Targeting Liver Cancer: First Steps toward a miRacle?

In a recent issue of Cell, Iliopoulos and colleagues demonstrate a novel and targetable epigenetic amplification loop in hepatocellular carcinoma involving HNF4α, miR-124, IL6-R, Stat3, miR-24, and miR-629. These results establish microRNAs as novel players in early stages of hepatocarcinogenesis and as potential targets for the treatment of hepatocellular carcinoma

Fibroblasts in liver cancer: functions and therapeutic translation

Accumulation of fibroblasts in the premalignant or malignant liver is a characteristic feature of liver cancer, but has not been therapeutically leveraged despite evidence for pathophysiologically relevant roles in tumour growth. Hepatocellular carcinoma is a largely non-desmoplastic tumour, in which fibroblasts accumulate predominantly in the pre-neoplastic fibrotic liver and regulate the risk for hepatocellular carcinoma development through a balance of tumour-suppressive and tumour-promoting mediators. By contrast, cholangiocarcinoma is desmoplastic, with cancer-associated fibroblasts contributing to tumour growth. Accordingly, restoring the balance from tumour-promoting to tumour-suppressive fibroblasts and mediators might represent a strategy for hepatocellular carcinoma prevention, whereas in cholangiocarcinoma, fibroblasts and their mediators could be leveraged for tumour treatment. Importantly, fibroblast mediators regulating hepatocellular carcinoma development might exert opposite effects on cholangiocarcinoma growth. This Review translates the improved understanding of tumour-specific, location-specific, and stage-specific roles of fibroblasts and their mediators in liver cancer into novel and rational therapeutic concepts.Copyright © 2023 Elsevier Ltd. All rights reserved

TLR4 Deficiency Protects against Hepatic Fibrosis and Diethylnitrosamine-Induced Pre-Carcinogenic Liver Injury in Fibrotic Liver

Background The development of hepatocellular carcinoma (HCC) is a common consequence of advanced liver fibrosis but the interactions between fibrogenesis and carcinogenesis are still poorly understood. Recently it has been shown that HCC promotion depends on Toll-like receptor (TLR) 4. Pre-cancerogenous events can be modelled in mice by the administration of a single dose of diethylnitrosamine (DEN), with HCC formation depending amongst others on interleukin (IL) 6 production. Mice lacking the hepatocanalicular phosphatidylcholine transporter ABCB4 develop liver fibrosis spontaneously, resemble patients with sclerosing cholangitis due to mutations of the orthologous human gene, and represent a valid model to study tumour formation in pre-injured cholestatic liver. The aim of this study was to investigate DEN-induced liver injury in TLR4-deficient mice with biliary fibrosis. Methods ABCB4-deficient mice on the FVB/NJ genetic background were crossed to two distinct genetic backgrounds (TLR4-sufficient C3H/HeN and TLR4-deficient C3H/HeJ) for more than 10 generations. The two congenic knockout and the two corresponding wild-type mouse lines were treated with a single dose of DEN for 48 hours. Phenotypic differences were assessed by measuring hepatic collagen contents, inflammatory markers (ALT, CRP, IL6) as well as hepatic apoptosis (TUNEL) and proliferation (Ki67) rates. Results Hepatic collagen accumulation is significantly reduced in ABCB4-/-:TLR4-/-double-deficient mice. After DEN challenge, apoptosis, proliferation and inflammatory markers are decreased in TLR4-deficient in comparison to TLR4-sufficient mice. When combining ABCB4 and TLR4 deficiency with DEN treatment, hepatic IL6 expression and proliferation rates are lowest in fibrotic livers from the double-deficient line. Consistent with these effects, selective digestive tract decontamination in ABCB4-/- mice also led to reduced tumor size and number after DEN. Conclusion This study demonstrates that liver injury upon DEN challenge depends on pre-existing fibrosis and genetic background. The generation of ABCB4-/: TLR4-/- double-deficient mice illustrates that TLR4-deficiency protects against hepatic injury in a preclinical mouse model of chronic liver disease

Perturbation of Tunneling Processes by Mechanical Degrees of Freedom in Mesoscopic Junctions

We investigate the perturbation in the tunneling current caused by non-adiabatic mechanical motion in a mesoscopic tunnel junction. A theory introduced by Caroli et al. \cite{bi1,bi2,bi3} is used to evaluate second order self-energy corrections for this non-equilibrium situation lacking translational invariance. Inelastic signatures of the mechanical degrees of freedom are found in the current-voltage $I(V)$ characteristics. These give rise to sharp features in the derivative spectrum, $d^2I/dV^2$.Comment: 22 pages LaTeX + 3 uuencoded PS picture

Fluid-solid phase transitions in 3D complex plasmas under microgravity conditions

Phase behavior of large three-dimensional complex plasma systems under microgravity conditions onboard the International Space Station is investigated. The neutral gas pressure is used as a control parameter to trigger phase changes. Detailed analysis of structural properties and evaluation of three different melting/freezing indicators reveal that complex plasmas can exhibit melting by increasing the gas pressure. Theoretical estimates of complex plasma parameters allow us to identify main factors responsible for the observed behavior. The location of phase states of the investigated systems on a relevant equilibrium phase diagram is estimated. Important differences between the melting process of 3D complex plasmas under microgravity conditions and that of flat 2D complex plasma crystals in ground based experiments are discussed.Comment: 13 pages, 10 figures; submitted to Phys. Rev.

ECC2K-130 on NVIDIA GPUs

Abstract. Computations of small discrete logarithms are feasible even in "secure" groups, and are used as subroutines in several cryptographic protocols in the literature. For example, the Boneh-Goh-Nissim degree-2-homomorphic public-key encryption system uses generic square-root discrete-logarithm methods for decryption. This paper shows how to use a small group-specific table to accelerate these subroutines. The cost of setting up the table grows with the table size, but the acceleration also grows with the table size. This paper shows experimentally that computing a discrete logarithm in an interval of order takes only 1.93