Rigidity Matching between Cells and the Extracellular Matrix Leads to the Stabilization of Cardiac Conduction

Biomechanical dynamic interactions between cells and the extracellular environment dynamically regulate physiological tissue behavior in living organisms, such as that seen in tissue maintenance and remodeling. In this study, the substrate-induced modulation of synchronized beating in cultured cardiomyocyte tissue was systematically characterized on elasticity-tunable substrates to elucidate the effect of biomechanical coupling. We found that myocardial conduction is significantly promoted when the rigidity of the cell culture environment matches that of the cardiac cells (4 kiloPascals). The stability of spontaneous target wave activity and calcium transient alternans in high frequency-paced tissue were both enhanced when the cell substrate and cell tissue showed the same rigidity. By adapting a simple theoretical model, we reproduced the experimental trend on the rigidity matching for the synchronized excitation. We conclude that rigidity matching in cell-to-substrate interactions critically improves cardiomyocyte-tissue synchronization, suggesting that mechanical coupling plays an essential role in the dynamic activity of the beating heart

Electrochemical response of biased nanoelectrodes in solution

Novel approaches to DNA sequencing and detection require the measurement of electrical currents between metal probes immersed in ionic solution. Here, we experimentally demonstrate that these systems maintain large background currents with a transient response that decays very slowly in time and noise that increases with ionic concentration. Using a non-equilibrium stochastic model, we obtain an analytical expression for the ionic current that shows these results are due to a fast electrochemical reaction at the electrode surface followed by the slow formation of a diffusion layer. During the latter, ions translocate in the weak electric field generated after the initial rapid screening of the strong fields near the electrode surfaces. Our theoretical results are in very good agreement with experimental findings

Activators and Inhibitors of Protein Kinase C (PKC): Their Applications in Clinical Trials

Protein kinase C (PKC), a family of phospholipid-dependent serine/threonine kinase, is classed into three subfamilies based on their structural and activation characteristics: conventional or classic PKC isozymes (cPKCs; α, βI, βII, and γ), novel or non-classic PKC isozymes (nPKCs; δ, ε, η, and θ), and atypical PKC isozymes (aPKCs; ζ, ι, and λ). PKC inhibitors and activators are used to understand PKC-mediated intracellular signaling pathways and for the diagnosis and treatment of various PKC-associated diseases, such as cancers, neurological diseases, cardiovascular diseases, and infections. Many clinical trials of PKC inhibitors in cancers showed no significant clinical benefits, meaning that there is a limitation to design a cancer therapeutic strategy targeting PKC alone. This review will focus on the activators and inhibitors of PKC and their applications in clinical trials

Protein Kinase C (PKC) Isozymes as Diagnostic and Prognostic Biomarkers and Therapeutic Targets for Cancer

Protein kinase C (PKC) is a large family of calcium- and phospholipid-dependent serine/threonine kinases that consists of at least 11 isozymes. Based on their structural characteristics and mode of activation, the PKC family is classified into three subfamilies: conventional or classic (cPKCs; α, βI, βII, and γ), novel or non-classic (nPKCs; δ, ε, η, and θ), and atypical (aPKCs; ζ, ι, and λ) (PKCλ is the mouse homolog of PKCι) PKC isozymes. PKC isozymes play important roles in proliferation, differentiation, survival, migration, invasion, apoptosis, and anticancer drug resistance in cancer cells. Several studies have shown a positive relationship between PKC isozymes and poor disease-free survival, poor survival following anticancer drug treatment, and increased recurrence. Furthermore, a higher level of PKC activation has been reported in cancer tissues compared to that in normal tissues. These data suggest that PKC isozymes represent potential diagnostic and prognostic biomarkers and therapeutic targets for cancer. This review summarizes the current knowledge and discusses the potential of PKC isozymes as biomarkers in the diagnosis, prognosis, and treatment of cancers

Hyaluronic acid and its derivative as a multi-functional gene expression enhancer: Protection from non-specific interactions, adhesion to targeted cells, and transcriptional activation

Hyaluronic acid (HA), a natural anionic mucopolysaccharide, can be deposited onto the cationic surface of DNA/polyethyleneimine (PEI) complexes to recharge the surface potential and reduce nonspecific interactions with proteins. HA can also be used as a ligand to target specific cell receptors. Furthermore, HA-coating enhanced the transcriptional activity of the plasmid/PEI complexes, probably by loosening the tight binding between DNA and PEI, which facilitated the approach of transcription factors. Amphoteric HA derivative having spermine side chains (Spn-HA) with a structure similar to HMG protein showed higher transcription-enhancing activity than HA. Plasmid/PEI/Spn-HA ternary complex exhibited 29-fold higher transgene expression efficiency than naked plasmid/PEI complexes in CHO cells

Efficacy and safety of scheduled early endoscopic ultrasonography‐guided ethanol reinjection for patients with pancreatic neuroendocrine tumors: Prospective pilot study

Endoscopic ultrasonography (EUS)‐guided ethanol injection was recently proposed for treatment of patients with small pancreatic neuroendocrine tumors (p‐NET); however, tips on how to carry out safe and effective procedures are unclear. We launched a pilot study for scheduled early EUS‐guided ethanol reinjection for small p‐NET. Major eligibility criteria were presence of pathologically diagnosed grade (G) 1 or G2, tumor size ≤2 cm and being a poor or rejected candidate for surgery. For the treatment, we used a 25‐gauge needle and pure ethanol. Contrast‐enhanced computed tomography (CE‐CT) was carried out on postoperative day 3, and if enhanced areas of the tumor were still apparent, an additional session was scheduled during the same hospitalization period. Primary endpoint was complete ablation rate at 1 month after treatment, and secondary endpoint was procedure‐related adverse events. A total of five patients were treated. Median size of the tumor was 10 (range: 7–14) mm. Of the five patients, three underwent an additional session. Median volume of ethanol injection per session was 0.8 (range: 0.3–1.0) mL, and the total was 1.0 (0.9–1.8) mL. Complete ablation was achieved in four of the five tumors (80%) with no adverse events. During 1 year of follow up, none of the patients reported any procedure‐related adverse events, and no recurrence of tumor. Scheduled early EUS‐guided ethanol reinjection appears to be safe and effective for treating small p‐NET (UMIN number: 000018834)