The Mechanisms and Physiological Consequences of Diurnal Hepatic Cell Size Fluctuations: A Brief Review.

Liver size in mammals fluctuates throughout the day and correlates with changes in hepatocyte size. However, the role of these daily changes in liver and hepatocyte size and the underlying molecular mechanisms remain largely unknown. In this review, we highlight the view that hepatocyte size, and thus, overall organ size, is subject to regulation by the circadian clock and feeding/fasting cycles. To that end, we provide an overview of the current literature dealing with this phenomenon and elaborate the role of feeding and nutrients in this process. We will discuss the role of hepatic protein content and synthesis, which are both subject to diurnal regulation, in daily hepatocyte and liver size fluctuations. Although there is evidence that changes in hepatocyte and liver size are associated with daily variations in macromolecule content, there is also evidence that these changes in size may be actively regulated by modifications of the cells' osmotic environment. Future research will need to examine the intriguing possibility that hepatocyte and liver size fluctuations may be required for normal liver function and to reveal the underlying molecular mechanisms behind this process.

Hepatocellular Carcinoma Differentiation: Research Progress in Mechanism and Treatment

Hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver. Although progress has been made in diagnosis and treatment, morbidity and mortality continue to rise. Chronic liver disease and liver cirrhosis are still the most important risk factors for liver cancer. Although there are many treatments, it can only be cured by orthotopic liver transplantation (OLT) or surgical resection. And the worse the degree of differentiation, the worse the prognosis of patients with liver cancer. Then it can be considered that restoring a better state of differentiation may improve the prognosis. The differentiation treatment of liver cancer is to reverse the dedifferentiation process of hepatocytes to liver cancer cells by means of drugs, improve the differentiation state of the tumor, and restore the normal liver characteristics, so as to improve the prognosis. Understanding the mechanism of dedifferentiation of liver cancer can provide ideas for drug design. Liver enrichment of transcription factors, imbalance of signal pathway and changes of tumor microenvironment can promote the occurrence and development of liver cancer, and restoring its normal level can inhibit the malignant behavior of tumor. At present, some drugs have been proved to be effective, but more clinical data are needed to support the effectiveness and reliability of drugs. The differentiation treatment of liver cancer is expected to become an important part of the treatment of liver cancer in the future.

The Immune Landscape of Hepatitis B Virus-Related Acute Liver Failure by Integration Analysis

Hepatitis B virus-related acute liver failure (HBV-ALF) is a common type of liver failure, associated with high short-term mortality and morbidity rates. However, the immune landscape of HBV-ALF and its correlation with cell death are currently unknown. Based on 3 Gene Expression Omnibus data sets, infiltrated immune cells were quantified by single-sample gene set enrichment analysis method. The expression levels of immune genes and the abundance of immune cells in liver failure were compared with those in normal liver. The enrichment scores of cell death gene sets from Kyoto Encyclopedia of Genes and Genomes (KEGG) were calculated by gene set variation analysis method, and a protein-protein interaction (PPI) network was constructed using Cytoscape. Besides 21 differentially expressed immune genes, we identified 11 types of differentially infiltrated immune cells in HBV-ALF compared with normal liver. Enriched pathways of these immune genes mainly consisted of chemokine receptors, chemokine binding, interleukin-10 signaling, and TNFs bind their physiological receptors by Reactome pathway analysis. In addition, the enrichment scores of apoptosis and necroptosis pathway instead of autophagy and ferroptosis were increased in liver failure compared with normal liver. PPI network and gene cluster analysis of immune genes and apoptosis and necroptosis genes suggested that hub genes were mainly related to immune response and apoptosis. In summary, our study offers a conceptual framework to understand the immune landscape of HBV-ALF, which might help to improve prognosis.

BTBD10 is a Prognostic Biomarker Correlated With Immune Infiltration in Hepatocellular Carcinoma

Background: BTBD10 serves as an activator of Akt family members through decreasing the protein phosphatase 2A-mediated dephosphorylation. The present study attempted to investigate the prognostic value of BTBD10 in hepatocellular carcinoma (HCC), specially, its relationship with tumor-infiltrating lymphocytes (TILs).Methods: BTBD10 expression was evaluated in HCC using The Cancer Genome Atlas (TCGA) and Xijing Hospital database, and verified in HCC cell lines. Cox analyses were performed to analyze independent prognostic risk factors for HCC. The optimal cut-off value of BTBD10 was calculated, by which all patients were divided into two groups to compare the overall survival (OS). The signaling pathways were predicted, by which BTBD10 may affect the progression of HCC. To investigate the impact of BTBD10 on HCC immunotherapy, correlations between BTBD10 and TILs, immune checkpoints, m6A methylation-related genes and ferroptosis-related genes were assessed. The distribution of half-maximal inhibitory concentration (IC50) of diverse targeted drugs was observed based on the differential expression of BTBD10.Results: BTBD10 expression was higher in HCC tissues and cell lines than that of normal liver tissues and cells. The patients with high expression of BTBD10 showed a worse OS, as compared to that of BTBD10 low-expressing group. Cox analyses indicated that BTBD10 was an independent prognostic risk factor for HCC. Several molecular pathways of immune responses were activated in HCC patients with high-expressing of BTBD10. Furthermore, BTBD10 expression was demonstrated to be positively correlated with tumor-infiltrating B cells, T cells, macrophages, neutrophils and dendritic cells. Meanwhile, the expression of BTBD10 was synchronized with that of several m6A methylation-related genes, ferroptosis-related genes and immune checkpoints. The IC50 scores of Sorafenib, Navitoclax, Veliparib, Luminespib, and Imatinib were found to be lower in BTBD10 high-expressing HCC group.Conclusion: BTBD10 negatively regulates tumor immunity in HCC and exhibits adverse effect on the prognosis of HCC, which could be a potential target for immunotherapy.

Distribution Characteristics and Species Diversity of Bacteria in Hepatocellular Carcinoma Tissues

This study was to explore the differences in the distribution and species diversity of bacteria between hepatocellular carcinoma (HCC) tissues and normal liver tissues. 28 HCC patients treated with surgery were selected as the research objects (HCC group), and 19 healthy volunteers with normal physical examinations were included in the control group (Normal group). The tumor specimens were obtained by intraoperative and biopsy puncture, and a 16S ribosomal ribonucleic acid (rRNA) library was constructed. Based on the sequencing data obtained by the IlluminaHi Seq sequencing platform, the differences of bacteria in the liver tissues of the HCC group and the Normal group were analyzed at the level of phyla, family, and genus. The Ace, Chao1, and Shannon of the two groups were compared. The results showed that IlluminaHi Seq sequencing obtained a total of 11,714,659 valid sequences, with an average of 131,625 sequences per sample. The proportions of Bacteroidetes, Firmicutes, and Proteobacteria in HCC group and Normal group were 48.75% versus 34.16%, 37.44% versus 18.02%, and 10.85% versus 39.26%, respectively. The Bacteroidaceae, Prevotellaceae, Lachnospiraceae, and Ruminococcaceae accounted for 22.49%, 20.62%, 16.54%, and 19.93% in Normal group; while those in the HCC tissues accounted for 26.83%, 14.22%, 11.14%, and 13.18%, respectively. The dominant bacteria at the genus level in HCC group and Normal group were Bacteroides and Prevotella-9, with the proportions of 24.19% versus 26.04% and 14.19% versus 8.44%, respectively. The difference in operational taxonomic unit (OTU) numbers of HCC and Normal group were compared and analyzed, which were 1,266 and 1,082, respectively, and the number of common OTU in the two tissues was 875. The Ace in HCC tissue and normal liver tissue were 1063.8±66.79 and 1003.6±52.19, respectively. The Ace in HCC tissue was greater than that in normal liver tissue (P < 0.05). The Chao1 and Shannon in HCC tissue were 1022.9±67.74 and 5.4269±0.3608, respectively; while those in normal liver tissue were 1003.6±66.79 and 5.2842±0.9714, respectively. The Chao1 and Shannon in HCC tissues were much higher than those in Normal group (P < 0.05). It showed that there was no difference in the types of bacterial species in HCC tissues, but the proportions of their flora at the level of phyla, family, and genus changed greatly, which may be related to the occurrence of HCC. This study could provide a reference for the diagnosis and treatment of HCC.

A Case of Carbamazepine-Induced Aggravation of Self-Limited Epilepsy with Centrotemporal Spikes Epilepsy and Valproate-Induced Hyperammonemic Encephalopathy in a Child with Heterozygous Gene Variant of Carbomoyl Phosphatase Synthetase Deficiency

Antiepileptics drugs are the mainstay of the management of epilepsy in children. Sodium valproate (VPA) and carbamazepine (CBZ) are widely used medications in childhood epilepsy. Hyperammonemia has been described as a known side effect of valproate therapy. It is known that VPA-associated HA is common among patients who hold genetic mutations of the carbomoyl phosphatase synthase 1 gene (CPS1). Aggravation of self-limited epilepsy with centrotemporal spikes (SLECTS) is a rare side effect of CBZ. Here, we present a child who had CBZ-induced aggravation of rolandic epilepsy and VPA-induced HA encephalopathy in the background of an unrecognised heterozygous gene variant of CPS1. An 8-year-old boy with SLECTS presented with a history of abnormal behaviours and drowsiness. He was apparently well until six years when he developed seizures in favour of rolandic epilepsy. His electroencephalogram (EEG) showed bilateral predominantly on the right-sided central-temporal spikes and waves. The diagnosis of SLECTS was made, and he was commenced on CBZ. Though he showed some improvement at the beginning, his seizure frequency increased when the dose of CBZ was increased. His repeat EEG showed electrical status in slow-wave sleep, and CBZ was stopped. Subsequently, he was started on VPA, and with that, he developed features of encephalopathy. He had elevated serum ammonia with normal liver functions. VPA was stopped with the suspicion of VPA-induced hyperammonemia. Tandem mass spectrometry did not show significant abnormality in the amino acid profile. Specific genetic analysis revealed a c.2756 C > T.p (Ser919Leu) heterozygote genetic mutation of the CSP 1 gene. This is a classic example where side effects of treatment determine the choice of antiepileptics drugs (AEDs) in childhood epilepsy. It is essential to keep in mind that SLECTS can be aggravated with certain AEDs, and VPA-induced HA in the absence of live failure could be due to underlying inherited metabolic disorders.

Timeliness of splenic time-to-peak affects liver tumor CT perfusion measurements

Aim In liver CT perfusion, the dual-input maximum slope (DI-MS) method is commonly used to estimate perfusion to aid diagnosis of tumors. The DI-MS method relies on a model that assumes the splenic time-to-peak (TTP) separates arterial and portal venous perfusion, and occurs prior to venous perfusion. In this preclinical study, we examined how the timeliness of splenic TTP affects DI-MS perfusion calculations of liver tumors. Materials and Methods We analyzed imaging data obtained from 11 New Zealand White rabbits bearing a single implanted VX2 tumor in liver. A liver 320-slice CT perfusion protocol (5,400 images per study) was used to generate images. Times for arterial and portal slopes were recorded, and hepatic arterial perfusion (HAP), portal perfusion (HPP) and perfusion index (HPI) for liver and tumor were separately calculated using manual and automated methods. T-test comparisons and Bland-Altman plot analyses were performed. Results Mean tumor TTP occurred at 9.79 s (SD=3.41) and splenic TTP at 9.75 s (SD=4.47, p=0.98). In 3/11 (27.27%) cases, tumor SP occurred prior to spleen (mean difference=1.33 s, SD=1.15 s). In these cases, mean automated HPP values were 43.8% (SD=52.48) higher compared to manually computed ones. There were statistically significant differences between automated and manual methods for normal liver and tumor HPI and HPP (p<0.01 and p<0.0001, respectively), but not HAP values (p=0.125 and p=0.78, respectively). There was also a statistically significant variation between methods for tumor HPP and HPI (p=0.001, respectively). Conclusion In 320-slice CT perfusion of liver in this preclinical model, we observed that tumor TTP occurred prior to splenic TTP in 27.27% of tumors in liver. This temporal relationship affects tumor perfusion calculations and should be identified to address potential deviations of model assumptions.

Self-assembled tocopherol-albumin nanoparticles with full biocompatibility for chemo-photothermal therapy against breast cancer

Background:: The combination of photothermal therapy (PTT) and chemotherapy has proven to be a promising strategy for cancer treatment. Various nanomaterials have shown great potential in combination therapy, including gold, graphene oxide, iron oxide, and other nanoparticles. However, their undefinable toxicity in vivo greatly slowed down their development for clinical applications. Objective: The present work aimed to develop a multifunctional nanoparticle for chemo-photothermal therapy composed of acknowledged biocompatible materials. Methods: A novel biocompatible nanoparticle (HIT-NPs) was self-assembled through the intrinsic interaction between D-α-tocopherol Succinate (TOS), human serum albumin (HSA) and indocyanine green (ICG). Doxorubicin (DOX) was then loaded due to the ion pairing between DOX and TOS. The feasibility of combined chemo-photothermal therapy induced by DOX-loaded HIT-NPs was carefully evaluated. Results: In vitro, HIT-NPs showed no cytotoxicity on human normal liver cells (HL-7702 cells) but obvious killing effects murine breast cancer cells (4T1 cells). The combined chemo-photothermal therapeutic effect on 4T1 cells was successfully obtained. DOX-loaded HIT-NPs could effectively accumulate in 4T1 subcutaneous tumors after intravenous injection, and the tumor temperature rapidly increased under laser exposure, indicating the feasibility of PTT in vivo. Conclusion: The self-assembled HIT-NPs could provide a promising platform for combined chemo-photothermal cancer therapy with full biocompatibility.

Normal liver-to-heart transit time and shunt fraction after transplenic injection of 99MTC-pertechnetate in healthy cats

Portosystemic shunts (PSS) are rare vascular anomalies in cats. Transsplenic portal scintigraphy (TSPS) can aid in diagnosing PSS in cats. Although the actual performance of the scan remains the same between species, it is questionable whether the generally accepted transit time of seven seconds for small dogs can be applied to cats, thereby influencing shunt fraction (SF) calculation. In this study, normal mean transit time and SF were determined in a population of cats without PSS following two methods established in canine medicine. For both, the mean ± SD transit time was calculated as 6.75 ± 1.58 seconds and 7.40 ± 1.64 seconds respectively, without significant difference between both methods. The results confirmed the validity of the generally used transit time of seven seconds for SF calculation in cats. The average normal SF (± SD) for the cats in this study was 0.73 % (±0.74; range 0.11-2.48%).

Formimidoyltransferase cyclodeaminase prevents the starvation-induced liver hepatomegaly and dysfunction through downregulating mTORC1

The liver is a crucial center in the regulation of energy homeostasis under starvation. Although downregulation of mammalian target of rapamycin complex 1 (mTORC1) has been reported to play pivotal roles in the starvation responses, the underpinning mechanisms in particular upstream factors that downregulate mTORC1 remain largely unknown. To identify genetic variants that cause liver energy disorders during starvation, we conduct a zebrafish forward genetic screen. We identify a liver hulk (lvh) mutant with normal liver under feeding, but exhibiting liver hypertrophy under fasting. The hepatomegaly in lvh is caused by enlarged hepatocyte size and leads to liver dysfunction as well as limited tolerance to starvation. Positional cloning reveals that lvh phenotypes are caused by mutation in the ftcd gene, which encodes the formimidoyltransferase cyclodeaminase (FTCD). Further studies show that in response to starvation, the phosphorylated ribosomal S6 protein (p-RS6), a downstream effector of mTORC1, becomes downregulated in the wild-type liver, but remains at high level in lvh. Inhibition of mTORC1 by rapamycin rescues the hepatomegaly and liver dysfunction of lvh. Thus, we characterize the roles of FTCD in starvation response, which acts as an important upstream factor to downregulate mTORC1, thus preventing liver hypertrophy and dysfunction.