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The multi-step process of hepatitis C virus (HCV) entry is facilitated by various host factors, including epidermal growth factor receptor (EGFR) and the tight junction proteins claudin-1 (CLDN1) and occludin (OCLN), which are thought to function at later stages of the HCV entry process. Using single particle imaging of HCV infection of polarized hepatoma spheroids, we observed that EGFR performs multiple functions in HCV entry, both phosphorylation-dependent and -independent. We previously observed, and in this study confirmed, that EGFR is not required for HCV migration to the tight junction. EGFR is required for the recruitment of clathrin to HCV in a phosphorylation-independent manner. EGFR phosphorylation is required for virion internalization at a stage following the recruitment of clathrin. HCV entry activates the RAF-MEK-ERK signaling pathway downstream of EGFR phosphorylation. This signaling pathway regulates the sorting and maturation of internalized HCV into APPL1- and EEA1-associated early endosomes, which form the site of virion uncoating. The tight junction proteins, CLDN1 and OCLN, function at two distinct stages of HCV entry. Despite its appreciated function as a "late receptor" in HCV entry, CLDN1 is required for efficient HCV virion accumulation at the tight junction. Huh-7.5 cells lacking CLDN1 accumulate HCV virions primarily at the initial basolateral surface. OCLN is required for the late stages of virion internalization. This study produced further insight into the unusually complex HCV endocytic process., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 So et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

High-throughput tests for early cancer detection can revolutionize public health and reduce cancer morbidity and mortality. Here we show a DNA methylation signature for hepatocellular carcinoma (HCC) detection in liquid biopsies, distinct from normal tissues and blood profiles. We developed a classifier using four CpG sites, validated in TCGA HCC data. A single F12 gene CpG site effectively differentiates HCC samples from other blood samples, normal tissues, and non-HCC tumors in TCGA and GEO data repositories. The markers were validated in a separate plasma sample dataset from HCC patients and controls. We designed a high-throughput assay using next-generation sequencing and multiplexing techniques, analyzing plasma samples from 554 clinical study participants, including HCC patients, non-HCC cancers, chronic hepatitis B, and healthy controls. HCC detection sensitivity was 84.5% at 95% specificity and 0.94 AUC. Implementing this assay for high-risk individuals could significantly decrease HCC morbidity and mortality., (© 2023. The Author(s).)

Introduction : Cancer has always been a menace for the society. Hepatocellular carcinoma (HCC) is one of the most lethal and 3rdlargest causes of deaths around the world. Area covered : The emergence of natural actives is considered as the greatest boon for fighting cancer. The natural actives take precedence over the traditional chemotherapeutic drugs in terms of their multi-target, multi-level and coordinated effects in the treatment of HCC. Literature reports have indicated the tremendous potential of bioactive natural products in inhibiting the HCC via molecular drug targeting, augmented bioavailability, and the ability for both passive or active targeting and stimulus-responsive drug release characteristics. This review provides a newer treatment approaches involved in the mechanism of action of different natural actives used for the HCC treatment via different molecular pathways. Besides, the promising advantage of natural bioactive-loaded nanocarriers in HCC treatment has also been also presented in this review. Expert opinion : The remarkable outcomes have been observed with therapeutic efficacy of the nanocarriers of natural actives in the treatment of HCC.Furthermore, it requires a thorough assessment of the safety and efficacy evaluation of the nanocarriers for the delivery of targeted natural active ingredients in HCC.].

Hepatocellular carcinoma (HCC) is the primary liver cancer that has shown a high incidence and mortality rate worldwide among several types of cancers. A large variety of chemotherapeutic agents employed for the treatment have a limited success rate owing to their limited site-specific drug targeting ability. Thus, there is a demand to develop novel approaches for the treatment of HCC. With advancements in nanotechnology-based drug delivery approaches, the challenges of conventional chemotherapy have been continuously decreasing. Nanomedicines constituted of lipidic and polymeric composites provide a better platform for delivering and opening new pathways for HCC treatment. A score of nanocarriers such as surface-engineered liposomes, nanoparticles, nanotubes, micelles, quantum dots, etc., has been investigated in the treatment of HCC. These nanocarriers are considered to be highly effective clinically for delivering chemotherapeutic drugs with high site-specificity ability and therapeutic efficiency. The present review highlights the current focus on the application of nanocarrier systems using various ligand-based receptor-specific targeting strategies for the treatment and management of HCC. Moreover, the article has also included information on the current clinically approved drug therapy for hepatocellular carcinoma treatment and updates of regulatory requirements for approval of such nanomedicines., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Aim: The present study focuses on the development and evaluation of the resveratrol (RV)-loaded cationic solid lipid nanoparticles (RV-c-SLNs) for the management of hepatocellular carcinoma (HCC)., Materials and Methods: Optimization of formulation was performed using factorial design, and further in vitro drug release, cytotoxicity, biodistribution, in vivo preclinical, and biochemical evaluation were carried out., Results: The optimized formulation exhibited uniform size, homogeneous disparity, positive zeta potential, and stability over 12-week storage at 25°C/60% RH. The in vitro drug release and cytotoxicity study showed 60% drug release within the first 6 hours and comparatively higher cytotoxicity on HepG2 cell line by resveratrol-solid lipid nanoparticle (RV-SLN) as compared to the RV solution. In addition, an anticancer action and biodistribution study on a rat model of HCC showed significant reduction of tumor volume and higher accumulation in the tumor tissue from RV-c-SLN ( P <0.01) over RV solution and RV-SLN. Furthermore, RV-c-SLN showed significant down-regulation in the levels of pro-inflammatory cytokines and balancing of antioxidant enzymes. Histopathological investigation showed reduced occurrence of hepatic nodules, necrosis formation, infiltration of inflammatory cells, blood vessels inflammation, and cell swelling., Conclusion: Overall, the obtained results construed that RV-c-SLN with improved antitumor activity as clearly evident from in vitro, in vivo, and biochemical investigations., Competing Interests: The authors report no conflicts of interest in this work., (© 2020 Rahman et al.)

The poorly water-soluble chemotherapeutic agents, paclitaxel (PTX), exhibit serious clinical side effects upon oral administration due to poor aqueous solubility and a high degree of toxic effects due to non-specific distribution to healthy tissues. In our efforts, we formulated biocompatible dietary lipid-based nanostructured lipidic carriers (NLCs) to enhance the oral bioavailability of PTX for treatment of the liver cancer. A three-factor, three-level Box-Behnken design was employed for formulation and optimization of PTX-loaded NLC formulations. PTX-loaded NLC formulation prepared by melt-emulsification in which glyceryl monostearate (GMS) was used as solid lipid and soybean oil as liquid lipid, while poloxamer 188 and Tween 80 (1:1) incorporated as a surfactant. In vitro drug release investigation was executed by dialysis bag approach, which indicated initial burst effect with > 60% drug release within a 4-h time period. Moreover, PTX-NLCs indicated high entrapment (86.48%) and drug loading efficiency (16.54%). In vitro cytotoxicity study of PTX-NLCs performed on HepG2 cell line by MTT assay indicated that PTX-NLCs exhibited comparatively higher cytotoxicity than commercial formulation (Intaxel®). IC 50 values of PTX-NLCs and Intaxel® after 24-h exposure were found to be 4.19 μM and 11.2 μM. In vivo pharmacokinetic study in Wistar rats also indicated nearly 6.8-fold improvement in AUC and C max of the drug from the PTX-NLCs over the PTX suspension. In a nutshell, the observed results construed significant enhancement in the biopharmaceutical attributes of PTX-NLCs as a potential therapy for the management of human liver carcinoma.

Aim: The present work describes the development of poly(lactic co-glycolic acid) (PLGA) nanoparticles (NPs) of rutin (RT) for the treatment of hepatocellular carcinoma in rats., Materials & Methods: RT-loaded PLGA NPs (RT-PLGA-NPs) were prepared by double emulsion evaporation method. Further these are optimized by Box-Behnken design. PLGA NPs were evaluated for size, polydispersity index, drug-loading capacity, entrapment, gastric stability, in vitro drug release, in vivo preclinical studies and biochemical studies., Results: Preclinical evaluation of RT-PLGA-NPs for anticancer activity through oral route exhibited significant improvement in hepatic, hematologic and renal biochemical parameters. Highly superior activity was observed in regulating oxidative stress and inflammatory markers, antioxidant enzymes, cytokines and inflammatory mediators and their role on plasma membrane ATPases responsible for destruction in liver tissues., Conclusion: Histopathological evaluation indicated reduced incidence of hepatic nodules, necrosis formation, infiltration of inflammatory cells, blood vessel inflammation and cell swelling with RT-PLGA-NP treatment along with considerable downregulation in the levels of proinflammatory cytokines.

Objective: To determine the clinical, biochemical and radiological prognostic indicators and to compare the performance of six staging systems in patients of hepatocellular carcinoma (HCC)., Study Design: Descriptive study., Place and Duration of Study: Department of Gastroenterology, Doctors Hospital, Lahore, from October 2007 to December 2013., Methodology: Patients with HCC were included. Baseline clinical, hematological and radiological variables were noted. Patients were followed for 5 years or till death. Survival predictors were identified using Cox proportional hazard analysis and 6 prognostic staging systems were evaluated by determining homogeneity, discriminatory ability and monotonicity., Results: Of the 228 patients included, male to female ratio was 2.6/1 (165/63) and mean age was 56.5 ±10.4 years. Majority of patients 189 (82.9%) were anti-HCV positive. Solitary HCC lesion was seen in 121 (53.1%) patients, 16 (7%) had 2 lesions while 73 (32%) had 3 or more lesions. Only 36 (15.8%) patients had palliative therapy for HCC. Survival rate was 45.2%, 25%, 12.3%, 7%, 2.2% and 1% for 6 months, 1, 2, 3, 4 and 5 years respectively. Male gender, portal vein thrombosis, serum albumin < 3.5 g/dl, tumor size ≥6 cm and alpha fetoprotein (AFP) ≥147 U/ml were bad prognostic indicators. OKUDA, GRETCH and early stages of CLIP had better homogeneity while CLIP showed superior discriminatory ability and monotonicity for predicting survival., Conclusion: Male gender, presence of portal vein thrombosis, low serum albumin, large tumor size and high AFP level are poor prognostic indicators in patients of HCC. CLIP has better performance in predicting mortality.

Objective: To determine the accuracy of serum alpha fetoprotein (AFP) for diagnosis of hepatocellular carcinoma (HCC) in patients with cirrhosis., Study Design: Observational study., Place and Duration of Study: Department of Medicine, The King Edward Medical University, Lahore, from November 2007 to August 2011., Methodology: Consecutive patients, diagnosed with HCC by contrast enhanced CT, MRI or biopsy were included as cases. Patients of cirrhosis with no evidence of HCC were enrolled as controls. Demographic, laboratory and radiological data were recorded. Serum AFP was determined in all patients at outset and was analyzed using ROC curve for its accuracy in diagnosing HCC., Results: A total of 275 patients were included; of them 173 had HCC and 102 had cirrhosis. One hundred and thirty nine cases (80.3%) with HCC and 86 (84.3%) without HCC had cirrhosis due to HCV. Stage of liver disease, as determined by Child Turcotte Pugh (CTP) score, was comparable; mean CTP value 7.97 ± 2.17 in HCC and 7.75 ± 2.21 in control group (p = 0.41). Area under curve (AUC) for AFP was 0.85 (95%, CI: 0.80 - 0.90) with optimum cut off value of 20.85 ng/ml which showed 72.2% sensitivity, 86.2% specificity, 89.9% positive predictive value, 64.7% negative predictive value and 77.4% overall accuracy in diagnosing patients with HCC., Conclusion: Despite sub-optimal sensitivity, alpha fetoprotein is still a valid screening test for diagnosis of hepatocellular carcinoma till other more sensitive markers are developed. Till then, it should be used in conjunction with ultrasound.

Objectives: To determine the tumour and general characteristics, especially survival, of patients presenting with hepatocellular carcinoma at our tertiary care cancer hospital., Patients and Methods: We retrospectively studied 584 charts of patients consecutively registered between 1995 and 2004 at the Shaukat Khanum Memorial Cancer Hospital and Research Centre, in Lahore, Pakistan. Descriptive statistics were obtained for gender, age, tumour size and morphology, alpha fetoprotein level, means of diagnosis, Child-Pugh status, risk factors, treatment given and follow-up. Survival analysis was conducted using the Kaplan-Meier method., Results: Mean age at presentation was 56 years. Four hundred and forty four (76%) were male. Average tumour diameter evaluable in 412 patients was 8 cm. HCC was unifocal in 194 (33%), multifocal in 303 (52%) and unevaluable in 106. Mean AFP was 4,198 u/ml (range 1 - 278,560). Methods of diagnosis were FNA in 71, biopsy in 26, imaging/AFP > 200 in 70, lipiodol angiogram in 42, combinations of two of these in 365 and biphasic CT scans in 10. Initial Child-Pugh available for 400/584 was A in 216, B in 147 and C in 37. Evidence of prior hepatitis B infection was found in 114, and for hepatitis C in 254. Other than the four patients who had TACE followed by surgical resection, treatment was offered to 79/584 patients: among the 48 who had TACE, 26 experienced cancer progression whereas 11 had stable disease ranging from 6 - 20 months; another 11 were lost to follow-up. Of the 14 patients who underwent local resection, 2 were lost to follow-up, 7 developed recurrences but 5 remained disease free for a mean of 33 months. Following ethanol ablation in 17 patients, disease progressed in 5 but remained stable in 2 for a mean of 13 months; 10 were lost to follow-up. At the time of writing, 56 patients are alive (mean follow-up 20 months), 210 are known to have died (mean follow-up 9 months), and 318 were lost to follow-up within 3 months. Median overall survival was 10.5 months, death being the point of interest for survival analysis. Child-Pugh class stratified analysis (400/584) revealed median survival of 12 months for class A, 7.7 months for class B and 4 months for class C (p < 0.001)., Conclusions: Most patients present with large, multifocal tumours, with poor liver function. Sixty one percent had evidence of prior infection with hepatitis B or C. The advanced stage at presentation, poor background liver function in many and the absence of a national liver transplantation program limit treatment options. Only 14% of patients were considered suitable for definitive treatment. Survival correlated with Child-Pugh status at presentation. Overall prognosis remains bleak. There is an urgent need to educate the public about the risks of hepatitis B and C and health professionals about early diagnosis and treatment, including possible development of a sustainable national liver transplant program.