Liver Carcinoma Research Articles

Outcomes in Patients with Liver Dysfunction Post SARS-CoV-2 Infection: What Should We Measure?

Since 2019, the COVID-19 pandemic wreaked havoc all over the world. Early in the course of the pandemic, multiple hepatic manifestations of COVID-19 were noted. We aim to categorize hepatic dysfunction and its outcome in COVID-19 infection. This is a review article based on a literature search in PubMed and Medline databases for articles detailing short-term and long-term outcomes of COVID-19 related liver dysfunction. The most common hepatic manifestation of COVID-19 was aspartate amino transferase (AST) predominant transaminase elevation. Transaminases improve once the COVID-19 infection resolves. In addition, COVID-19 cholangiopathy, autoimmune hepatitis associated COVID-19, and splanchnic venous thrombosis triggered by COVID-19 are other manifestations. Patients with preexisting liver disease, especially those with cirrhosis, have poor prognosis with COVID-19 infections compared to the general population. Elevations in liver tests were associated with severe COVID-19 infections. Patients with chronic liver disease have a higher risk of morbidity and mortality from COVID-19 infection. Among patients with chronic liver disease, decompensated liver cirrhosis, hepatocellular carcinoma and alcohol-associated liver disease were associated with an increased risk of severity and mortality from COVID-19 infection. Interactions between antiviral therapy for COVID-19 and hepatitis B/hepatitis C medications must be considered in patients with chronic viral hepatitis and COVID-19 infection. COVID-19 vaccination-related hepatic dysfunction has been reported. COVID-19 is here to stay. Hepatic dysfunction in COVID-19 signals severe COVID-19 infections. Patients with chronic liver disease have higher mortality from COVID-19 than general population. It is important to remember the lessons learned throughout the covid pandemic to take care of patients with COVID-19 now and in the future. Further studies are needed to document long-term outcomes in patients with COVID-19 who developed hepatic dysfunction.

Differential genomic effects of four nano-sized and one micro-sized CeO2 particles on HepG2 cells.

The objective of this research was to perform a genomics study of five cerium oxide particles, 4 nano and one micrometer-sized particles which have been studied previously by our group with respect to cytotoxicity, biochemistry and metabolomics. Human liver carcinoma HepG2 cells were exposed to between 0.3 to 300 ug/ml of CeO2 particles for 72 hours and then total RNA was harvested. Fatty acid accumulation was observed with W4, X5, Z7 and less with Q but not Y6. The gene expression changes in the fatty acid metabolism genes correlated the fatty acid accumulation we detected in the prior metabolomics study for the CeO2 particles named W4, Y6, Z7 and Q, but not for X5. In particular, the observed genomics effects on fatty acid uptake and fatty acid oxidation offer a possible explanation of why many CeO2 particles increase cellular free fatty acid concentrations in HepG2 cells. The major genomic changes observed in this study were sirtuin, ubiquitination signaling pathways, NRF2-mediated stress response and mitochondrial dysfunction. The sirtuin pathway was affected by many CeO2 particle treatments. Sirtuin signaling itself is sensitive to oxidative stress state of the cells and may be an important contributor in CeO2 particle induced fatty acid accumulation. Ubiquitination pathway regulates many protein functions in the cells, including sirtuin signaling, NRF2 mediated stress, and mitochondrial dysfunction pathways. NRF2-mediated stress response and mitochondrial were reported to be altered in many nanoparticles treated cells. All these pathways may contribute to the fatty acid accumulation in the CeO2 particle treated cells.

In vitro chemopreventive and cytotoxic effects of Amazon mosses Leucobryum martianum (Hornsch.) and Leucobryum laevifolium (Broth) extracts.

Several bioactive compounds, such as polyphenols, demonstrate low toxicity and prominent effects on cancer cells with antioxidant, anti-inflammatory, and antitumor activities. Such compounds can be found in Amazon mosses Leucobryum martianum (Hornsch.) Hampe ex Müll. Hal. (Hornsch.) and Leucobryum laevifolium (Broth). Antimutagenic assay with Salmonella enterica serovar Typhimurium and cytotoxicity with different eukaryotic cell lines were carried out to screen aqueous, hydroalcoholic, and ethanolic extracts of those Amazon mosses for anticancer potential. The results indicate the capacity of all extracts of both mosses to exert chemopreventive effects against 4-nitroquinoline-N-oxide (4NQO) and 2-aminoanthracene (2-AA), which are direct or indirect mutagens. In particular, the ethanolic and aqueous extract from L. martianum. The ethanolic extract from L. martianum induces significant cytotoxicity by mitochondrial metabolism and cell membrane disruption pathways to tumor or non-tumor cells. The aqueous extract from L. martianum showed a mainly cytotoxic response in the HepG2 cells, a human liver carcinoma, reaching ~90% cytotoxicity. The same extract did not induce significant damage to normal liver cells (F C3H cells) by membrane interaction pathway. The selective cytotoxicity in the aqueous extract of L. martianum makes it a candidate against liver cancer. Further studies, including in vivo models, are necessary to validate the efficacy and safety of the aqueous extract of L. martianum.

The using of genetic markers as a possibility of predicting the rate of progress of liver fibrosis in patients with chronic hepatitis B

According to recent WHO estimates, chronic HBV infection is one of the leading causes of death and disability in patients with infectious diseases. From 780 thousand to 1 million deaths are annually recorded in the world as a result of cirrhosis of the liver and hepatocellular carcinoma. Pathogenetic features of the course and outcomes of chronic hepatitis B are determined by the immunological, genetic factors of the host, as well as the molecular biological structure of the virus. The aim of the work was to study the interaction of polymorphic loci of the cytokine genes SMAD 7 (rs4939827), TNFα (rs1800620), IL-10 (rs1800896), IL-4 (rs2243250) and the degree of structural changes in the liver based on the non-invasive Fibrotest technique in patients with chronic hepatitis B as part of a search for possible predictors of predisposition to the rapid progression of liver fibrosis. The study included 82 patients with chronic hepatitis B. Assessment of morphological changes (stage of fibrosis) was carried out by the method of non-invasive diagnosis of FibroScan, which is an alternative to puncture biopsy of the liver. It has been suggested that homozygous alleles СС IL-4 (rs2243250), GG TNFα (rs1800620), СС SMAD family member 7 (rs4939827) have a protective effect on the course of chronic hepatitis B, as these variants of allelic polymorphism of cytokine genes were found mainly in patients with CHB with a degree of fibrosis F0-F1. The heterozygous genotypes СТ IL-4 (rs2243250) and GA TNFα (rs1800620), the mutant homozygous ТТ SMAD family member 7 (rs4939827) have a profibrotic effect on the course of chronic hepatitis B, as they are found mainly in patients with chronic hepatitis B with degree of fibrosis F3. The established relationship between the liver fibrosis stage according to the METAVIR scale and the polymorphism of the cytokine genes SMAD 7 (rs4939827), TNFα (rs1800620) and IL-4 (rs2243250) made it possible to create a prognostic scale for assessing the individual risk of rapid progression of liver fibrosis. The proposed scale, due to a comprehensive assessment of the polymorphism of cytokine gene alleles and the stage of liver fibrosis using the METAVIR scale, makes it possible to carry out an individual assessment of the risk of progression of chronic hepatitis and, possibly, draw up a personalized treatment plan for the patient. Coding of the studied polymorphisms and subsequent counting can be automated, which does not require significant financial investments. The possibilities of the prognostic scale are proven on the example of a group of patients who received the antifibrotic agent bicyclol in comparison with the control group.

Real Time Volumetric MRI for MR-Guided 3D Motion Tracking via Sparse Prior-Augmented Neural Representation Learning

To reconstruct volumetric MRI from orthogonal cine acquisition aided by sparse priors of 2 static 3D MRI through implicit neural representation (NeRP) learning, with the goal of eliminating large-scale training datasets for data-driven sparse MRI reconstruction and supporting clinical workflow of real time 3D motion tracking during MR-guided radiotherapy. A multi-layer perceptron network was trained to learn the NeRP of a patient-specific MRI dataset, where the network takes 4D data coordinates of voxel locations and motion states as inputs and outputs corresponding voxel intensities. By first learning the NeRP of 2 static 3D MRI with different breathing motion states, prior knowledge of patient breathing motion was embedded into network weights through optimization. The prior knowledge was then augmented from 2 to 31 motion states by querying the optimized network at interpolated/extrapolated motion state coordinates. Starting from the prior-augmented network as an initialization point, the network was further trained using sparse samples of 2 orthogonal cine slices. The final volumetric reconstruction was obtained by querying the trained network at desired 3D spatial locations. We evaluated the proposed method using 5-minute volumetric MRI time series with 340 ms temporal resolution collected from 7 liver carcinoma patients. The time series was acquired using golden-angle radial MRI sequence and reconstructed through retrospective sorting. Two MRI with inhale and exhale states respectively were selected from the first 30 sec of the time series for prior embedding and augmentation. The remaining 4.5-min time series was used for volumetric reconstruction evaluation, where we retrospectively subsampled each MRI to 2 orthogonal slices and compared network-reconstructed images to ground truth images in terms of image quality and the capability of supporting 3D target motion tracking. Across the 7 patients evaluated, the peak signal to noise ratio between model reconstruction and ground truth was 54.66 ± 6.16 dB and the structural similarity index measure was 0.99 ± 0.01. Gross tumor volume (GTV) contours estimated by deforming a reference state MRI to model-reconstructed and ground truth MRI showed good consistency. The 95-percentile Hausdorff distance between GTV contours was 1.89 ± 1.13 mm, which is less than the voxel dimension. The mean GTV centroid position difference between ground truth and model estimation was less than 1 mm in all 3 orthogonal directions. Volumetric MRI from orthogonal cine acquisition with sparse priors is feasible by modeling prior knowledge through implicit neural representation learning. The model-reconstructed images showed sufficient accuracy in supporting 3D motion tracking of abdominal targets. By eliminating the need for large scale training datasets, the method promises to enable clinical implementation of 3D motion tracking for precision radiation therapy.

Distinct Morphological and Molecular Profiles of NAFLD and NAFLD-associated HCC Revealed by Immunohistochemistry and MicroRNA Analysis.

Non-alcoholic fatty liver disease (NAFLD) is a common hepatic condition that can progress to hepatocellular carcinoma (HCC) in non-cirrhotic livers. To better understand the development of NAFLD-associated HCC, we performed an integrated morphological and molecular analysis to identify new insights that can improve the follow-up of NAFLD patients. Our study included a cohort of 14 NAFLD-associated HCC and 41 NAFLD patients. We analyzed clinical parameters, a four-microRNA (miRNA) panel (miR-21-5p, miR-34a-5p, miR-130a-3p, and miR-155-3p) panel and their relationship with p53 and β-catenin expression. In the study cohort, the NAFLD-associated HCC patients were predominantly male, older, had significantly altered hepatic function, and a higher incidence of hypertension, type 2 diabetes, and dyslipidemia. Morphologically, the NAFLD-HCC group had substantially higher steatosis, ballooning, and fibrosis grades than the NAFLD group. The β-catenin expression was higher in both adjacent non-tumoral liver tissue (ANT) from NAFLD-associated HCC patients and in HCC tissue com-pared with NAFLD samples. The 4 miRNAs panel showed a dysregulated expression profile between NAFLD, ANT and HCC samples. This study provides important insights regarding the molecular mechanisms underlying HCC progression in NAFLD patients, allowing for the development of better screening strategies for the early detection of NAFLD-associated HCC.

Liquid biopsy kinetics and detection of ERBB2 amplification/HER2-positivity in refractory hepatocellular carcinoma

Hepatocellular Carcinoma (HCC) is the most common primary liver carcinoma, accounting for 75–85% of all cases. For patients with advanced unresectable and/or metastatic HCC, treatment options primarily include immunotherapy combinations and/or oral tyrosine kinase inhibitors. For patients with alpha-fetoprotein (AFP) levels above 400 ng/ml, ramucirumab, an anti-VEGF agent, is also approved in the second-line setting. However, none of these therapies are based on a specific molecular marker and the role of molecular testing is limited. In fact, HCC is unique in the sense that a biopsy may not be pursued if imaging findings are classic for HCC, in the appropriate clinical context. Herein, we report a case of a patient with metastatic HCC and a huge disease burden where a circulating tumor DNA (ctDNA) liquid biopsy done as part of our standard of care serendipitously revealed a very high ERBB2 copy number amplification (>78). This was corroborated by HER2 immunohistochemical staining, which demonstrated strong diffuse membranous HER2 3+ expression; tissue next-generation sequencing also identified an ERBB2 unadjusted copy number gain of 183. Furthermore, we were able to demonstrate the feasibility of using both ctDNA and circulating tumor cells (CTCs) to determine the heterogeneity of HER2 and response to dual HER2 blockade trastuzumab/pertuzumab (MyPathway regimen). In addition to the utility of liquid biopsies increasing opportunities for precision medicine, this n-of-1 precision medicine case illustrates and reiterates the need for comprehensive panel-based NGS testing that employs both DNA/RNA for all patients with advanced or metastatic cancers. It also supports the agnostic potential of ERBB2/HER2 as an actionable marker.

An attempt to establish and apply global benchmarks for liver resection of malignant hepatic tumors

BackgroundBenchmarking is a process of continuous self-evaluation and comparison with best-in-class hospitals to guide quality improvement initiatives. We sought to define global benchmarks relative to liver resection for malignancy and to assess their achievement in hospitals in the United States. MethodsPatients who underwent curative-intent liver resection for hepatocellular carcinoma, intrahepatic cholangiocarcinoma, or colorectal or neuroendocrine liver metastases between 2000 and 2019 were identified from an international multi-institutional database. Propensity score matching was conducted to balance baseline characteristics between open and minimally invasive approaches. Best-in-class hospitals were defined relative to the achievement rate of textbook oncologic outcomes and case volume. Benchmark values were established relative to best-in-class institutions. The achievement of benchmark values among hospitals in the National Cancer Database was then assessed. ResultsAmong 2,624 patients treated at 20 centers, a majority underwent liver resection for hepatocellular carcinoma (n = 1,609, 61.3%), followed by colorectal liver metastases (n = 650, 24.8%), intrahepatic cholangiocarcinoma (n = 299, 11.4%), and neuroendocrine liver metastases (n = 66, 2.5%). Notably, 1,947 (74.2%) patients achieved a textbook oncologic outcome. After propensity score matching, 6 best-in-class hospitals with the highest textbook oncologic outcome rates (≥75.0%) were identified. Benchmark values were calculated for margin positivity (≤11.7%), 30-day readmission (≤4.1%), 30-day mortality (≤1.6%), minor postoperative complications (≤24.7%), severe complications (≤12.4%), and failure to achieve the textbook oncologic outcome (≤22.8%). Among the National Cancer Database hospitals, global benchmarks for margin positivity, 30-day readmission, 30-day mortality, severe complications, and textbook oncologic outcome failure were achieved in 62.9%, 27.1%, 12.1%, 7.1%, and 29.3% of centers, respectively. ConclusionThese global benchmarks may help identify hospitals that may benefit from quality improvement initiatives, aiming to improve patient safety and surgical oncologic outcomes.

IMMT promotes hepatocellular carcinoma formation via PI3K/AKT/mTOR pathway

Abstract Objectives Hepatocellular carcinoma (HCC) remains a global challenge. Finding new specific targets has significant clinical value for the treatment of hepatocellular carcinoma. In this study, we discovered a new biomarker targeting HCC. At present, the role of Inner Membrane Mitochondrial Protein (IMMT) in various malignant tumors is receiving increasing attention, but its molecular mechanism of action in the malignant process of HCC has not been fully elucidated. This study aims to investigate the key regulatory mechanisms of IMMT in the formation of HCC. Methods Using TCGA data and clinical HCC samples, we first studied the expression of IMMT in HCC tissues and its correlation with malignant prognosis of patients. The regulatory effect of IMMT on HCC was studied by lentivirus infection. In vitro, the effects of IMMT on the proliferation, migration and apoptosis of cells were investigated by CCK8, colony formation assay, transwell and flow cytometry. Consistently, in vivo experiments, the regulation of tumor growth by IMMT was studied by constructing subcutaneous transplanted tumor and liver carcinoma in situ. In terms of mechanism, we predicted and verified the downstream genes of IMMT with the help of string database. Results We found that IMMT was significantly up-regulated in HCC tissues and was significantly positively correlated with poor prognosis of patients. Functionally, we demonstrated that IMMT knockdown significantly inhibited HCC cell proliferation, migration and promoted cell apoptosis in vitro. Similarly, the knockdown of IMMT also significantly weakened the progression of tumors in vivo. In terms of mechanism, we demonstrate for the first time that IMMT can regulate the progression of HCC by influencing the activation of PI3K-AKT-mTOR pathway. Conclusions Collectively, our research findings elucidate the hitherto unexplored important role of the IMMT/PI3K/AKT/mTOR axis in the formation of HCC, and provide a new biomarker for clinical diagnosis and treatment of HCC.

Precise construction of Regorafenib-loaded gold nanoparticles: investigation of antiproliferative activity and apoptosis induction in liver cancer cells

Regorafenib (Reg) inhibits the growth of liver cancer cells in vitro and animal model. However, due to its poor bioavailability, its potential as a chemopreventive or therapeutic drug is severely restricted. In this work, we developed two environmentally friendly delivery systems by synthesizing Regorafenib-gold nanoparticles conjugates Reg@GNPs1 and Reg@GNPs2, employing a dual role of Reg to reduce Au3+ and stabilize the synthesized GNPs. UV-Vis’s spectroscopy, Fourier transform infrared spectroscopy, and Powder-XRD verified the fabrication of Reg@GNPs. Reg@GNPs1 and Reg@GNPs2 were both found to be spherical and uniform in size (10 ± 2 and 2 ± 33 nm, respectively) using transmission electron microscopy. Similar negative zeta potential (−35.0 ± 2.5 and −37.0 ± 1.6 mV) was observed by dynamic light scattering analysis, even though the hydrodynamic diameter of the nanoconjugates ranged from 65.0 ± 1.7 to 153.0 ± 2.2 nm. Reg@GNPs1 and Reg@GNPs2 were calculated to have a Reg loading of 46% and 48%, respectively. Selectivity towards the non-cancerous cell line (L929) cells, whereas the MTT assay in vitro showed the antiproliferative effects of Reg@GNPs on three liver carcinoma (Hep3B, BEL7402, and HepG2) cell lines. Several fluorescent staining techniques were used to examine liver cancer cell morphology. Flow cytometric analysis confirmed that the effects of the superior Reg@GNPs nanoconjugate on cell proliferation than free Reg. In conclusion, the acquired results show that the novel synthesized GNPs loaded with Reg are stable as an anticancer agent, with minimal toxicity against non-cancerous cells, as determined by cytotoxicity and IC50 evaluations.

Retrospective herbal accession on liver cirrhosis: current insights and future prospects

Chronic liver disease encompasses a spectrum of liver conditions spanning fatty liver, hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Despite advancements in conventional medicine, growing emphasis is placed on phytomedicine by researchers. Herbal medicine's allure stems from its perceived potential for both treating and preventing ailments, fueled by the notion that it's a safe and "natural" alternative to conventional treatments. This review offers a thorough and systematic examination of current knowledge concerning the role of conventional medicinal herbs and phytochemicals in addressing chronic liver diseases. It also highlights the potential challenges that warrant future investigation. With chronic liver diseases being a complex and pressing health issue, this review contributes to the evolving understanding of herbal interventions and underscores the necessity for rigorous research to substantiate their effectiveness and safety.

Bioactivity-Guided Synthesis: In Silico and In Vitro Studies of β-Glucosidase Inhibitors to Cope with Hepatic Cytotoxicity.

The major cause of hyperglycemia can generally be attributed to β-glucosidase as per its involvement in non-alcoholic fatty liver disease. This clinical condition leads to liver carcinoma (HepG2 cancer). The phthalimides and phthalamic acid classes possess inhibitory potential against glucosidase, forming the basis for designing new phthalimide and phthalamic acid analogs to test their ability as potent inhibitors of β-glucosidase. The study also covers in silico (molecular docking and MD simulations) and in vitro (β-glucosidase and HepG2 cancer cell line assays) analyses. The phthalimide and phthalamic acid derivatives were synthesized, followed by spectroscopic characterization. The mechanistic complexities associated with β-glucosidase inhibition were identified via the docking of the synthesized compounds inside the active site of the protein, and the results were analyzed in terms of the best binding energy and appropriate docking pose. The top-ranked compounds were subjected to extensive MD simulation studies to understand the mode of interaction of the synthesized compounds and binding energies, as well as the contribution of individual residues towards binding affinities. Lower RMSD/RMSF values were observed for 2c and 3c, respectively, in the active site, confirming more stabilized, ligand-bound complexes when compared to the free state. An anisotropic network model was used to unravel the role of loop fluctuation in the context of ligand binding and the dynamics that are distinct to the bound and free states, supported by a 3D surface plot. An in vitro study revealed that 1c (IC50 = 1.26 µM) is far better than standard acarbose (2.15 µM), confirming the potential of this compound against the target protein. Given the appreciable potential of the candidate compounds against β-glucosidase, the synthesized compounds were further tested for their cytotoxic activity against hepatic carcinoma on HepG2 cancer cell lines. The cytotoxicity profile of the synthesized compounds was performed against HepG2 cancer cell lines. The resultant IC50 value (0.048 µM) for 3c is better than the standard (thalidomide: IC50 0.053 µM). The results promise the hypothesis that the synthesized compounds might become potential drug candidates, given the fact that the β-glucosidase inhibition of 1c is 40% better than the standard, whereas compound 3c holds more anti-tumor activity (greater than 9%) against the HepG2 cell line than the known drug.

MBOAT7 rs641738 Variant Is Not Associated with an Increased Risk of Hepatocellular Carcinoma in a Latin American Cohort

BackgroundThe rs641738 C > T single-nucleotide polymorphism of MBOAT7 has been associated with hepatocellular carcinoma (HCC) and nonalcoholic fatty liver disease (NAFLD). Latin Americans have high rates of HCC and NAFLD, but no assessment between MBOAT7 and HCC has been performed in this population.AimsWe provide the first assessment of the impact of MBOAT7 on HCC risk in Latin Americans.MethodsPatients were prospectively recruited into the ESCALON network, designed to collect samples from Latin American patients with HCC in 6 South American countries (Argentina, Ecuador, Brazil, Chile, Peru, and Colombia). A European cohort and the general Hispanic population of gnomAD database were included for comparison. Associations between HCC and MBOAT7 were evaluated using logistic regression.ResultsIn total, 310 cases of HCC and 493 cases of cirrhosis without HCC were assessed. The MBOAT7 TT genotype was not predictive of HCC in Latin Americans (TT vs CC OR adjusted = 1.15, 95% CI 0.66–2.01, p = 0.610) or Europeans (TT vs CC OR adjusted = 1.20, 95% CI 0.59–2.43, p = 0.621). No significant association was noted on subgroup analysis for NAFLD, viral hepatitis, or alcohol-related liver disease. The TT genotype was increased in the NAFLD-cirrhosis cohort of Latin Americans compared to a non-cirrhotic NAFLD cohort (TT vs CC + CT OR = 2.75, 95% CI 1.10–6.87, p = 0.031).ConclusionThe rs631738 C > T allele of MBOAT7 was not associated with increased risk of HCC in Latin Americans or Europeans. An increase in the risk of cirrhosis was noted with the TT genotype in Latin Americans with NAFLD.Graphical

Plain language summary of the HIMALAYA study: tremelimumab and durvalumab for unresectable hepatocellular carcinoma (liver cancer).

This is a summary of results from a phase 3 clinical study called HIMALAYA. HIMALAYA looked at treatment with one dose of a medication called tremelimumab combined with multiple doses of a medication called durvalumab (the STRIDE regimen) or multiple doses of durvalumab alone. These treatments were compared with a medication called sorafenib in participants with unresectable hepatocellular carcinoma (HCC). HCC is a type of liver cancer that is difficult to treat because it is often diagnosed when it is unresectable, meaning it can no longer be removed with surgery. Sorafenib has been the main treatment for unresectable HCC since 2007. However, people who take sorafenib may experience side effects that can reduce their quality of life, so alternative medicines are being trialed. Tremelimumab and durvalumab are types of drugs called immunotherapies, and they both work in different ways to help the body's immune system fight cancer. Participants who took STRIDE lived longer than participants who took sorafenib, whilst participants who took durvalumab alone lived a similar length of time as participants who took sorafenib. Participants who took STRIDE or durvalumab had a lower relative risk of experiencing worsening in their quality of life than participants who took sorafenib. The side effects that participants who received STRIDE or durvalumab experienced were expected for these types of treatments and could mostly be managed. Overall, STRIDE is more effective than sorafenib for people with unresectable HCC. Clinical Trial Registration: NCT03298451 (HIMALAYA) (ClinicalTrials.gov).

Reduced Lipid Peroxidation Predicts Unfavorable Prognosis in Hepatocellular Carcinoma, but Not Intrahepatic Cholangiocarcinoma.

Primary liver cancer, including hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), remains a significant contributor to cancer-related mortality worldwide. Oxidative stress and lipid peroxidation play a key role in chronic liver diseases and have been shown to be pivotal for tumor initiation and progression. 4-hydroxy-nonenal (4-HNE), one of the major mediators of oxidative stress and a well-established biomarker for lipid peroxidation, can act as a signal transducer, inducing inflammation and exerting carcinogenic effects. However, the role of 4-HNE in primary liver cancer remains poorly explored. In this study, we investigated 4-HNE levels in 797 liver carcinomas, including 561 HCC and 236 iCCA, by immunohistochemistry. We then correlated 4-HNE levels with comprehensive clinical data and survival outcomes. In HCC, lower expression levels of 4-HNE were associated with vascular invasion, a high tumor grade, a macrotrabecular-massive HCC subtype, and poor overall survival. Concerning iCCA, large duct iCCA showed significantly higher 4-HNE levels when compared to small duct iCCA. Yet, in iCCA, 4-HNE levels did not correlate with known prognostic parameters or survival outcomes. To conclude, in HCC but not in iCCA, low amounts of 4-HNE predict unfavorable survival outcomes and are associated with aggressive tumor behavior. These findings provide insights into the role of 4-HNE in liver cancer progression and may enable novel therapeutic strategies.

Metabolic profiling and cytotoxic activities of ethanol extract of Dypsis leptocheilos aerial parts and its green synthesized silver nanoparticles supported by network pharmacology analysis

Cancer, which is characterized by uncontrolled cell growth and division with loss of physiological functions. It is one of the most fatal diseases in the world. For thousands of years, natural treatments, particularly those made from natural products, have been used to cure a variety of diseases, including cancer. Several Arecaceae species have been suggested as potential treatments for a range of cancer types. Arecaceae have a long history of use in folk medicine to treat tumors and a variety of infectious disorders. The green synthesis of silver nanoparticles (SNP) using the total ethanolic extract of Dypsis leptocheilos aerial parts (TEEDL) as a reducing agent was investigated for their cytotoxic activity (using the MTT assay) for the first time. A color change from faint yellow to reddish brown in the first stages of SNP synthesis, indicating the synthesis of nanoparticles. The prepared nanoparticles were also elucidated by using UV-visible spectroscopy, Fourier Transforms infrared spectroscopy (FT-IR), transmission electron microscope (TEM), and Zeta potential. The purified silver nanoparticle preparation demonstrated more promising cytotoxic activity against tested various cell lines than TEEDL. Cell viability by using the MTT assay demonstrated the cytotoxic activity of (TEEDL-based SNPs) against breast cancer cells (MCF-7), liver carcinoma (HepG2), colon carcinoma (HCT-116), and prostate carcinoma (PC-3) cell lines with IC50 = 4.49 ± 0.23, 0.95 ± 0.05, 1.8 ± 0.1, and 2.74 ± 0.52 µg/mL, respectively. To find out which of the secondary metabolites are responsible for this activity, the metabolic profile of TEEDL was investigated. It detected 29 compounds. Finally, a network pharmacology analysis was conducted to find out the annotated genes identified by the major identified flavonoidal compounds. The results identified 145 genes annotated by the 10 major flavonoidal compounds. AKR1B1and CA7 were highly represented genes. Four-gene disease networks were constructed; (gene-breast cancers), (gene-liver cancers), and (gene-colon cancers), and (gene-prostate cancers). KEGG pathway analysis showed the top biological pathways related to all genes were nitrogen metabolism pathway, the VEGF signaling pathway, and EGFR tyrosine kinase inhibitor resistance.

Synthesis and its characterisation of selenium/silver/chitosan and cellular toxicity against liver carcinoma cells studies

Liver cancer is one of the most common lethal malignancy in the world. To treat liver cancer, new cure options are crucial. The use of natural substances along nanosciences may provide healing with lower toxicity and a smaller amount of side properties. In this research, The three-component selenium-silver-chitosan nanocomposite (Se-Ag-CS NCs) were synthesised with the help of ultrasound in a stepwise manner. The as-synthesised Se-Ag-CS NCs were characterised accordingly by applying powder X-Ray diffraction (PXRD), Fourier transforms infrared spectroscopy (FTIR), field emission scanning electron microscopy (FESEM), energy dispersive x-ray analysis (EDX), transmission electron microscopy (TEM), dynamic light scattering (DLS) and potential. The PXRD demonstrated that the NCs were synthesised successfully and the grain sizes of 27.3 were obtained. The FESEM and TEM analyses have shown the NCs have a nano-sized structure with spherical and rod-like morphologies in a coating of CS. The DLS analysis also revealed that NCs were synthesised in nanoscale particles. The NCs’ surface charge was also positive due to the presence of chitosan. Different concentrations of NCs (0, 0.125, 0.250, 0.500, and 1 mg/ml) were tested at different times (24, 48, and 72 h) to measure cytotoxicity against liver cancer cells. The results showed at a concentration of 1 mg/mL in 72 h, the most toxicity effects were applied to liver cancer cells. Moreover, the results indicated NCs can inhibit the growth of cancer cells in a dose-dependent manner, while the toxicity of nanocomposite on normal cells was less. It is important to create nanocomposites derived from natural polymers as a new strategy in cancer treatment that can fight cancer cells while having low toxicity for normal cells. Therefore, the present results can be considered in improving cancer-fighting methods.

Synthesis, Biological Evaluation, and Molecular Docking of Novel Azolylhydrazonothiazoles as Potential Anticancer Agents.

A novel set of thiazolylhydrazonothiazoles bearing an indole moiety were synthesized by subjection reactions of carbothioamide derivative and hydrazonoyl chlorides (or α-haloketones). The cytotoxicity of the synthesized compounds was evaluated against the colon carcinoma cell line (HCT-116), liver carcinoma cell line (HepG2), and breast carcinoma cell line (MDA-MB-231), and demonstrated encouraging activity. Furthermore, when representative products were assessed for toxicity against normal cells, minimal toxic effects were observed, indicating their potential safety for use in pharmacological studies. The mechanism of action of the tested products, as inhibitors of the epidermal growth factor receptor tyrosine kinase domain (EGFR TK) protein, was suggested through docking studies that assessed their binding scores and modes, in comparison to a reference standard (W19), thus endorsing their anticancer activity.

Genomic Analysis in the Categorization of Poorly Differentiated Primary Liver Carcinomas.

A subset of primary liver carcinomas (PLCs) cannot be classified as hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma (iCCA) based on morphology and immunohistochemistry (IHC). This includes tumors with morphology suggestive of HCC but lacking hepatocellular marker expression, tumors with ambiguous morphology characterized by co-expression of hepatocellular and cholangiocytic markers, and undifferentiated pleomorphic carcinomas with no discernible line of differentiation on morphology or IHC. This study examines the role of genomic analysis in the categorization of these tumors. Genomic analysis was performed on 16 PLCs that could not be definitely classified as HCC or iCCA based on morphology and IHC using a capture-based next-generation sequencing assay (n=15) or single gene mutational analysis (n=1). Genomic alterations in TERT promoter were seen in 9/16 cases (56%) and strongly favored HCC. Genomic alterations favoring iCCA were seen in 5/16 cases (31%) and included mutations in IDH1 , PBRM1 , BAP1 , and ERBB2 , as well as FGFR2 fusion. Genomic changes were helpful in classifying 14/16 (87%) PLCs. Though not specific, these genomic alterations can provide valuable diagnostic clues in selected morphologically and immunohistochemically unclassifiable cases. Given the important differences in management between HCC and iCCA, routine use of genomic analysis in diagnostically challenging settings should be considered.

Irreversible electroporation of hepatocellular carcinoma and colorectal cancer liver metastases: A nationwide multicenter study with short- and long-term follow-up

IntroductionA nationwide multicenter study was performed to examine short- and long-term effects of irreversible electroporation (IRE) for hepatocellular carcinoma (HCC) and colorectal cancer liver metastases (CRCLM). IRE is an alternative method when thermal ablation is contraindicated because of risk for serious thermal complications. MethodsAll consecutive patients in Sweden treated with IRE because of HCC or CRCLM, were included between 2011 and 2018. We evaluated medical records and radiological imaging to obtain information regarding patient-, tumor-, and treatment characteristics. We also assessed local tumor progression, and survival. ResultsIn total 206 tumors in 149 patients were treated with IRE. Eighty-seven patients (58.4%) had colorectal cancer liver metastases, and 62 patients (41.6%) had hepatocellular carcinoma. Median tumor size was 20 mm (i.q.r. 14–26 mm). Median overall survival for CRCLM and HCC, were 27.0 months (95% CI 22.2–31.8 months), and 35.0 months (95% CI 13.8–56.2 months), respectively. Median follow-up time was 58 months (95% CI 50.6–65.4). Local ablation success at six and twelve months for HCC was 58.3% and 40.3%, and for CRCLM 37.7% and 25.4%. The median time to local tumor progression (LTP) for HCC was 21.0 months (95% CI: 9.5–32.5 months), and for CRCLM 6.0 months (95% CI: 4.5–7.5 months). At 30-day follow-up, 15.4% (n = 23) of patients suffered from a complication rated as Clavien-Dindo grade 1-3a. Three patients (2.0%) had grade 3b-5 with one death in a thromboembolic event. ConclusionIRE is a safe ablation modality for patients with liver tumors that are located in such a way that other treatment options are unsuitable.