High Keratin 8/18 Ratio Predicts Aggressive Hepatocellular Cancer Phenotype.

BACKGROUND & AIMS: Steatohepatitis (SH) and SH-associated hepatocellular carcinoma (HCC) are of considerable clinical significance. SH is morphologically characterized by steatosis, liver cell ballooning, cytoplasmic aggregates termed Mallory-Denk bodies (MDBs), inflammation, and fibrosis at late stage. Disturbance of the keratin cytoskeleton and aggregation of keratins (KRTs) are essential for MDB formation. METHODS: We analyzed livers of aged Krt18-/- mice that spontaneously developed in the majority of cases SH-associated HCC independent of sex. Interestingly, the hepatic lipid profile in Krt18-/- mice, which accumulate KRT8, closely resembles human SH lipid profiles and shows that the excess of KRT8 over KRT18 determines the likelihood to develop SH-associated HCC linked with enhanced lipogenesis. RESULTS: Our analysis of the genetic profile of Krt18-/- mice with 26 human hepatoma cell lines and with data sets of >300 patients with HCC, where Krt18-/- gene signatures matched human HCC. Interestingly, a high KRT8/18 ratio is associated with an aggressive HCC phenotype. CONCLUSIONS: We can prove that intermediate filaments and their binding partners are tightly linked to hepatic lipid metabolism and to hepatocarcinogenesis. We suggest KRT8/18 ratio as a novel HCC biomarker for HCC.

Amyloid fibril polymorphism: a challenge for molecular imaging and therapy.

The accumulation of misfolded proteins (MPs), both unique and common, for different diseases is central for many chronic degenerative diseases. In certain patients, MP accumulation is systemic (e.g. TTR amyloid), and in others, this is localized to a specific cell type (e.g. Alzheimer's disease). In neurodegenerative diseases, NDs, it is noticeable that the accumulation of MP progressively spreads throughout the nervous system. Our main hypothesis of this article is that MPs are not only markers but also active carriers of pathogenicity. Here, we discuss studies from comprehensive molecular approaches aimed at understanding MP conformational variations (polymorphism) and their bearing on spreading of MPs, MP toxicity, as well as MP targeting in imaging and therapy. Neurodegenerative disease (ND) represents a major and growing societal challenge, with millions of people worldwide suffering from Alzheimer's or Parkinson's diseases alone. For all NDs, current treatment is palliative without addressing the primary cause and is not curative. Over recent years, particularly the shape-shifting properties of misfolded proteins and their spreading pathways have been intensively researched. The difficulty in addressing ND has prompted most major pharma companies to severely downsize their nervous system disorder research. Increased academic research is pivotal for filling this void and to translate basic research into tools for medical professionals. Recent discoveries of targeting drug design against MPs and improved model systems to study structure, pathology spreading and toxicity strongly encourage future studies along these lines to provide an opportunity for selective imaging, prognostic diagnosis and therapy.

Systemic Amyloidosis in an African Tiger Snake (Telescopus semiannulatus).

An adult male African tiger snake (Telescopus semiannulatus) was diagnosed with disseminated mycobacteriosis and a hepatic biliary cystadenocarcinoma. Histologically, the spleen was largely replaced by extracellular deposits of eosinophilic, fibrillar to hyaline material. Similar material was also present in the testicular interstitium and occasional blood vessel walls. This material was congophilic with strong green birefringence under polarized light and emitted fluorescence when bound to the luminescent-conjugated oligothiophene, h-FTAA, an amyloid binding probe. Ultrastructurally, deposits were composed of aggregates of haphazardly arranged, non-branching fibrils up to 8 nm in diameter and of indeterminate length. These findings all supported a diagnosis of amyloidosis, most likely amyloid A (AA) type based on concurrent inflammatory disease in this snake. However, immunohistochemistry for serum amyloid A was negative. There are only rare previous reports of amyloidosis in reptiles and many have been incompletely characterized. This case presents a thorough investigation into an occurrence of systemic amyloidosis in a snake, including a novel use of luminescent-conjugated oligothiophene binding in a reptile to confirm the diagnosis.

Organic bioelectronics in medicine.

A major challenge in the growing field of bioelectronic medicine is the development of tissue interface technologies promoting device integration with biological tissues. Materials based on organic bioelectronics show great promise due to a unique combination of electronic and ionic conductivity properties. In this review, we outline exciting developments in the field of organic bioelectronics and demonstrate the medical importance of these active, electronically controllable materials. Importantly, organic bioelectronics offer a means to control cell-surface attachment as required for many device-tissue applications. Experiments have shown that cells readily attach and proliferate on reduced but not oxidized organic bioelectronic materials. In another application, the active properties of organic bioelectronics were used to develop electronically triggered systems for drug release. After incorporating drugs by advanced loading strategies, small compound drugs were released upon electrochemical trigger, independent of charge. Another type of delivery device was used to achieve well-controlled, spatiotemporal delivery of cationic drugs. Via electrophoretic transport within a polymer, cations were delivered with single-cell precision. Finally, organic bioelectronic materials are commonly used as electrode coatings improving the electrical properties of recording and stimulation electrodes. Because such coatings drastically reduce the electrode impedance, smaller electrodes with improved signal-to-noise ratio can be fabricated. Thus, rapid technological advancement combined with the creation of tiny electronic devices reacting to changes in the tissue environment helps to promote the transition from standard pharmaceutical therapy to treatment based on 'electroceuticals'. Moreover, the widening repertoire of organic bioelectronics will expand the options for true biological interfaces, providing the basis for personalized bioelectronic medicine.