enriched in tumor cell–derived vesicles released from two different cell lines. Of these, lincRNA-VLDLR (linc-VLDLR) was significantly upregulated in malignant hepatocytes. Exposure of HCC cells to diverse anticancer agents such as sorafenib, camptothecin, and doxorubicin increased linc-VLDLR expression in cells as well as within EVs released from these cells. Incubation with EVs reduced chemotherapy-induced cell death and also increased linc-VLDLR expression in recipient cells. RNAi-mediated knockdown of linc-VLDLR decreased cell viability and abrogated cell-cycle progression. Moreover, knockdown of VLDLR reduced expression of ABCG2 (ATP-binding cassette, subfamily G member 2), whereas overexpression of this protein reduced the effects of VLDLR knockdown on sorafenib-induced cell death. Here, linc-VLDLR is identified as an EV-enriched lncRNA that contributes to cellular stress responses. Implications: These findings provide new insight into the role of EVs and demonstrate the capacity of lncRNAs to mediate chemotherapeutic stress response in HCC. Mol Cancer Res; 12(10); 1377–87. ©2014 AACR.

The microRNAs (miRNAs) are small noncoding RNAs that are potent regulators of gene expression and can regulate several diverse biological functions. This minireview provides an overview of recent studies that have examined the role and involvement of miRNAs in cholangiocarcinomas. These studies provide evidence for deregulated expression of miRNA and are providing new insights into the potential contribution of these in the pathogenesis of cholangiocarcinoma.

AbstractBackground & AimsNon‐ischaemic cardiomyopathy (NIC) is an early complication of liver transplantation (LT). Our aims were to define the prevalence, associated clinical factors, and prognosis of this condition.MethodsA retrospective study was performed on patients undergoingLTat our institution from January 2005 to December 2012. Patients who developedNICwere identified. Data collected included demographic and clinical data.ResultsA total 1460 transplants were performed in this period and seventeen patients developedNIC. Pretransplant medianQTc interval was 459 (range, 405–530), and median E/A ratio was 1 (range, 0.71–1.67). Fourteen patients (82%) were severely malnourished and required nutritional support. Thirteen patients (76%) had renal insufficiency. Median time to onset was 2 days post‐transplant (range, 0–20). Echocardiograms showed global left ventricular hypokinesis and a decrease in ejection fraction (EF) from a median of 65% (range, 50–81) pretransplant to a median of 21% (range, 15–32). Median raw model for end‐stage liver disease (MELD) score was 29 in patients withNICvs. 18 in patients without cardiomyopathy (P = 0.01). There was no significant difference between recipients withNICvs. recipients without cardiomyopathy regarding donor age, donor risk index, and cold and warm ischaemia time. Recovery of cardiac function occurred in 16 patients, with a medianEFof 44% (range, 25–65%) at the time of discharge. The last echocardiogram available showed a medianEFof 59% (range, 49–73%). One‐year survival of NIC patients was 94.1%.ConclusionNon‐ischaemic cardiomyopathy is a rare complication afterLT. Patients withNICare critically ill, with highMELDscore, and severe malnutrition.

Blood-brain barrier (BBB) dysfunction in acute liver failure (ALF) results in increased BBB permeability that often precludes the patients from obtaining a life-saving liver transplantation. It remains controversial whether matrix metalloproteinase-9 (MMP-9) from the injured liver contributes to the deregulation of BBB function in ALF. We selectively upregulated a physiologic inhibitor of MMP-9 (TIMP-1) with a single intracerebroventricular injection of TIMP-1 cDNA plasmids at 48 and 72 hours, or with pegylated-TIMP-1 protein. Acute liver failure was induced with tumor necrosis factor-α and D-(+)-galactosamine in mice. Permeability of BBB was assessed with sodium fluorescein (NaF) extravasation. We found a significant increase in TIMP-1 within the central nervous system (CNS) after the administration of TIMP-1 cDNA plasmids and that increased TIMP-1 within the CNS resulted in an attenuation of BBB permeability, a reduction in activation of epidermal growth factor receptor and p38 mitogen-activated protein kinase signals, and a restoration of the tight junction protein occludin in mice with experimental ALF. Pegylated TIMP-1 provided similar protection against BBB permeability in mice with ALF. Our results provided a proof of principle that MMP-9 contributes to the BBB dysfunction in ALF and suggests a potential therapeutic role of TIMP-1 in ALF.

AbstractMicroRNAs (miRNAs) are small, regulatory non‐coding RNAs that have potent effects on gene expression. Several miRNA are deregulated in cellular processes involved in human liver diseases and regulation of cellular processes. Recent studies have identified the involvement of miR‐29 in hepatic fibrosis and carcinogenesis. Although several targets of miR‐29 have been identified, there is limited information regarding the cell‐type specific roles of miR‐29 in the liver, and we sought to evaluate the role of this miRNA in hepatic pathobiology. We report the generation of a tissue–specific knockout mouse to evaluate the role of miR‐29 in hepatic fibrosis and carcinogenesis in response to injury. We hypothesized that miR‐29 contributes to the hepatocyte driven response to chronic cellular injury that results in fibrosis. In support of this hypothesis, fibrosis and mortality were enhanced in miR29 knockout mice in response to carbon tetrachloride. Genome‐wide gene expression analysis identified an over‐representation of genes associated with fibrosis. The oncofetal RNA H19 was modulated in a miR‐29 dependent manner following exposure to carbon tetrachloride in vivo. The impact of a hepatocyte specific miR‐29 knockout on survival following chronic hepatic injury in vivo implicates this miRNA as a potential target for intervention. These results provide evidence of the involvement of miR‐29 in chronic hepatic injury, and suggest a role for deregulated hepatocyte expression of miR‐29 in the response to hepatic injury, fibrosis and carcinogenesis.