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Clinical and Experimental Medicine Jun 2024Ferroptosis and cuproptosis are recently discovered forms of cell death that have gained interest as potential cancer treatments, particularly for hepatocellular...
Ferroptosis and cuproptosis are recently discovered forms of cell death that have gained interest as potential cancer treatments, particularly for hepatocellular carcinoma. Long non-coding RNAs (lncRNAs) influence cancer cell activity by interacting with various nucleic acids and proteins. However, the role of ferroptosis and cuproptosis-related lncRNAs (FCRLs) in cancer remains underexplored. Ferroptosis and cuproptosis scores for each sample were assessed using Gene Set Variation Analysis (GSVA). Weighted correlation network analysis identified the FCRLs most relevant to our study. A risk model based on FCRLs was developed to categorize patients into high-risk and low-risk groups. We then compared overall survival (OS), tumor immune microenvironment, and clinical characteristics between these groups. The IPS score and ImmuCellAI webpage were used to predict the association between FCRL-related signatures and immunotherapy response. Finally, we validated the accuracy of FCRLs in hepatocellular carcinoma cell lines using induction agents (elesclomol and erastin). Patients in different risk subgroups showed significant differences in OS, immune cell infiltration, pathway activity, and clinical characteristics. Cellular assays revealed significant changes in the expression of AC019080.5, AC145207.5, MIR210HG, and LINC01063 in HCC cell lines following the addition of ferroptosis and cuproptosis inducers. We created a signature of four FCRLs that accurately predicted survival in HCC patients, laid the foundation for basic research related to ferroptosis and cuproptosis in hepatocellular carcinoma, and provided therapeutic recommendations for HCC patients.
Topics: Humans; Carcinoma, Hepatocellular; Ferroptosis; Liver Neoplasms; RNA, Long Noncoding; Prognosis; Gene Expression Regulation, Neoplastic; Cell Line, Tumor; Tumor Microenvironment; Male; Female; Biomarkers, Tumor; Middle Aged
PubMed: 38907744
DOI: 10.1007/s10238-024-01397-x -
Diagnostic Pathology Jun 2024Catenin (Cadherin-Associated Protein), Beta 1 (CTNNB1) genomic alterations are rare in prostate cancer (PCa). Gain-of-function mutations lead to overexpression of...
BACKGROUND
Catenin (Cadherin-Associated Protein), Beta 1 (CTNNB1) genomic alterations are rare in prostate cancer (PCa). Gain-of-function mutations lead to overexpression of β-catenin, with consequent hyperactivation of the Wnt/β-catenin signaling pathway, implicated in PCa progression and treatment resistance. To date, successful targeted treatment options for Wnt/β-catenin - driven PCa are lacking.
METHODS
We report a rare histologic transformation of a CTNNB1 (β-catenin) mutated metastatic castration resistant prostate cancer (mCRPC), clinically characterized by highly aggressive disease course. We histologically and molecularly characterized the liver metastatic tumor samples, as well as successfully generated patient-derived organoids (PDOs) and patient-derived xenograft (PDX) from a liver metastasis. We used the generated cell models for further molecular characterization and drug response assays.
RESULTS
Immunohistochemistry of liver metastatic biopsies and PDX tumor showed lack of expression of typical PCa (e.g., AR, PSA, PSAP, ERG) or neuroendocrine markers (synaptophysin), compatible with double-negative CRPC, but was positive for nuclear β-catenin expression, keratin 7 and 34βE12. ERG rearrangement was confirmed by fluorescent in situ hybridization (FISH). Drug response assays confirmed, in line with the clinical disease course, lack of sensitivity to common drugs used in mCRPC (e.g., enzalutamide, docetaxel). The casein kinase 1 (CK1) inhibitor IC261 and the tankyrase 1/2 inhibitor G700-LK showed modest activity. Moreover, despite harbouring a CTNNB1 mutation, PDOs were largely insensitive to SMARCA2/4- targeting PROTAC degraders and inhibitor.
CONCLUSIONS
The reported CTNNB1-mutated mCRPC case highlights the potential challenges of double-negative CRPC diagnosis and underlines the relevance of further translational research to enable successful targeted treatment of rare molecular subtypes of mCRPC.
Topics: Humans; Male; beta Catenin; Mutation; Prostatic Neoplasms, Castration-Resistant; Liver Neoplasms; Animals; Biomarkers, Tumor; Aged; Disease Progression
PubMed: 38907236
DOI: 10.1186/s13000-024-01511-3 -
Scientific Reports Jun 2024Our aim was to explore whether programmed death receptor-1 (PD-1) inhibitors would improve the prognosis of unresectable hepatocellular carcinoma (HCC) treated with...
Our aim was to explore whether programmed death receptor-1 (PD-1) inhibitors would improve the prognosis of unresectable hepatocellular carcinoma (HCC) treated with transarterial chemoembolization (TACE) plus lenvatinib. In this single-center retrospective study, patients with unresectable HCC who underwent TACE and were administered lenvatinib with or without PD-1 inhibitors were enrolled and divided into the TACE + lenvatinib group and TACE + lenvatinib + PD-1 group. Overall survival (OS), progression-free survival (PFS) and tumor response were assessed by the Response Evaluation Criteria in Solid Tumors (RECIST v1.1 and mRECIST). Treatment-related adverse events (AEs) were evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE, version 5.0). In total, 35 eligible patients with unresectable HCC were included; 82.9% of patients had Hepatitis B virus (HBV) infection, and 88.6% of patients had liver cirrhosis. A total of 88.6% of patients had multiple tumors, and the median diameter of the largest tumor was 10.1 cm. A total of 14.3% of patients had extrahepatic metastasis, and 51.4% of patients had portal vein tumor thrombus. The percentages of BCLC stages A, B and C were 5.7%, 28.6% and 65.7%, respectively. There were 16 patients in the TACE + lenvatinib group and 19 patients in the TACE + lenvatinib + PD-1 group. The median follow-up time was 7.7 months (ranging from 1.7 to 31.6 months). Neither group reached the median overall survival. Under RECIST v1.1 criteria, the median PFS was 10.4 and 7.9 months in the TACE + lenvatinib and TACE + lenvatinib + PD-1 groups (HR, 1.13; 95% CI 0.45-2.84; p = 0.80), the objective response rates (ORR) were 31.3% and 31.6% (p > 0.05), and the disease control rates (DCR) were 93.8% and 78.9% (p > 0.05), respectively. Under mRECIST criteria, the median PFS was 10.4 and 10.1 months (HR, 0.98; 95% CI 0.38-2.54, p = 0.97), the ORR was 62.5% and 63.2% (p > 0.05), and the DCR was 93.8% and 73.7% (p > 0.05), respectively. Overall, AEs were relatively similar between the two groups. PD-1 inhibitors did not improve the PFS and tumor response of unresectable HCC treated with TACE plus lenvatinib. Hepatitis B infection, liver cirrhosis, portal vein tumor thrombus, multiple tumors and large tumor diameter may be potential factors that affect the efficacy of PD-1 inhibitors but need further validation.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Quinolines; Male; Female; Phenylurea Compounds; Retrospective Studies; Chemoembolization, Therapeutic; Middle Aged; Aged; Prognosis; Programmed Cell Death 1 Receptor; Immune Checkpoint Inhibitors; Adult
PubMed: 38906915
DOI: 10.1038/s41598-024-63571-1 -
Journal of Nuclear Medicine : Official... Jun 2024The benefit of multicompartment dosimetry in the radioembolization of neuroendocrine neoplasms is not firmly established. We retrospectively assessed its potential with...
The benefit of multicompartment dosimetry in the radioembolization of neuroendocrine neoplasms is not firmly established. We retrospectively assessed its potential with patient outcome. Forty-three patients were eligible. The association of mean absorbed dose (MAD) for tumors and treatment response was tested per lesion with a receiver operating characteristic curve analysis, and the association of MAD with progression-free survival (PFS) and overall survival was tested per patient using uni- and multivariate Cox regression analyses. The area under the curve for treatment response based on MAD was 0.79 (cutoff, 196.6 Gy; < 0.0001). For global PFS, grade (grade 2 vs. 1: hazard ratio [HR], 2.51; = 0.042; grade 3 vs. 1: HR, 62.44; < 0.001), tumor origin (HR, 6.58; < 0.001), and MAD (HR, 0.998; = 0.003) were significant. For overall survival, no prognostic parameters were significant. In line with prior publications, a MAD of more than 200 Gy seemed to favor treatment response. MAD was also associated with PFS and may be of interest for radioembolization planning for neuroendocrine neoplasm patients.
PubMed: 38906556
DOI: 10.2967/jnumed.124.267774 -
Cell Chemical Biology Jun 2024Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the biosynthesis of nicotinamide adenine dinucleotide (NAD), making it a potential target for cancer therapy....
Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the biosynthesis of nicotinamide adenine dinucleotide (NAD), making it a potential target for cancer therapy. Two challenges hinder its translation in the clinic: targeting the extracellular form of NAMPT (eNAMPT) remains insufficient, and side effects are observed in normal tissues. We previously utilized proteolysis-targeting chimera (PROTAC) to develop two compounds capable of simultaneously degrading iNAMPT and eNAMPT. Unfortunately, the pharmacokinetic properties were inadequate, and toxicities similar to those associated with traditional inhibitors arose. We have developed a next-generation PROTAC molecule 632005 to address these challenges, demonstrating exceptional target selectivity and bioavailability, improved in vivo exposure, extended half-life, and reduced clearance rate. When combined with nicotinic acid, 632005 exhibits safety and robust efficacy in treating NAPRT-deficient pan-cancers, including xenograft models with hematologic malignancy and prostate cancer and patient-derived xenograft (PDX) models with liver cancer. Our findings provide clinical references for patient selection and treatment strategies involving NAMPT-targeting PROTACs.
Topics: Nicotinamide Phosphoribosyltransferase; Humans; Animals; Niacin; Mice; Antineoplastic Agents; Male; Proteolysis; Cell Proliferation; Mice, Nude; Cytokines; Cell Line, Tumor; Female; Xenograft Model Antitumor Assays; Molecular Structure; Neoplasms
PubMed: 38906111
DOI: 10.1016/j.chembiol.2024.05.007 -
Noise & HealthThe effectiveness of family music therapy for patients with advanced palliative care hepatocellular carcinoma and their main caregivers was investigated.
OBJECTIVE
The effectiveness of family music therapy for patients with advanced palliative care hepatocellular carcinoma and their main caregivers was investigated.
METHODS
The clinical data of liver cancer patients and their main caregivers admitted to Wuwei City People's Hospital from August 2022 to April 2023 were retrospectively analysed. Patients were divided into observation group A and control group A according to whether they received family music therapy, and caregivers were divided into control group B and observation group B. The general demographic data, self-rating depression scale (SDS), self-rating anxiety scale (SAS), cancer-related fatigue scale (CFS), Pittsburgh sleep quality index (PSQI), anticipatory grief scale (AGS), and caregiver burden inventory (CBI) scores of the patients and their primary caregivers were collected. Propensity score matching (PSM) was used to balance the baseline data of the two groups. Then, data were analysed using t-test and chi-squared (χ2) test.
RESULTS
After 1:1 PSM, 45 samples were included in each group. Before management, no significant differences in SDS, SAS, AGS, CFS, PSQI and CBI scores were found among the groups (P > 0.05). After management, the SDS, SAS and CFS scores of observation group A were lower than those of control group A (P < 0.05). The AGS, PSQI and CBI scores of observation group B were lower than those of control group B (P < 0.05).
CONCLUSIONS
The effect of family music supplement therapy is ideal, which can relieve the negative emotions of patients, reduce the degree of cancer-related fatigue, enhance the sleep quality of the main caregivers and reduce anticipatory grief and the burden of care.
Topics: Humans; Music Therapy; Palliative Care; Male; Caregivers; Female; Retrospective Studies; Middle Aged; Liver Neoplasms; Aged; Adult; Carcinoma, Hepatocellular
PubMed: 38904811
DOI: 10.4103/nah.nah_17_24 -
Mikrochimica Acta Jun 2024Hepatocellular carcinoma (HCC) is the most common liver malignancy and is characterized by increasing incidence and high mortality rates. Current methods for the...
Hepatocellular carcinoma (HCC) is the most common liver malignancy and is characterized by increasing incidence and high mortality rates. Current methods for the screening and diagnosis of HCC exhibit inherent limitations, highlighting the ever-growing need for the development of new methods for the early diagnosis of HCC. The aim of this work was to develop a novel electrochemical aptasensor for the detection of HepG2 cells, a type of circulating tumor cells that can be used as biomarkers for the early detection of HCC. A carbon screen-printed electrode was functionalized with a composite suspension containing graphene oxide, chitosan, and polyaniline nanoparticles to increase the electrode surface and provide anchoring sites for the HepG2 cell-specific aptamer. The aptamer was immobilized on the surface of the functionalized electrode using multipulse amperometry, an innovative technique that significantly reduces the time required for aptamer immobilization. The innovative platform was successfully employed for the first time for the amplification-free detection of HepG2 cells in a linear range from 10 to 200,000 cells/mL, with a limit of detection of 10 cells/mL. The platform demonstrated high selectivity and stability and was successfully used for the detection of HepG2 cells in spiked human serum samples with excellent recoveries.
Topics: Humans; Hep G2 Cells; Aptamers, Nucleotide; Liver Neoplasms; Electrochemical Techniques; Carcinoma, Hepatocellular; Graphite; Biosensing Techniques; Limit of Detection; Aniline Compounds; Electrodes; Chitosan
PubMed: 38904692
DOI: 10.1007/s00604-024-06479-x -
Przeglad Epidemiologiczny Jun 2024Actinomycosis is a very rare, infectious disease, which is especially difficult to diagnose due to non-specific symptoms and the ability to emulate neoplasms or...
Actinomycosis is a very rare, infectious disease, which is especially difficult to diagnose due to non-specific symptoms and the ability to emulate neoplasms or inflammatory changes. Due to those facts, it is often misdiagnosed or diagnosed too late to be successfully treated. This article presents the case of 31-year-old Caucasian female with recurrent upper respiratory tract infections and tonsillitis as the potential risk factors of actinomycosis. Upon examination of material collected through the course of tonsillectomy, the patient was diagnosed with actinomycosis of the left palatine tonsil. Despite the introduction of antibiotic therapy, initial progression was noted with the appearance of numerous, hypodense changes in the liver and the spleen, which regressed during further antibiotic treatment. According to our team's knowledge, this is the first described case of a patient with actinomycosis occurring simultaneously in the cervico-facial and abdominal area. The unusual localization and potential dissemination of actinomycosis should be considered in clinical practice.
Topics: Humans; Female; Adult; Actinomycosis; Tonsillitis; Anti-Bacterial Agents; Actinomycosis, Cervicofacial; Abdomen
PubMed: 38904308
DOI: 10.32394/pe.77.50 -
International Journal of Biological... 2024Stable infiltration of myeloid cells, especially tumor-associated M2 macrophages, acts as one of the essential features of the tumor immune microenvironment by promoting...
Stable infiltration of myeloid cells, especially tumor-associated M2 macrophages, acts as one of the essential features of the tumor immune microenvironment by promoting the malignant progression of hepatocellular carcinoma (HCC). However, the factors affecting the infiltration of M2 macrophages are not fully understood. In this study, we found the molecular subtypes of HCC with the worst prognosis are characterized by immune disorders dominated by myeloid cell infiltration. Myeloid cell nuclear differentiation antigen (MNDA) was significantly elevated in the most aggressive subtype and exhibited a positively correlation with M2 infiltration and HCC metastasis. Moreover, MNDA functioned as an independent prognostic predictor and has a good synergistic effect with some existing prognostic clinical indicators. We further confirmed that MNDA was primarily expressed in tumor M2 macrophages and contributed to the enhancement of its polarization by upregulating the expression of the M2 polarization enhancers. Furthermore, MNDA could drive the secretion of M2 macrophage-derived pro-metastasis proteins to accelerate HCC cells metastasis both and . In summary, MNDA exerts a protumor role by promoting M2 macrophages polarization and HCC metastasis, and can serve as a potential biomarker and therapeutic target for HCC.
Topics: Carcinoma, Hepatocellular; Liver Neoplasms; Humans; Macrophages; Myeloid Cells; Animals; Cell Line, Tumor; Mice; Male; Tumor Microenvironment; Female; Neoplasm Metastasis
PubMed: 38904028
DOI: 10.7150/ijbs.91877 -
International Journal of Biological... 2024Hepatocellular carcinoma (HCC) is a deadly malignancy with limited treatment options. As a first-line treatment for advanced HCC, Lenvatinib has been applicated in...
Hepatocellular carcinoma (HCC) is a deadly malignancy with limited treatment options. As a first-line treatment for advanced HCC, Lenvatinib has been applicated in clinic since 2018. Resistance to Lenvatinib, however, has severely restricted the clinical benefits of this drug. Therefore, it is urgent to explore the potential resistance mechanisms of Lenvatinib and identify appropriate methods to reduce resistance for the treatment of HCC. We identified SAHA, a HDAC inhibitor, to have effective anti-tumor activity against Lenvatinib-resistant HCC organoids by screening a customized drug library. Mechanism analysis revealed that SAHA upregulates PTEN expression and suppresses AKT signaling, which contributes to reversing Lenvatinib resistance in liver cancer cells. Furthermore, combinational application of Lenvatinib and HDAC inhibitor or AKT inhibitor synergistically inhibits HCC cell proliferation and induces cell apoptosis. Finally, we confirmed the synergistic effects of Lenvatinib and SAHA, or AZD5363 in primary liver cancer patient derived organoids. Collectively, these findings may enable the development of Lenvatinib combination therapies for HCC.
Topics: Quinolines; Phenylurea Compounds; Humans; Carcinoma, Hepatocellular; Histone Deacetylase Inhibitors; Liver Neoplasms; Proto-Oncogene Proteins c-akt; Cell Line, Tumor; Apoptosis; Cell Proliferation; Animals; Vorinostat; Drug Synergism; Mice; Drug Resistance, Neoplasm
PubMed: 38904018
DOI: 10.7150/ijbs.93375