Therapeutic potential of SOX9 dysruption in Combined Hepatocellular Carcinoma-Cholangiocarcinoma.

Combined hepatocellular carcinoma-cholangiocarcinoma (cHCC-CCA) represents a challenging subtype of primary liver cancer with limited treatment options and a poor prognosis. Recently, we and others have highlighted the context-dependent roles of the biliary-specific transcription factor SOX9 in the pathogenesis of liver cancers using various Cre applications in Sox9 (flox/flox) strains, to achieve elimination for exon 2 and 3 of the Sox9 gene locus as a preventive manner. Here, we reveal the contrasting responses of developmental Sox9 elimination using Alb-Cre;Sox9 (flox/flox) ( Sox9 LKO) versus CRISPR/Cas9 -based tumor specific acute Sox9 CKO in SB-HDTVI-based Akt-YAP1 and Akt-NRAS cHCC-CCA formation. Sox9 LKO specifically abrogates the Akt-YAP1 CCA region while robustly stimulating the proliferation of remaining poorly differentiated HCC pertaining liver progenitor cell characteristics, whereas Sox9 CKO potently prevents Akt-YAP1 and Akt-NRAS cHCC-CCA development irrespective of fate of tumor cells compared to respective controls. Additionally, we find that Akt-NRAS , but not Akt-YAP1 , tumor formation is partially dependent on the Sox9-Dnmt1 cascade. Pathologically, SOX9 is indispensable for Akt-YAP1 -mediated HC-to-BEC/CCA reprogramming but required for the maintenance of CCA nodules. Lastly, therapeutic elimination of Sox9 using the OPN-CreERT2 strain combined with an inducible CRISPR/Cas9 -based Sox9 iKO significantly reduces Akt-YAP1 cHCC-CCA tumor burden, similar to Sox9 CKO. Thus, we contrast the outcomes of acute Sox9 deletion with developmental Sox9 knockout models, emphasizing the importance of considering adaptation mechanisms in therapeutic strategies. This necessitates the careful consideration of genetic liver cancer studies using developmental Cre and somatic mutant lines, particularly for genes involved in hepatic commitment during development. Our findings suggest that SOX9 elimination may hold promise as a therapeutic approach for cHCC-CCA and underscore the need for further investigation to translate these preclinical insights into clinical applications.

Primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD): a condition exemplifying the crosstalk of the gut-liver axis.

The close relationship between primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) provides a good opportunity to comprehend the gut-liver axis. The gut and the liver have reciprocal interactions, including how gut inflammation influences the liver through immune cells and the microbiota and how the microbiota in the gut modifies bile acids, which are produced and secreted from the liver. PSC-IBD shows distinct clinical findings from classical IBD. In addition, a distinct genetic predisposition and unique microbiota composition suggest that PSC-IBD is an independent disease entity. Understanding the pathogenesis of PSC-IBD helps to develop novel and effective therapeutic agents. Given the high risk of malignancies associated with PSC-IBD, it is critical to identify patients at high risk and implement appropriate surveillance and monitoring strategies. In this review, we provide an overview of PSC-IBD, which exemplifies the gut-liver axis.

Treatment of primary sclerosing cholangitis combined with inflammatory bowel disease.

Primary sclerosing cholangitis (PSC) is a progressive cholestatic, inflammatory, and fibrotic disease that is strongly associated with inflammatory bowel disease (IBD). PSC-IBD represents a unique disease entity and patients with this disease have an increased risk of malignancy development, such as colorectal cancer and cholangiocarcinoma. The pathogenesis of PSC-IBD involves genetic and environmental factors such as gut dysbiosis and bile acids alteration. However, despite the advancement of disease characteristics, no effective medical therapy has proven to have a significant impact on the prognosis of PSC. The treatment options for patients with PSC-IBD do not differ from those for patients with PSC alone. Potential candidate drugs have been developed based on the pathogenesis of PSC-IBD, such as those that target modulation of bile acids, inflammation, fibrosis, and gut dysbiosis. In this review, we summarize the current medical treatments for PSC-IBD and the status of new emerging therapeutic agents.

Frequency-selective acoustic and haptic smart skin for dual-mode dynamic/static human-machine interface.

Accurate transmission of biosignals without interference of surrounding noises is a key factor for the realization of human-machine interfaces (HMIs). We propose frequency-selective acoustic and haptic sensors for dual-mode HMIs based on triboelectric sensors with hierarchical macrodome/micropore/nanoparticle structure of ferroelectric composites. Our sensor shows a high sensitivity and linearity under a wide range of dynamic pressures and resonance frequency, which enables high acoustic frequency selectivity in a wide frequency range (145 to 9000 Hz), thus rendering noise-independent voice recognition possible. Our frequency-selective multichannel acoustic sensor array combined with an artificial neural network demonstrates over 95% accurate voice recognition for different frequency noises ranging from 100 to 8000 Hz. We demonstrate that our dual-mode sensor with linear response and frequency selectivity over a wide range of dynamic pressures facilitates the differentiation of surface texture and control of an avatar robot using both acoustic and mechanical inputs without interference from surrounding noise.

Ferroelectric Multilayer Nanocomposites with Polarization and Stress Concentration Structures for Enhanced Triboelectric Performances.

Although ferroelectric composites have been reported to enhance the performance of triboelectric (TE) devices, their performances are still limited owing to randomly dispersed particles. Herein, we introduce high-performance TE sensors (TESs) based on ferroelectric multilayer nanocomposites with alternating poly(vinylidenefluoride-co-trifluoroethylene) (PVDF-TrFE) and BaTiO3 (BTO) nanoparticle (NP) layers. The multilayers comprising alternating soft/hard layers can induce stress concentration and increase the effective stress-induced polarization and interfacial polarization between organic and inorganic materials, leading to a dielectric constant (17.06) that is higher than those of pure PVDF-TrFE films (13.9) and single PVDF-TrFE/BTO nanocomposites (15.9) at 10 kHz. As a result, the multilayered TESs with alternating BTO NP layers exhibit TE currents increased by 2.3 and 1.5 times compared to pure PVDF-TrFE without BTO NPs and PVDF-TrFE/BTO nanocomposites without multilayer structures, respectively. The multilayered TESs exhibit a high pressure sensitivity of 0.94 V/kPa (48.7 nA/kPa) and output power density of 29.4 µWcm-2, enabling their application in the fabrication of highly sensitive healthcare monitoring devices and high-performance acoustic sensors. The suggested architecture of ferroelectric multilayer nanocomposites provides a robust platform for TE devices and self-powered wearable electronics.