Cost-Effectiveness Analysis of Hepatic Arterial Chemotherapy for Advanced Hepatocellular Carcinoma in China: A Comparative Analysis of HAIC-FO and Sorafenib.

BACKGROUND The FOHAIC-1 trial showed hepatic arterial infusion chemotherapy with infusional fluorouracil, leucovorin, and oxaliplatin (HAIC-FO) improved survival, compared with sorafenib, in patients with advanced hepatocellular carcinoma (HCC). The aim of this study was to conduct a cost-effectiveness comparison between HAIC-FO and sorafenib from the perspective of the Chinese healthcare system. MATERIAL AND METHODS The economic evaluation was conducted between July 2023 and February 2024, spanning a 10-year investment horizon. A Markov model was developed to perform a cost-effectiveness analysis of HAIC-FO vs sorafenib. Health states incorporated in the model comprised progression-free disease, progressed disease, and death. Transition probabilities were derived from data obtained from the FOHAIC-1 trial. Incremental cost-effectiveness ratio (ICER) was calculated to evaluate cost-effectiveness. Additionally, one-way and probabilistic sensitivity analyses assessed the model's robustness. RESULTS The HAIC-FO group accrued a total cost of $22,781, whereas the sorafenib group totaled $18,795. In terms of effectiveness, the HAIC-FO group achieved 1.06 quality-adjusted life years (QALYs), whereas the sorafenib group attained 0.65 QALYs. Compared with sorafenib, HAIC-FO yielded an additional 0.41 QALYs at a cost of additional $3,985, resulting in an incremental cost of $9,720 per QALY gained. The one-way sensitivity analysis revealed the final ICER remained below the willingness-to-pay (WTP) threshold of $30,492 per QALY, when considering parameter fluctuations. Additionally, probabilistic sensitivity analysis indicated a 99.8% probability that the ICER for HAIC-FO compared with sorafenib would fall below the WTP threshold. CONCLUSIONS Compared with sorafenib, HAIC-FO emerged as a cost-effective first-line treatment option for patients facing advanced HCC in China.

Small conductance calcium-activated potassium channel contributes to stress induced endothelial dysfunctions.

Patients with Takotsubo syndrome displayed endothelial dysfunction, but underlying mechanisms have not been fully clarified. This study aimed to explore molecular signalling responsible for catecholamine excess induced endothelial dysfunction. Human cardiac microvascular endothelial cells were challenged by epinephrine to mimic catecholamine excess. Patch clamp, FACS, ELISA, PCR, and immunostaining were employed for the study. Epinephrine (Epi) enhanced small conductance calcium-activated potassium channel current (ISK1-3) through activating α1 adrenoceptor. Phenylephrine enhanced edothelin-1 (ET-1) and reactive oxygen species (ROS) production, and the effects involved contribution of ISK1-3. H2O2 enhanced ISK1-3 and ET-1 production. Enhancing ISK1-3 caused a hyperpolarization, which increases ROS and ET-1 production. BAPTA partially reduced phenylephrine-induced enhancement of ET-1 and ROS, suggesting that α1 receptor activation can enhance ROS/ET-1 generation in both calcium-dependent and calcium-independent ways. The study demonstrates that high concentration catecholamine can activate SK1-3 channels through α1 receptor-ROS signalling and increase ET-1 production, facilitating vasoconstriction.

Novel insights in the pathomechanism of Brugada syndrome and fever-related type 1 ECG changes in a preclinical study using human-induced pluripotent stem cell-derived cardiomyocytes.

BACKGROUND: Brugada syndrome (BrS) is causing sudden cardiac death (SCD) mainly at young age. Studying the underlying mechanisms associated with BrS type I electrocardiogram (ECG) changes in the presence of fever and roles of autophagy for BrS remains lacking. OBJECTIVES: We sought to study the pathogenic role of an SCN5A gene variant for BrS with fever-induced type 1 ECG phenotype. In addition, we studied the role of inflammation and autophagy in the pathomechanism of BrS. METHODS: Human-induced pluripotent stem cell (hiPSC) lines from a BrS patient harboring a pathogenic variant (c.3148G>A/p. Ala1050Thr) in SCN5A and two healthy donors (non-BrS) and a CRISPR/Cas9 site-corrected cell line (BrS-corr) were differentiated into cardiomyocytes (hiPSC-CMs) for the study. RESULTS: Reductions of Nav 1.5 expression, peak sodium channel current (INa ) and upstroke velocity (Vmax ) of action potentials with an increase in arrhythmic events were detected in BrS compared to non-BrS and BrS-corr cells. Increasing the cell culture temperature from 37 to 40°C (fever-like state) exacerbated the phenotypic changes in BrS cells. The fever-effects were enhanced by protein kinase A (PKA) inhibitor but reversed by PKA activator. Lipopolysaccharides (LPS) but not increased temperature up to 40°C enhanced the autophagy level in BrS-hiPSC-CMs by increasing reactive oxidative species and inhibiting PI3K/AKT signalling, and hence exacerbated the phenotypic changes. LPS enhanced high temperature-related effect on peak INa shown in BrS hiPSC-CMs. Effects of LPS and high temperature were not detected in non-BrS cells. CONCLUSIONS: The study demonstrated that the SCN5A variant (c.3148G>A/p.Ala1050Thr) caused loss-of-function of sodium channels and increased the channel sensitivity to high temperature and LPS challenge in hiPSC-CMs from a BrS cell line with this variant but not in two non-BrS hiPSC-CM lines. The results suggest that LPS may exacerbate BrS phenotype via enhancing autophagy, whereas fever may exacerbate BrS phenotype via inhibiting PKA-signalling in BrS cardiomyocytes with but probably not limited to this variant.

Antiarrhythmic Effects of Vernakalant in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes from a Patient with Short QT Syndrome Type 1.

(1) Background: Short QT syndrome (SQTS) may result in sudden cardiac death. So far, no drugs, except quinidine, have been demonstrated to be effective in some patients with SQTS type 1 (SQTS1). This study was designed to examine the potential effectiveness of vernakalant for treating SQTS1 patients, using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from a patient with SQTS1. (2) Methods: Patch clamp and calcium imaging techniques were used to examine the drug effects. (3) Results: Vernakalant prolonged the action potential duration (APD) in hiPSC-CMs from a SQTS1-patient (SQTS1-hiPSC-CMs). In spontaneously beating SQTS1-hiPSC-CMs, vernakalant reduced the arrhythmia-like events induced by carbachol plus epinephrine. Vernakalant failed to suppress the hERG channel currents but reduced the outward small-conductance calcium-activated potassium channel current. In addition, it enhanced Na/Ca exchanger currents and late sodium currents, in agreement with its APD-prolonging effect. (4) Conclusions: The results demonstrated that vernakalant can prolong APD and reduce arrhythmia-like events in SQTS1-hiPSC-CMs and may be a candidate drug for treating arrhythmias in SQTS1-patients.

Gold Nanoparticles for Targeting the Fibrotic Heart: A Probe Indicating Vascular Permeability.

Excessive ß-adrenergic stimulation induces cardiac fibrosis and inflammation and eventually leads to heart failure. It remains unclear whether the inflammatory factor and infiltration of macrophages are initiated from cardiac cells or the vascular system. We used 13-nm polyethylene glycol (PEG)-coated gold nanoparticles (GNPs) as size probes because they cannot penetrate normal vascular walls, and we found that over-stimulation of ß-adrenoceptors mediates cardiac inflammation and fibrosis by increasing vascular permeability. Stimulation with isoproterenol (ISO, a ß-adrenoceptor agonist) induced tissue-specific inflammatory infiltration and fibrosis in the hearts of mice. Consistent with these findings, 13-nm PEG-coated GNP as size probes were also observed to have tissue-specific targeting of the fibrotic heart, indicating over-stimulation of ß-adrenoceptors, increased vascular permeability in the heart, and initiated cardiac inflammation and fibrosis.

Bacteria and poisonous plants were the primary causative hazards of foodborne disease outbreak: a seven-year survey from Guangxi, South China.

BACKGROUND: Foodborne diseases are a worldwide public health problem. However, data regarding epidemiological characteristics are still lacking in China. We aimed to analyze the characteristics of foodborne diseases outbreak from 2010 to 2016 in Guangxi, South China. METHODS: A foodborne disease outbreak is the occurrence of two or more cases of a similar foodborne disease resulting from the ingestion of a common food. All data are obtained from reports in the Public Health Emergency Report and Management Information System of the China Information System for Disease Control and Prevention, and also from special investigation reports from Guangxi province. RESULTS: A total of 138 foodborne diseases outbreak occurred in Guangxi in the past 7 years, leading to 3348 cases and 46 deaths. Foodborne disease outbreaks mainly occurred in the second and fourth quarters, and schools and private homes were the most common sites. Ingesting toxic food by mistake, improper cooking and cross contamination were the main routes of poisoning which caused 2169 (64.78%) cases and 37 (80.43%) deaths. Bacteria (62 outbreaks, 44.93%) and poisonous plants (46 outbreaks, 33.33%) were the main etiologies of foodborne diseases in our study. In particular, poisonous plants were the main cause of deaths involved in the foodborne disease outbreaks (26 outbreaks, 56.52%). CONCLUSIONS: Bacteria and poisonous plants were the primary causative hazard of foodborne diseases. Some specific measures are needed for ongoing prevention and control against the occurrence of foodborne diseases.

Blockage of endoplasmic reticulum stress attenuates nilotinib-induced cardiotoxicity by inhibition of the Akt-GSK3ß-Nox4 signaling.

Cardiotoxicity is a critical side-effect of nilotinib during treatment for cancer, such as chronic myeloid leukemia, while the potential signaling mechanisms remain unclear. The role of and the relationship between endoplasmic reticulum (ER) stress and mitochondrial dysfunction was investigated in nilotinib-induced cardiac H9C2 injury as a suitable cell model. Our results showed that ER stress was persistently induced in nilotinib-treated cells, evidenced by increase of GRP78, CHOP, ATF4 and XBP1 as well as phospho-PERKThr980. The results from 4-phenylbutyrate (PBA, an ER stress inhibitor) and SC79 (a specific Akt activator) suggested that ER stress increased activity of glycogen synthase kinase-3 beta (GSK3ß) that is reflected by decrease of phospho-GSK3ßSer9, through downregulation of phospho-AktSer473, and that prolonged ER stress and activated GSK3ß involved nilotinib-induced apoptosis. In addition, the data from JNK inhibition using SP600125 showed that over-activated JNK was responsible for Akt de-phosphorylation. Moreover, the abundance of NADPH oxidase (Nox4) was significantly increased following nilotinib treatment, which was prevented by SB216763 (a specific GSK3ß inhibitor). Additionally, mitochondrial dysfunction was indicated by reduced mitochondrial membrane potential (MMP) level and increased reactive oxygen species level. In nilotinib-treated cells, knockdown of Nox4 preserved MMP level, abrogated reactive oxygen species production, and decreased apoptosis. Accordingly, our data demonstrated that inhibition of ER stress may protect cardiomyocytes against nilotinib toxicity potentially through inactivation of Akt-GSK3ß-Nox4 signaling. These findings may provide an attractive therapeutic target for treatment of nilotinib-related cardiotoxicity.

Caspase-Independent Pathway is Related to Nilotinib Cytotoxicity in Cultured Cardiomyocytes.

BACKGROUND/AIMS: Cardiotoxicity is a predominant side-effect of nilotinib during chronic myeloid leukemia treatment. The underlying molecular mechanism remains unclear. The role of autophagy and mitochondrial signaling was investigated in nilotinib-treated cardiac H9C2 cells. METHODS: Cytotoxicity was assessed using Cell Death Detection kit. Immunoblot and immunofluorescence staining was performed, and cathepsin B and caspase3 activity was assessed in nilotinib-treated H9C2 cells with or without distinct pathway inhibitor or specific siRNA. RESULTS: Nilotinib time- and dose-dependently induced H9C2 apoptosis, which was not completely prevented by the pan caspase inhibitor z-VAD-fmk. Following nilotinib treatment, mitochondrial membrane potential decreased significantly accompanied with remarkable morphological changes. Nuclear translocation of mitochondrial apoptosis inducing factor (AIF) and increased p53 was detected in nilotinib-treated cells. AIF knockdown prevented nilotinib-induced increase of p53 and apoptosis. Additionally, increased cathepsin B activity was detected, and inhibition of cathepsin B by CA-074Me prevented nilotinib-induced apoptosis and nuclear translocation of AIF. Moreover, increased Atg5 and transition of LC3-I to LC3-II was revealed following nilotinib treatment. Increased cathepsin B activity and apoptosis by nilotinib was significantly prohibited by specific autophagy inhibitor bafilomycin A and Atg5 knockdown. CONCLUSION: Our findings demonstrate that nilotinib increases autophagy and cathepsin B activity, leading to mitochondrial AIF release and nuclear translocation, which is responsible for p53 and apoptosis induction in H9C2 cells.

No overt structural or functional changes associated with PEG-coated gold nanoparticles accumulation with acute exposure in the mouse heart.

In this study, we investigated the cardiac biodistribution of polyethylene glycol (PEG)-coated AuNPs and their effects on cardiac function, structure and inflammation in both normal and cardiac remodeling mice. The model of cardiac remodeling was induced by subcutaneously injection of isoproterenol (ISO), a non-selective beta-adrenergic agonist, for 7 days. After AuNPs were injected intravenously in mice for 7 consecutive days, Au content in different organs was determined quantitatively by inductively coupled plasma mass spectrometry (ICP-MS), cardiac function and structure were measured by echocardiography, cardiac fibrosis was examined with picrosirius red staining, the morphology of cardiomyocytes was observed with hematoxylin and eosin (H & E) staining. The accumulation of AuNPs in hearts did not affect cardiac function or induce cardiac hypertrophy, cardiac fibrosis and cardiac inflammation under normal physiological condition. Cardiac AuNPs content was 6-fold higher in the cardiac remodeling mouse than normal mice. However, the increased accumulation of AuNPs in the heart did not aggravate ISO-induced cardiac hypertrophy, cardiac fibrosis or cardiac inflammation. These observations suggest that PEG-coated AuNPs possess excellent biocompatibility under both physiological and pathological conditions. Thus, AuNPs may be safe for cardiac patients and hold great promise for further development for various biomedical applications.

[Study of the Saposhnikovia divaricata with space mutagenesis by Fourier transform infrared spectroscopy].

The outer space Saposhnikovia divaricata of the fourth generation was studied and compared with the ground group and comparison group for the first time. The intensity of carbonyl absorption peak at 1640 cm(-1) is stronger than the other two, indicating that chromone content was enhanced obviously. The peaks at 2927 and 2856 cm(-1) were assigned to --CH2-- groups, the peak at 1050 cm(-1) was due to the C-O groups, and the intensities at 2927, 2856 and 1050 cm(-1) were stronger than other samples, indicating that polysaccharide and glycoside contents were enhanced obviously. The intensity of lactone absorption peak at 1743 cm(-1) was stronger than the ground group and weaker than the comparison, indicating that coumarin content was higher than ground group and lower than the comparison. The major components and the structures remained intact, and the effective component contents were enhanced in the outer space Saposhnikovia divaricata. Using FTIR can analyse and characterize the intrinsic quality of the outer space medicinal materials.