Hepatocellular carcinoma (HCC) is currently one of the most prevalent cancers worldwide. Associated risk factors include, but are not limited to, cirrhosis and underlying liver diseases, including ...chronic hepatitis B or C infections, excessive alcohol consumption, nonalcoholic fatty liver disease (NAFLD), and exposure to chemical carcinogens. It is crucial to detect this disease early on before it metastasizes to adjoining parts of the body, worsening the prognosis. Serum biomarkers have proven to be a more accurate diagnostic tool compared to imaging. Among various markers such as nucleic acids, circulating genetic material, proteins, enzymes, and other metabolites, alpha-fetoprotein (AFP) is a protein marker primarily used to diagnose HCC. However, current methods need a large sample and carry a high cost, among other challenges, which can be improved using biosensing technology. Early and accurate detection of AFP can prevent severe progression of the disease and ensure better management of HCC patients. This review sheds light on HCC development in the human body. Afterward, we outline various types of biosensors (optical, electrochemical, and mass-based), as well as the most relevant studies of biosensing modalities for non-invasive monitoring of AFP. The review also explains these sensing platforms, detection substrates, surface modification agents, and fluorescent probes used to develop such biosensors. Finally, the challenges and future trends in routine clinical analysis are discussed to motivate further developments.
Hepatocellular carcinoma is currently the most common malignancy of the liver. It typically occurs due to a series of oncogenic mutations that lead to aberrant cell replication. Most commonly, ...hepatocellular carcinoma (HCC) occurs as a result of pre-occurring liver diseases, such as hepatitis and cirrhosis. Given its aggressive nature and poor prognosis, the early screening and diagnosis of HCC are crucial. However, due to its plethora of underlying risk factors and pathophysiologies, patient presentation often varies in the early stages, with many patients presenting with few, if any, specific symptoms in the early stages. Conventionally, screening and diagnosis are performed through radiological examination, with diagnosis confirmed by biopsy. Imaging modalities tend to be limited by their requirement of large, expensive equipment; time-consuming operation; and a lack of accurate diagnosis, whereas a biopsy’s invasive nature makes it unappealing for repetitive use. Recently, biosensors have gained attention for their potential to detect numerous conditions rapidly, cheaply, accurately, and without complex equipment and training. Through their sensing platforms, they aim to detect various biomarkers, such as nucleic acids, proteins, and even whole cells extracted by a liquid biopsy. Numerous biosensors have been developed that may detect HCC in its early stages. We discuss the recent updates in biosensing technology, highlighting its competitive potential compared to conventional methodology and its prospects as a tool for screening and diagnosis.
Abstract only Background: A pertinent question is why only a subset of fetal/neonatal cardiomyocytes (CMs) spontaneously proliferate. Using single-cell RNAseq, we previously showed a specific ...population of CMs that is more responsive to cell cycle induction (Abouleisa et al., Circulation, 2022). This population is characterized by expression of the transmembrane scavenger receptor, CD36 (fatty acid (FA) internalization receptor). Here, we aim to investigate the mechanism by which CD36 modulates CMs decision to enter into the cell cycle in neonatal P1 CMs. Methods and Results: Our single-cell RNAseq from primary CMs isolated from P1 hearts demonstrated that CD36 is specifically expressed in the spontaneously proliferating CMs and the CMs that respond to the exogenous cell cycle stimulation. CMs isolated from P1 CD36 knockout mice (CD36 KO ) showed 50% less proliferation capacity compared to WT P1 CMs. Interestingly, CD36 KO mice are born with smaller hearts which contain fewer CMs compared with their WT littermates. Furthermore, compared with WT littermates, which completely regenerate the heart apex following apical resection at P1, CD36 KO showed minimal regenerative capacity. Surprisingly, CD36 KO CMs didn’t show significant disruption in FA oxidation or glycolysis; however, bulk RNAseq data from the P1 CD36 KO hearts showed significant downregulation in the expression of retinoic acid (RA)-dependent signaling genes (e.g., PPARδ and RXRa) and a significant increase in PPARα expression. Confirming a causal role of CD36 in CM proliferation, we found that Cd36 is crucial in regulating the entry and interactions of RA or retinoid precursors in CMs. The CD36 + FACS-sorted CMs express significantly higher levels of PPARδ, RXRa, and FABP5 and lower levels of PPARα, which are crucial in regulating the response to cell proliferation. Furthermore, small molecule activation of PPARδ doubled cell cycle entry in P1 CMs and completely restored proliferation in CD36 KO CMs. These data suggest that CD36 is essential to prime CMs proliferation during development by regulating RA/PPARδ/RXR transcriptional signaling. Conclusions: These findings suggest that the CD36-RA-PPARδ signaling axis modulates the CMs’ ability of P1 to spontaneously enter the cell cycle.
Abstract
Aims
Gene therapies to induce cardiomyocyte (CM) cell cycle re-entry have shown a potential to treat subacute ischaemic heart failure (IHF) but have not been tested in the more relevant ...setting of chronic IHF. Our group recently showed that polycistronic non-integrating lentivirus encoding Cdk1/CyclinB1 and Cdk4/CyclinD1 (TNNT2-4Fpolycistronic-NIL) is effective in inducing CM cell cycle re-entry and ameliorating subacute IHF models and preventing the subsequent IHF-induced congestions in the liver, kidneys, and lungs in rats and pigs. Here, we aim to test the long-term efficacy of TNNT2-4Fpolycistronic-NIL in a rat model of chronic IHF, a setting that differs pathophysiologically from subacute IHF and has greater clinical relevance.
Methods and results
Rats were subjected to a 2-h coronary occlusion followed by reperfusion; 4 weeks later, rats were injected intramyocardially with either TNNT2-4Fpolycistronic-NIL or LacZ-NIL. Four months post-viral injection, TNNT2-4Fpolycistronic-NIL–treated rats showed a significant reduction in scar size and a significant improvement in left ventricular (LV) systolic cardiac function but not in the LV dilatation associated with chronic IHF. A mitosis reporter system developed in our lab showed significant induction of CM mitotic activity in TNNT2-4Fpolycistronic-NIL–treated rats.
Conclusion
This study demonstrates, for the first time, that TNNT2-4Fpolycistronic-NIL gene therapy induces CM cell cycle re-entry in chronic IHF and improves LV function, and that this salubrious effect is sustained for at least 4 months. Given the high prevalence of chronic IHF, these results have significant clinical implications for developing a novel treatment for this deadly disease.
Mitochondrial transplantation therapy is an innovative strategy for the treatment of mitochondrial dysfunction. The approach has been reported to be useful in the treatment of cardiac ischemic ...reperfusion injuries in human clinical trials and has also been shown to be useful in animal studies as a method for treating mitochondrial dysfunction in various tissues, including the heart, liver, lungs, and brain. On the other hand, there is no methodology for using preserved mitochondria. Research into the pharmaceutical formulation of mitochondria to promote mitochondrial transplantation therapy as the next step in treating many patients is urgently needed. In this review, we overview previous studies on the therapeutic effects of mitochondrial transplantation. We also discuss studies related to immune responses that occur during mitochondrial transplantation and methods for preserving mitochondria, which are key to their stability as medicines. Finally, we describe research related to mitochondrial targeting drug delivery systems (DDS) and discuss future perspectives of mitochondrial transplantation.
Systemic chemotherapy has shown a significant survival benefit in patients with hepatocellular carcinoma (HCC). However, it is associated with various immune-related adverse events (irAEs). We report ...a case with grade 3 diarrhea and grade 2 colitis following systemic chemotherapy, successfully treated with prednisolone. An 89-year-old man was incidentally detected with a 140-mm hypervascular intrahepatic nodule on contrast-enhanced computed tomography (CECT). Washout of the contrast medium was also detected, and protein induced by vitamin K deficiency or antagonists-II (PIVKA-II) was elevated. Since the Albumin-Bilirubin (ALBI) grade was 2a without any distant metastasis, transarterial chemoembolization (TACE) was performed to treat the HCC, but several intrahepatic nodules were seen in both lobes. Therefore, the patient was treated with lenvatinib for 1 year and 4 months. A complete response according to modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria was achieved in 2 months; however, multiple hypervascular nodules were detected again. Since the ALBI grade was 1, a second round of chemotherapy with atezolizumab and bevacizumab was initiated. Although a complete response was achieved, the therapy was discontinued due to grade 3 diarrhea and grade 2 colitis after the sixth course. Based on the stool analysis and culture, CECT, and colonoscopy, the diagnosis was atezolizumab-associated colitis. Diarrhea was controlled following the oral administration of 0.5 mg/ kg/day of prednisolone, and atezolizumab-bevacizumab therapy was successfully reinitiated without recurrence of colitis. The management of irAEs is important for a significant survival benefit. Systemic chemotherapy with atezolizumab and bevacizumab can be resumed despite a grade 3 irAE due to atezolizumab. Keywords: hepatocellular carcinoma, immune checkpoint inhibitors, immune-related adverse events, ICI-mediated colitis, IL-17, PIVKA-II
To investigate the main factors that control the dissolved radiocesium concentration in river water in the area affected by the Fukushima Daiichi nuclear power plant accident, the correlations ...between the dissolved 137Cs concentrations at 66 sites normalized to the average 137Cs inventories for the watersheds with the land use, soil components, topography, and water quality factors were assessed. We found that the topographic wetness index is significantly and positively correlated with the normalized dissolved 137Cs concentration. Similar positive correlations have been found for European rivers because wetland areas with boggy organic soils that weakly retain 137Cs are mainly found on plains. However, for small Japanese river watersheds, the building area ratio in the watershed strongly affected the dissolved 137Cs concentration. One reason for this would be because the high concentrations of solutes, such as K+ and dissolved organic carbon, discharged in urban areas would inhibit 137Cs absorption to soil particles. A multiple regression equation was constructed to predict the normalized dissolved 137Cs concentration with the topography, land use, soil component, and water quality data as explanatory variables. The best model had the building land use as the primary predictor. When comparing two multiple regression models in which the explanatory variables were limited to (1) the land use and soil composition and (2) the water quality, the water quality model underestimated the high normalized dissolve 137Cs concentration in urban areas. This poor reproducibility indicates that the dissolved 137Cs concentration value in urban areas cannot be solely explained by the solid-liquid distribution of 137Cs owing to the influence of the water quality, but some specific 137Cs sources in urban areas would control the dissolved 137Cs concentration.
Display omitted
•Dissolved 137Cs concentration decreased by one order of magnitude between 2012 and 2017.•Normalized dissolved 137Cs concentration well correlated with the building area ratio.•Topographic wetness index generally predicted dissolved 137Cs concentration.•High dissolved 137Cs concentration in urban areas cannot be explained by water quality.
Static and dynamic mechanical properties of the movable floating gate are investigated for a newly proposed highspeed and nonvolatile nanoelectromechanical memory, which features a buckled floating ...gate incorporating the nanocrystalline silicon quantum dots integrated onto the gate of a MOSFET. By conducting a 3D finite element simulation, we analyze the structural parameter dependence of the switching force F s needed for the buckled floating gate to flip-flop between its bistable states and derive the relationship F s infin L -4 T Z 0 3 where L, T, and Z 0 represent the length, thickness, and equilibrium displacement of the buckled floating gate, respectively. We demonstrate that the switching frequency can be increased while maintaining the switching force when we downscale all the floating gate dimensions proportionally along with the scaling law. We also show that the switching voltage can be reduced down to less than 15 V while maintaining the ON/OFF operation range of the sense MOSFET by optimizing the cavity structure which sustains the inside buckled floating gate
To investigate the main factors that control the dissolved radiocesium concentration in river water in the area affected by the Fukushima Daiichi nuclear power plant accident, the correlations ...between the dissolved
Cs concentrations at 66 sites normalized to the average
Cs inventories for the watersheds with the land use, soil components, topography, and water quality factors were assessed. We found that the topographic wetness index is significantly and positively correlated with the normalized dissolved
Cs concentration. Similar positive correlations have been found for European rivers because wetland areas with boggy organic soils that weakly retain
Cs are mainly found on plains. However, for small Japanese river watersheds, the building area ratio in the watershed strongly affected the dissolved
Cs concentration. One reason for this would be because the high concentrations of solutes, such as K
and dissolved organic carbon, discharged in urban areas would inhibit
Cs absorption to soil particles. A multiple regression equation was constructed to predict the normalized dissolved
Cs concentration with the topography, land use, soil component, and water quality data as explanatory variables. The best model had the building land use as the primary predictor. When comparing two multiple regression models in which the explanatory variables were limited to (1) the land use and soil composition and (2) the water quality, the water quality model underestimated the high normalized dissolve
Cs concentration in urban areas. This poor reproducibility indicates that the dissolved
Cs concentration value in urban areas cannot be solely explained by the solid-liquid distribution of
Cs owing to the influence of the water quality, but some specific
Cs sources in urban areas would control the dissolved
Cs concentration.
PDF
