Search Results (293)

Positron emission tomography (PET) imaging targeting glypican-3 (GPC3) holds promise for improving the detection and characterization of hepatocellular carcinoma (HCC). Preclinical and early clinical studies have largely utilized high-molecular-weight antibodies radiolabeled with isotopes such as ⁸⁹Zr and ¹²⁴I, demonstrating high affinity and tumor uptake but suffering from prolonged circulation times and suboptimal signal-to-background ratios. To address these limitations, interest has shifted toward low-molecular-weight vectors—synthetic peptides and small antibody fragments—labeled with shorter-lived radionuclides (e.g., ⁶⁸Ga and ¹⁸F) to enable rapid pharmacokinetics and same-day imaging protocols. Emerging platforms such as affibodies and aptamers offer further advantages in target affinity and reduced immunogenicity. However, clinical translation requires rigorous validation: larger, histologically confirmed cohorts, head-to-head comparison with CT/MRI, and correlation with hard clinical endpoints. Moreover, leveraging GPC3 expression as a biomarker could guarantee a deeper knowledge of tumor biology—differentiation grade and vascular invasion risk—and guide theranostic strategies. While β-emitters (⁹⁰Y, ¹⁷⁷Lu) have been explored for GPC3-directed therapy, their efficacy is influenced by oxygenation and cell-cycle status, whereas α-emitters (²²⁵Ac) may overcome these constraints, albeit with challenges in radionuclide selection and daughter nuclide management. Finally, dual-targeting probes combining GPC3 and prostate-specific membrane antigen (PSMA) have demonstrated superior uptake and retention in murine models, suggesting a versatile approach for future clinical diagnostics and therapy planning. Full article

Background/Objectives: Reprogramming of the cellular metabolism is a hallmark of cancer, offering therapeutic opportunities to target cancer cell vulnerabilities for therapeutic purposes. 3-Bromopyruvate (3BP) is a small alkylating agent that functions as an anti-metabolite, targeting key substrates in cancer metabolism and demonstrating antitumor activity across multiple cancer types. However, unformulated 3BP is associated with significant toxicity. This study investigates the efficacy of KAT/3BP, a clinical derivative of 3BP currently in phase 1 trials for hepatocellular carcinoma, in preclinical lymphoma models. Results: In vitro, KAT/3BP exhibited cytotoxic activity across 12 lymphoma cell lines—including diffuse large B-cell lymphoma and mantle cell lymphoma—with a median IC₅₀ of 3.7 μM. It also remained effective against lymphoma cell lines with acquired resistance to FDA-approved therapies. In vivo, treatment with KAT/3BP led to reduced tumor size in a syngeneic mouse model, with the combination of oral and intratumoral administration showing the greatest efficacy. Furthermore, KAT/3BP demonstrated synergistic activity when combined with standard lymphoma therapies such as bendamustine and R-CHOP. Conclusions: Our findings highlight the potential of KAT/3BP as a novel therapeutic option, either as a single agent or in combination regimens, for treating lymphomas. Full article

This research is designed to explore the effect of roasting on the release, bioaccessibility, and bioactivity of polyphenols in highland barley (HB). The findings of in vitro digestion indicated that roasting significantly improved the bioaccessibility of polyphenols in HB flour (gastrointestinal digestion stage: raw HB: 187.28%, roasted HB: 285.65%; colonic fermentation stage: raw HB: 188.13%, roasted HB: 255.36%) and enhanced its antioxidant activity. Moreover, the inhibitory impacts of polyphenols on the activities of α -amylase, α-glucosidase, and lipase mainly occur in the small intestine. Roasting increased inhibitory activities of polyphenols on α-amylase, α-glucosidase, and lipase in the small intestine (p < 0.05), with IC50 values of 71.31 ± 1.35 μg FAE/mL, 60.44 ± 1.35 μg FAE/mL, and 52.94 ± 2.51 μg FAE/mL, respectively. HepG2 cells, a human hepatocellular carcinoma cell line, are commonly employed in oxidative stress and antioxidant studies due to their ability to mirror the protective effects of bioactive compounds against oxidative damage in liver cells. This study aimed to establish a model of H₂O₂-induced oxidative stress injury in HepG2 cells and to evaluate the protective effect of digested HB polyphenol extract against oxidative injury. It was found that the polyphenols extracted from roasted HB help reduce reactive oxygen species (ROS) and malondialdehyde (MDA) through increased activities of superoxide dismutase (SOD), glutathione (GSH), catalase (CAT), glutathione peroxidase (GPx), and total antioxidant capacity (T-AOC), thereby providing enhanced defense against oxidative damage in HepG2 cells. The findings of this research pave the way for the development of new functional foods utilizing roasted HB. Full article

MTH1 (MutT Homolog 1) protein is one of the enzymes that protect cells from mutagenetic actions of reactive oxygen species. It sanitizes the pool of free nucleotides, making sure that oxidized dNTPs are not incorporated into the DNA. Any misfunction of it would lead to mutations. As such, it has attracted interest of cancer researchers, and multiple studies have been conducted over the years to determine its role in tumor cells. It has been found that MTH1 is not downregulated in most tumor tissues but, to the contrary, often overexpressed. This suggests that MTH1 is used by cancer as an adaptation to increased oxidative stress caused by metabolic reprogramming to support excessive proliferation. Based on this premise, many recent studies have evaluated MTH1 as either prognostic factor, general biomarker or therapeutic target in cancer. Here, we summarize all available research on MTH1 mRNA, protein and its enzymatic activity in clinical samples across various cancer types, identifying a subset of cancers where MTH1 plays an important role. This is particularly evident in cancers characterized by high metabolic activity and oxygen-rich environments, such as hepatocellular carcinoma, renal cell carcinoma, or non-small cell lung adenocarcinoma. Full article

The transforming growth factor-β (TGF-β) signaling pathway is involved in various cellular functions, including immunological response, extracellular matrix formation, differentiation, growth and development, and cell cycle regulation. The TGF β receptor type 1 (TGF-βR1) has emerged as a key component of this pathway, exhibiting significant overexpression in diverse malignancies, including hepatocellular carcinoma, gastric cancer, breast cancer, and colon cancer. Multiple therapeutic targets have been identified for the TGF-β signaling pathway, encompassing antibodies, ligand traps, vaccines, antisense oligonucleotides, and small-molecule TGF-βR1 kinase inhibitors. This review delineates the structural and functional characteristics of the small-molecule TGF-βR1 kinase inhibitors. The inhibitors discussed herein are categorized based on shared pharmacophoric features, notably a five-membered heterocyclic ring linked to three distinct features (R1, R2, and R3). These features interact with amino acids within the selectivity pocket, hinge region, or solvent-exposed area, respectively. These insights contribute to a clearer understanding of the structural requirements for selective TGF-βR1 inhibition. The presented findings in this review article offer a valuable foundation for future drug discovery efforts targeting the TGF-β signaling pathway. Full article

Background/Objectives: Upregulation of phosphoglycerate mutase 5 (PGAM5) is correlated with reduced survival outcomes in hepatocellular carcinoma (HCC). PGAM5 knockdown or knockout attenuates HCC growth in in vitro and in vivo models. A novel small molecule inhibitor of PGAM5, LFHP-1c, has recently been characterized. The objective of this study was to determine if LFHP-1c effectively reduces HCC viability in cell models. Methods: The hepatoma and HCC cell lines, HepG2 and HuH7, respectively, were treated with LFHP-1c. Label-free imaging was used to quantify growth. Cellular viability and reactive oxygen species (ROS) production were measured using luminescent or fluorescent assays. Expression of antioxidant and metabolic proteins was measured by immunoblot. HepG2 and HuH7 PGAM5 knockout cell lines were used as negative controls. Results: Treatment with LFHP-1c reduced cell growth and viability in HepG2 and HuH7 cell lines. Reactive oxygen species production was upregulated in both wild-type and PGAM5 knockout cell lines following LFHP-1c exposure. Cell viability was reduced following LFHP-1c treatment in PGAM5 knockout cell lines. Conclusions: LFHP-1c reduces hepatoma and HCC viability and enhances ROS production, but these effects are independent of PGAM5. Full article

Chronic liver diseases are marked by persistent inflammation and can evolve into liver fibrosis, cirrhosis, and hepatocellular carcinoma. In an affected liver, hepatic stellate cells (HSCs) transition from a quiescent to an activated state and adopt a myofibroblast-like cell phenotype. While these activated cells play a role in supporting liver regeneration, they can also have detrimental effects on liver function as the disease progresses to fibrosis and cirrhosis. These findings highlight the dynamic switching between different signaling pathways involving Ras, Rho GTPases, and Notch signaling. Notably, two specific members of the Ras and Rho GTPases, Eras and Rnd3, are predominantly expressed in quiescent HSCs, while Mras and Rhoc are more abundant in their activated forms. In addition, this study highlights the critical role of cytosolic Notch1 in quiescent HSCs and Rock in activated HSCs. We hypothesize that distinct yet interdependent intracellular signaling networks regulate HSC fate decisions in two key ways: by maintaining HSC quiescence and homeostasis and by facilitating HSC activation, thereby influencing processes such as proliferation, transdifferentiation, and mesenchymal transition. The proposed signaling model, combined with specific methodological tools for maintaining HSCs in a quiescent state, will deepen our understanding of the mechanisms underlying chronic liver disease and may also pave the way for innovative therapies. These therapies could include small molecule drugs targeting Ras- and Rho-dependent pathways. Full article

Resistance to tyrosine kinase inhibitors (TKIs, e.g., sorafenib and lenvatinib) presents a significant hurdle for hepatocellular carcinoma (HCC) treatment, underscoring the need to decipher the underlying mechanisms for improved therapeutic strategies. MicroRNAs (miRNAs) have emerged as critical modulators in HCC progression and TKI resistance. In this study, we report a positive correlation between the expression levels of a tumor suppressor miRNA, miR-142-3p, and increased sensitivity to sorafenib and lenvatinib, supported by clinical data from the BIOSTORM HCC cohort. Overexpression of miR-142-3p in TKI-resistant HCC cells significantly inhibited proliferation and colony formation, induced apoptosis, increased cell cycle arrest at the G2 phase, and reduced migration and invasion by reversing epithelial–mesenchymal transition. Notably, combining miR-142-3p with lenvatinib synergistically inhibited growth in both inherent and acquired TKI-resistant HCC cells by modulating critical signaling pathways, including STAT3, PI3K/AKT, MAPK, YAP1, and by impeding autophagic influx. RNA-sequencing of a TKI-resistant HCC cell line ± miR-142-3p overexpression identified YES1 and TWF1 as direct downstream target genes of miR-142-3p, both of which are key genes associated with drug resistance in HCC. Small interfering RNA (siRNA)-mediated knockdown of these genes mirrored the antitumor effects of miR-142-3p and enhanced TKI sensitivity, with YES1 knockdown decreasing YAP1 phosphorylation, and TWF1 knockdown inhibiting autophagy. Collectively, these findings indicate that restoring miR-142-3p expression or targeting its downstream effectors YES1 and TWF1 offers a promising strategy to overcome drug resistance and improve therapeutic outcome in HCC. Full article

The impact of the microbiota on radiation (RT)-induced toxicity and cancer response to radiotherapy is an emerging area of interest. In this review, we summarize the available preclinical and clinical evidence concerning microbiota modulation of RT toxicity and efficacy in the main gastrointestinal (GI) districts. A huge amount of data supports the clinical application of microbiota modulation, particularly through prebiotics and probiotics, to prevent or mitigate radiotherapy-induced toxicity in rectal cancer. Preclinical and clinical studies also support the observation of microbiota modulation to impact the toxicity and efficacy of treatment in esophageal cancer, hepatocellular carcinoma (HCC), and anal squamous cell carcinoma (ASCC). However, insufficient evidence remains to endorse microbiota modulation as a strategy to enhance tumor radiosensitivity in clinical practice. Well-designed studies focusing on prebiotics, probiotics, and fecal microbiota transplantation are needed across all GI sites to evaluate their potential to improve treatment efficacy, as suggested by promising preclinical findings. The impact of pre-treatment microbiota analyses should be addressed in prospective studies to verify the efficacy of patient-level tailored strategies. Additionally, the repurposing of radioprotective agents with innovative delivery systems, such as encapsulated amifostine, holds significant promise for mitigating small bowel toxicity, thereby enabling more effective RT treatment. Full article

Background/Objectives: Studies have indicated that forgoing lung shunt fraction measurement in select patients undergoing Yttrium 90 (Y90) transarterial radioembolization (TARE) may be safe without sacrificing efficacy. This study evaluated the safety and efficacy of a streamlined treatment in patients with small hepatocellular carcinoma (HCC) receiving resin-based TARE. Methods: Patients who received single-session Y90 TARE between September 2023 and May 2024 were retrospectively evaluated. Treatment response was evaluated at the 3-month follow-up using the modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria. Adverse events (AEs) ≥ Grade 3 were recorded post-procedurally at 3 months. The time from the interventional radiology clinic visit to the procedure date was compared to patients receiving the conventional TARE treatment. Results: Ten consecutive patients were treated with 12 treatments. Each treatment targeted an isolated lesion with median size of 2.5 cm (IQR: 2.1, 2.9). Two patients received two treatments (one for treatment of a separate lesion and the other for the initial incomplete targeting of the tumor). The median delivered tumor dose was 377.7 Gy (IQR: 246.5, 570.1). No patients developed ≥ Grade 3 AEs post-TARE. Complete response was achieved in 11/12 patients (92%). The conventional cohort consisted of 60 patients, all OPTN T2 treated with radiation segmentectomy with glass microspheres. Patients undergoing SSMT had a median time from clinic visit to treatment of 26.5 days (IQR: 15.3, 39) vs. 61 days (IQR: 48, 88.8) in the conventional TARE group (p < 0.001). Conclusions: Streamlined single-session resin-based Y90-TARE in patients with OPTN T2 stage HCC is feasible, efficacious, safe, and associated with reduced time to treatment. Full article

Hepatocellular carcinoma (HCC) is a lethal malignancy associated with drug resistance, resulting in a poor prognosis. High mobility group box 1 (HMGB1) is a chromatin-binding protein that regulates HCC progression. The overexpression of HMGB1 has been found to promote tumorigenesis and drug resistance. In this study, we aimed to investigate the role of HMGB1 expression in tumorigenesis and metastasis and its impact on sorafenib and oxaliplatin resistance. Tissue samples from patients with HCC (n = 48) were subjected to immunohistochemistry. The expression of HMGB1 was correlated with clinical pathology parameters. Moreover, the HCC cell line HuH-7 was used to study the regulatory effect of HMGB1 on cell proliferation, cell adhesion, migration, and invasion by using the siRNA (small interfering RNA) silencing method. Furthermore, drug challenges were performed to determine the effect of HMGB1 on the sensitivity to chemotherapeutic drugs (sorafenib and oxaliplatin). HMGB1 was significantly overexpressed in tumor tissues, highlighted by the expression increment in patients with M1 advanced metastasis tumors with immunoreactivity scores 2.61 and 6.50 for adjacent and tumor tissues, respectively (p-values = 0.0035). The involved mechanisms were then described through the suppression of HCC cell adhesion, migration, and invasion by HMGB1 silencing. Notably, the inhibition of HMGB1 expression promoted sorafenib/oxaliplatin sensitivity in the HCC cell line by increasing the cell toxicity by about 13–18%. Our study demonstrated that HMGB1 shows potential as a promising biomarker and a target for HCC treatment that is involved in tumorigenesis, metastasis, and chemo-drug resistance. Full article

Background: Liver cancer, specifically hepatocellular carcinoma (LIHC), ranks as the second most common cause of cancer-related fatalities globally. Moreover, the occurrence rate of LIHC is steadily increasing. A recently identified gene, SPSB2, has been implicated in cell signaling, impacting the development and progression of non-small cell lung cancer. Nevertheless, studies on the role of SPSB2 in the pathogenesis of LIHC are lacking. Methods: Using the TCGA, GTEx, and GEO databases, we obtained differentially expressed genes that affect the prognosis of patients with LIHC. We utilized the Kruskal–Wallis test, along with univariate and multivariate COX regression analyses, to determine the correlation between SPSB2 and patient clinical indicators. Potential biological functions of SPSB2 in LIHC were explored by enrichment analysis, ssGSEA, and Spearman correlation analysis. Finally, LIHC cell lines Huh7 and SMMC-7721 were used to validate the biological function of SPSB2. Results: The results showed LIHC patients with higher SPSB2 expression had a poorer prognosis, and SPSB2 expression was significantly correlated with LIHC patients’ Histologic grade, Pathologic T stage, Prothrombin time, Pathologic stage, BMI, weight, adjacent hepatic tissue inflammation, AFP level, and OS event (p < 0.05). SPSB2 shows notable enrichment in pathways linked to tumorigenesis and the immune system. Moreover, its expression is strongly connected to immune cells and immune checkpoints. Knockdown of SPSB2 expression in Huh7 cells and SMMC-7721 cells inhibits SPSB2’s biological functions, including proliferation, invasion, metastasis, and other phenotypes. Conclusions: SPSB2 plays a crucial role in the development of LIHC. It is related to the immune response and unfavorable outcomes. SPSB2 may function as a clinical biomarker for prognosis. Full article

Liver transplantation (LT) is the standard of care for both end-stage liver failure and hepatocellular carcinoma (HCC). Side effects of the main used immunosuppressive drugs have a noteworthy impact on the long-term outcome of LT recipients. Consequently, to achieve a balance between optimal immunosuppression and minimal side effects is a cornerstone of the post-LT period. Today, there are no validated markers for overimmunosuppression and underimmunosuppression, only a few drugs have therapeutic drug monitoring, and immunosuppression regimens vary from center to center and from country to country. Currently, there are many drugs with different efficacy and safety profiles. Using different agents permits a decrease in the dosage and minimizes the toxicities. A small subset of recipients achieves immunotolerance with the chance to stop immunosuppressive therapy. This article focuses on the side effects of immunosuppressive drugs, which significantly impact long-term outcomes for LT recipients. The primary aim is to highlight the balance between achieving effective immunosuppression and minimizing adverse effects, emphasizing the role of personalized therapeutic strategies. Moreover, this review evaluates the mechanisms of action and specific complications associated with immunosuppressive agents. Finally, special attention is given to strategies for reducing immunosuppressive burdens, improving patient quality of life, and identifying immunotolerant individuals. Full article

Objective: Liver cirrhosis (LC) progression induces intestinal microbiota abnormalities, such as small intestinal bacterial overgrowth (SIBO), and these changes lead to the inflow of gut pathogens and their degradation products into the vessels, causing cirrhotic complications such as hepatic encephalopathy (HE). Methods: To clarify the relationship between the development of overt HE and SIBO, we conducted a three-year observation after assessment of SIBO in patients with LC. Results: In the analysis of 107 patients, with a mean follow-up duration of 29.4 months, 31 were diagnosed with SIBO and 30 with covert HE. In the Cox multivariate regression analysis for prognosis, the Child–Pugh score, blood urea nitrogen level, and the Union for International Cancer Control (UICC) stage of hepatocellular carcinoma were derived using the following five factors: white blood cell count, blood urea nitrogen level, Child–Pugh score, UICC stage, and serum aspartate aminotransferase and alkaline phosphatase levels (p = 0.002, hazard ratio [HR] 3.733, 95% confidence interval [CI] 1.592–8.754, p = 0.001, HR 1.076, 95% CI 1.030–1.123, and p < 0.001, HR 2.767, 95% CI 1.780–4.302, respectively). Furthermore, in the Cox multivariate regression analysis for overt HE development, covert HE and methane-producing SIBO were derived using the following four factors: methane-producing SIBO, UICC stage, covert HE, and serum ammonia levels (p = 0.038, HR 5.008, 95% CI 1.096–22.892 and p = 0.006, HR 8.597, 95% CI 1.881–39.291, respectively). Conclusions: M-SIBO positivity was a significant predictor of overt HE. Full article

Canopy FGF signaling regulator 2 (CNPY2) has emerged as a crucial player in cancer development by promoting cell proliferation, tissue repair, and angiogenesis. This review synthesizes the current understanding of CNPY2’s role in solid tumors, particularly renal cell carcinoma, prostate cancer, hepatocellular carcinoma, and non-small-cell lung cancer. CNPY2 modulates key pathways such as p53, MYLIP, NF-κB, and AKT/GSK3β, thereby driving tumor growth and progression. In renal cell carcinoma, CNPY2 paradoxically promotes tumor growth through p53 upregulation, while in hepatocellular carcinoma, CNPY2 drives cell cycle progression via p53 destabilization. In prostate cancer, it enhances tumor progression by stabilizing androgen receptors through MYLIP interaction, and in non-small-cell lung cancer, it contributes to chemoresistance and metastasis through NF-κB and AKT/GSK3β signaling. Additionally, CNPY2 influences the tumor microenvironment, impacting immune function and metastatic potential. As a potential biomarker, CNPY2 shows promise for cancer detection and prognosis, particularly when used in combination with other markers. Early therapeutic strategies, including siRNA and miRNA approaches, are under exploration, though challenges remain due to CNPY2’s expression in normal tissues and potential off-target effects. This review underscores the need for further research to fully elucidate CNPY2’s oncogenic mechanisms and develop targeted therapies. Improved understanding of CNPY2’s diverse roles may lead to novel diagnostic and therapeutic approaches in solid tumors. Full article