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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 -
International Journal of Biological... 2024Tumor-associated macrophages (TAMs) represent a predominant cellular component within the tumor microenvironment (TME) of pancreatic neuroendocrine neoplasms (pNENs)....
Hypoxic tumor-derived exosomal miR-4488 induces macrophage M2 polarization to promote liver metastasis of pancreatic neuroendocrine neoplasm through RTN3/FABP5 mediated fatty acid oxidation.
Tumor-associated macrophages (TAMs) represent a predominant cellular component within the tumor microenvironment (TME) of pancreatic neuroendocrine neoplasms (pNENs). There is a growing body of evidence highlighting the critical role of exosomes in facilitating communication between tumor cells and TAMs, thereby contributing to the establishment of the premetastatic niche. Nonetheless, the specific mechanisms through which exosomes derived from tumor cells influence macrophage polarization under hypoxic conditions in pNENs, and the manner in which these interactions support cancer metastasis, remain largely unexplored. Recognizing the capacity of exosomes to transfer miRNAs that can modify cellular behaviors, our research identified a significant overexpression of miR-4488 in exosomes derived from hypoxic pNEN cells. Furthermore, we observed that macrophages that absorbed circulating exosomal miR-4488 underwent M2-like polarization. Our investigations revealed that miR-4488 promotes M2-like polarization by directly targeting and suppressing RTN3 in macrophages. This suppression of RTN3 enhances fatty acid oxidation and activates the PI3K/AKT/mTOR signaling pathway through the interaction and downregulation of FABP5. Additionally, M2 polarized macrophages contribute to the formation of the premetastatic niche and advance pNENs metastasis by releasing MMP2, thereby establishing a positive feedback loop involving miR-4488, RTN3, FABP5, and MMP2 in pNEN cells. Together, these findings shed light on the role of exosomal miRNAs from hypoxic pNEN cells in mediating interactions between pNEN cells and intrahepatic macrophages, suggesting that miR-4488 holds potential as a valuable biomarker and therapeutic target for pNENs.
Topics: MicroRNAs; Pancreatic Neoplasms; Exosomes; Humans; Animals; Mice; Neuroendocrine Tumors; Macrophages; Liver Neoplasms; Cell Line, Tumor; Fatty Acids; Oxidation-Reduction; Tumor Microenvironment; Fatty Acid-Binding Proteins; Nerve Tissue Proteins; Mice, Nude; Signal Transduction
PubMed: 38904015
DOI: 10.7150/ijbs.96831 -
International Journal of Medical... 2024PtdIns (3,4,5) P3-dependent Rac exchanger 1 (PREX1), also known as PREX1, a member of the Rac guanine nucleotide exchange factors (Rac-GEF) family. Studies have...
PtdIns (3,4,5) P3-dependent Rac exchanger 1 (PREX1), also known as PREX1, a member of the Rac guanine nucleotide exchange factors (Rac-GEF) family. Studies have suggested that PREX1 plays a role in mediating oncogenic pathway activation and controlling various biological mechanisms in different types of cancer, including liver hepatocellular carcinoma (LIHC). However, the function of PREX1 in the pathogenesis of LIHC and its potential role on immunological regulation is not clearly elucidated. The expression level and the clinical role of PREX1 in LIHC was analyzed based on database from the Cancer Genome Atlas (TCGA), TNM plotter and University of Alabama Cancer Database (UALCAN). We investigated the relationship between PREX1 and immunity in LIHC by TISIDB, CIBERSORT and single cell analysis. Immunotherapy responses were assessed by the immunophenoscores (IPS). Moreover, biological functional assays were performed to further investigate the roles of PREX1 in liver cancer cell lines. Higher expression of PREX1 in LIHC tissues than in normal liver tissues was found based on public datasets. Further analysis revealed that PREX1 was associated with worse clinical characteristics and dismal prognosis. Pathway enrichment analysis indicated that PREX1 participated in immune-related pathways. Through CIBERSORT and single cell analysis, we found a remarkable correlation between the expression of PREX1 and various immune cells, especially macrophages. In addition, high PREX1 expression was found to be associated with a stronger response to immunotherapy. Furthermore, assays indicated that depletion of PREX1 can suppress invasion and proliferation of LIHC cells. Elevated expression of PREX1 indicates poor prognosis, influences immune modulation and predicts sensitivity of immunosuppression therapy in LIHC. Our results suggested that PREX1 may be a prognostic biomarker and therapeutic target, offering new treatment options for LIHC.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Prognosis; Biomarkers, Tumor; Gene Expression Regulation, Neoplastic; Single-Cell Analysis; Gene Expression Profiling; Cell Line, Tumor; Guanine Nucleotide Exchange Factors; Male; Transcriptome; Phospholipid Transfer Proteins; Tumor Microenvironment; Female
PubMed: 38903921
DOI: 10.7150/ijms.94812 -
Trials Jun 2024Disease recurrence remains one of the biggest concerns in patients after resection of pancreatic ductal adenocarcinoma (PDAC). Despite (neo)adjuvant systemic therapy,...
Recurrent disease detection after resection of pancreatic ductal adenocarcinoma using a recurrence-focused surveillance strategy (RADAR-PANC): protocol of an international randomized controlled trial according to the Trials within Cohorts design.
BACKGROUND
Disease recurrence remains one of the biggest concerns in patients after resection of pancreatic ductal adenocarcinoma (PDAC). Despite (neo)adjuvant systemic therapy, most patients experience local and/or distant PDAC recurrence within 2 years. High-level evidence regarding the benefits of recurrence-focused surveillance after PDAC resection is missing, and the impact of early detection and treatment of recurrence on survival and quality of life is unknown. In most European countries, recurrence-focused follow-up after surgery for PDAC is currently lacking. Consequently, guidelines regarding postoperative surveillance are based on expert opinion and other low-level evidence. The recent emergence of more potent local and systemic treatment options for PDAC recurrence has increased interest in early diagnosis. To determine whether early detection and treatment of recurrence can lead to improved survival and quality of life, we designed an international randomized trial.
METHODS
This randomized controlled trial is nested within an existing prospective cohort in pancreatic cancer centers in the Netherlands (Dutch Pancreatic Cancer Project; PACAP) and the United Kingdom (UK) (Pancreas Cancer: Observations of Practice and survival; PACOPS) according to the "Trials within Cohorts" (TwiCs) design. All PACAP/PACOPS participants with a macroscopically radical resection (R0-R1) of histologically confirmed PDAC, who provided informed consent for TwiCs and participation in quality of life questionnaires, are included. Participants randomized to the intervention arm are offered recurrence-focused surveillance, existing of clinical evaluation, serum cancer antigen (CA) 19-9 testing, and contrast-enhanced computed tomography (CT) of chest and abdomen every three months during the first 2 years after surgery. Participants in the control arm of the study will undergo non-standardized clinical follow-up, generally consisting of clinical follow-up with imaging and serum tumor marker testing only in case of onset of symptoms, according to local practice in the participating hospital. The primary endpoint is overall survival. Secondary endpoints include quality of life, patterns of recurrence, compliance to and costs of recurrence-focused follow-up, and the impact on recurrence-focused treatment.
DISCUSSION
The RADAR-PANC trial will be the first randomized controlled trial to generate high level evidence for the current clinical equipoise regarding the value of recurrence-focused postoperative surveillance with serial tumor marker testing and routine imaging in patients after PDAC resection. The Trials within Cohort design allows us to study the acceptability of recurrence-focused surveillance among cohort participants and increases the generalizability of findings to the general population. While it is strongly encouraged to offer all trial participants treatment at time of recurrence diagnosis, type and timing of treatment will be determined through shared decision-making. This might reduce the potential survival benefits of recurrence-focused surveillance, although insights into the impact on patients' quality of life will be obtained.
TRIAL REGISTRATION
Clinicaltrials.gov, NCT04875325 . Registered on May 6, 2021.
Topics: Humans; Carcinoma, Pancreatic Ductal; Pancreatic Neoplasms; Neoplasm Recurrence, Local; Randomized Controlled Trials as Topic; Pancreatectomy; Time Factors; Quality of Life; Prospective Studies; Multicenter Studies as Topic; Treatment Outcome; Predictive Value of Tests; Netherlands; United Kingdom; Research Design; Early Detection of Cancer
PubMed: 38902836
DOI: 10.1186/s13063-024-08223-5 -
European Journal of Medical Research Jun 2024As a hepatotropic virus, hepatitis B virus (HBV) can establish a persistent chronic infection in the liver, termed, chronic hepatitis B (CHB), which causes a series of... (Review)
Review
As a hepatotropic virus, hepatitis B virus (HBV) can establish a persistent chronic infection in the liver, termed, chronic hepatitis B (CHB), which causes a series of liver-related complications, including fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). HCC with HBV infection has a significantly increased morbidity and mortality, whereas it could be preventable. The current goal of antiviral therapy for HBV infection is to decrease CHB-related morbidity and mortality, and achieve sustained suppression of virus replication, which is known as a functional or immunological cure. The natural history of chronic HBV infection includes four immune phases: the immune-tolerant phase, immune-active phase, inactive phase, and reactivation phase. However, many CHB patients do not fit into any of these defined phases and are regarded as indeterminate. A large proportion of indeterminate patients are only treated with dynamic monitoring rather than recommended antiviral therapy, mainly due to the lack of definite guidelines. However, many of these patients may gradually have significant liver histopathological changes during disease progression. Recent studies have focused on the prevalence, progression, and carcinogenicity of indeterminate CHB, and more attention has been given to the prevention, detection, and treatment for these patients. Herein, we discuss the latest understanding of the epidemiology, clinical characteristics, and therapeutic strategies of indeterminate CHB, to provide avenues for the management of these patients.
Topics: Humans; Hepatitis B, Chronic; Antiviral Agents; Hepatitis B virus; Liver Neoplasms; Carcinoma, Hepatocellular; Liver Cirrhosis; Disease Progression
PubMed: 38902822
DOI: 10.1186/s40001-024-01942-0 -
BMC Public Health Jun 2024Although the risk of CVD is increased in cancer survivors, few studies have investigated the CVD risk in survivors of gastrointestinal (GI) cancer. Therefore, we...
INTRODUCTION
Although the risk of CVD is increased in cancer survivors, few studies have investigated the CVD risk in survivors of gastrointestinal (GI) cancer. Therefore, we evaluated the CVD risk using the 10-year atherosclerotic cardiovascular disease (ASCVD) risk score for GI cancer survivors and associated physical activity factors.
METHODS
Using the 2014-2019 Korean National Health and Nutrition Examination Surveys, data were collected for 262 GI cancer survivors and 1,310 cancer-free controls matched at a 1:5 ratio based on age and sex. The International Physical Activity Questionnaire Short-Form was used to assess physical activity, and the Euro QoL Questionnaire 5-Dimensional Classification (EQ-5D) was used to assess the health-related quality of life.
RESULTS
A multiple logistic regression analysis demonstrated a lower risk of ASCVD in GI cancer survivors than in controls (adjusted odds ratio [aOR] = 0.73, 95% confidence interval [CI] = 0.55-0.97). Moreover, the risk of having a high ASCVD score was significantly lower in individuals who performed sufficient aerobic physical activity (aOR = 0.59, 95% CI = 0.47-0.75) and those with an EQ-5D score 1 or 2 (aOR = 0.36, 95% CI = 0.20-0.65 and aOR = 0.31, 95% CI = 0.16-0.58, respectively).
CONCLUSIONS
This population-based study demonstrated that engaging in sufficient physical activity can reduce the ASCVD risk among GI cancer survivors.
Topics: Humans; Male; Female; Cancer Survivors; Middle Aged; Gastrointestinal Neoplasms; Exercise; Republic of Korea; Cardiovascular Diseases; Nutrition Surveys; Aged; Adult; Quality of Life; Risk Factors; Case-Control Studies; Risk Assessment
PubMed: 38902653
DOI: 10.1186/s12889-024-19097-2 -
Scientific Reports Jun 2024This study aimed to investigate impacts of Omicron infection on cancer patients in China. A retrospective study was conducted, including 347 cancer patients undergoing...
Completion rates and myelosuppression degrees of cancer patients receiving radiotherapy or chemoradiotherapy unchanged regardless of delay duration after Omicron infection.
This study aimed to investigate impacts of Omicron infection on cancer patients in China. A retrospective study was conducted, including 347 cancer patients undergoing radiotherapy or chemoradiotherapy between July 2022 and March 2023. Three groups involved: 108 patients without SARS-CoV-2 infection (non-COVID-19 group), 102 patients beginning treatment 10 days after first SARS-CoV-2 infection (≥ 10 days COVID-19 group), and 137 patients beginning treatment less than 10 days after first SARS-CoV-2 infection (< 10 days COVID-19 group). SAA, hsCRP, ALT, etc., were used to assess COVID-19 infection. Serum levels of SAA, hsCRP and IL-6 were all raised in two COVID-19-infected groups (SAA < 0.01, hsCRP < 0.01, IL-6 < 0.05), but PCT, ALT, LDH and HBDH levels were only elevated in ≥ 10 days COVID-19 group (PCT = 0.0478, ALT = 0.0022, LDH = 0.0313, HBDH = 0.0077). Moreover, moderate and severe infected cases were higher in ≥ 10 days COVID-19 group than < 10 days COVID-19 group (12/102 vs 5/137, p = 0.0211), but no significance in myelosuppression and completion rates among three groups. Omicron infection led to inflammation, liver and cardiovascular injury on cancer patients, but delay duration of radiotherapy or chemoradiotherapy after infection did not affect the completion rates and myelosuppression of current therapy. Besides, severity of Omicron infection was even worse among cancer patients who received delayed treatment.
Topics: Humans; COVID-19; Female; Male; Middle Aged; Neoplasms; Chemoradiotherapy; Retrospective Studies; Aged; SARS-CoV-2; Adult; China
PubMed: 38902401
DOI: 10.1038/s41598-024-65019-y -
World Journal of Gastroenterology Jun 2024At present, liver transplantation (LT) is one of the best treatments for hepatocellular carcinoma (HCC). Accurately predicting the survival status after LT can...
BACKGROUND
At present, liver transplantation (LT) is one of the best treatments for hepatocellular carcinoma (HCC). Accurately predicting the survival status after LT can significantly improve the survival rate after LT, and ensure the best way to make rational use of liver organs.
AIM
To develop a model for predicting prognosis after LT in patients with HCC.
METHODS
Clinical data and follow-up information of 160 patients with HCC who underwent LT were collected and evaluated. The expression levels of alpha-fetoprotein (AFP), des-gamma-carboxy prothrombin, Golgi protein 73, cytokeratin-18 epitopes M30 and M65 were measured using a fully automated chemiluminescence analyzer. The best cutoff value of biomarkers was determined using the Youden index. Cox regression analysis was used to identify the independent risk factors. A forest model was constructed using the random forest method. We evaluated the accuracy of the nomogram using the area under the curve, using the calibration curve to assess consistency. A decision curve analysis (DCA) was used to evaluate the clinical utility of the nomograms.
RESULTS
The total tumor diameter (TTD), vascular invasion (VI), AFP, and cytokeratin-18 epitopes M30 (CK18-M30) were identified as important risk factors for outcome after LT. The nomogram had a higher predictive accuracy than the Milan, University of California, San Francisco, and Hangzhou criteria. The calibration curve analyses indicated a good fit. The survival and recurrence-free survival (RFS) of high-risk groups were significantly lower than those of low- and middle-risk groups ( < 0.001). The DCA shows that the model has better clinical practicability.
CONCLUSION
The study developed a predictive nomogram based on TTD, VI, AFP, and CK18-M30 that could accurately predict overall survival and RFS after LT. It can screen for patients with better postoperative prognosis, and improve long-term survival for LT patients.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Nomograms; Male; Liver Transplantation; Middle Aged; Female; Risk Factors; alpha-Fetoproteins; Biomarkers, Tumor; Prognosis; Adult; Retrospective Studies; Aged; Treatment Outcome; Keratin-18; Decision Support Techniques
PubMed: 38899335
DOI: 10.3748/wjg.v30.i21.2763 -
Journal of Nanobiotechnology Jun 2024Tumor-associated macrophages (TAMs) are a promising target for cancer immunotherapy, but delivering therapeutic agents to TAMs within the tumor microenvironment (TME) is...
Tumor-associated macrophages (TAMs) are a promising target for cancer immunotherapy, but delivering therapeutic agents to TAMs within the tumor microenvironment (TME) is challenging. In this study, a photosensitive, dual-targeting nanoparticle system (M.RGD@Cr-CTS-siYTHDF1 NPs) was developed. The structure includes a shell of DSPE-modified RGD peptides targeting integrin receptors on tumor cells and carboxymethyl mannose targeting CD206 receptors on macrophages, with a core of chitosan adsorbing m6A reading protein YTHDF1 siRNA and chromium nanoparticles (Cr NPs). The approach is specifically designed to target TAM and cancer cells, utilizing the photothermal effect of Cr NPs to disrupt the TME and deliver siYTHDF1 to TAM. In experiments with tumor-bearing mice, M.RGD@Cr-CTS-siYTHDF1 NPs, when exposed to laser irradiation, effectively killed tumor cells, disrupted the TME, delivered siYTHDF1 to TAMs, silenced the YTHDF1 gene, and shifted the STAT3-STAT1 equilibrium by reducing STAT3 and enhancing STAT1 expression. This reprogramming of TAMs towards an anti-tumor phenotype led to a pro-immunogenic TME state. The strategy also suppressed immunosuppressive IL-10 production, increased expression of immunostimulatory factors (IL-12 and IFN-γ), boosted CD8 + T cell infiltration and M1-type TAMs, and reduced Tregs and M2-type TAMs within the TME. In conclusion, the dual-targeting M.RGD@Cr-CTS-siYTHDF1 NPs, integrating dual-targeting capabilities with photothermal therapy (PTT) and RNA interference, offer a promising approach for molecular targeted cancer immunotherapy with potential for clinical application.
Topics: Animals; Mice; Immunotherapy; RNA, Small Interfering; Humans; Liver Neoplasms; Cell Line, Tumor; Tumor Microenvironment; Tumor-Associated Macrophages; RNA-Binding Proteins; Nanoparticles; Metal Nanoparticles; Photosensitizing Agents
PubMed: 38898486
DOI: 10.1186/s12951-024-02612-3 -
International Journal of... 2024Hepatocellular carcinoma (HCC) is the most common and fatal primary liver cancer. Genetic variants of DNA repair systems can reduce DNA repair capability and increase...
Hepatocellular carcinoma (HCC) is the most common and fatal primary liver cancer. Genetic variants of DNA repair systems can reduce DNA repair capability and increase HCC risk. This study aimed to examine, in Egyptian hepatitis C virus (HCV) patients, the relationship between the X-ray repair cross-complementing group 1 (XRCC1) rs1799782 single nucleotide polymorphism (SNP) and HCC susceptibility. We included 100 adult HCV-positive patients with HCC and 100 adult HCV-positive patients with liver cirrhosis as pathological controls. XRCC1 rs1799782 SNP genotyping was done in both groups using quantitative real-time PCR (qPCR). The distribution of genotypes in patients and controls was compared using several inheritance models. We found that the CT genotype, when analyzed under both the co-dominant (OR (95 % CI): 2.147 (1.184-3.893), = .012) and the over-dominant (OR (95 % CI): 2.055 (1.153-3.660), = .015) models, as well as the combined CT and TT genotypes under the dominant model (OR (95 % CI) of 1.991 (1.133-3.497), = .017), were associated with increased susceptibility to HCC. The frequency of the T allele was higher among HCC participants (32%) compared to those with cirrhosis (23.5%) and carrying the T allele increased the risk of HCC by 1.532 times, however, these associations did not reach statistical significance (-values >0.05). Moreover, the variant T allele was associated with worse clinical manifestations and laboratory results among the HCC group, but AFP levels were not affected significantly. Egyptians with XRCC1 rs1799782 SNP may have a higher risk of HCV-related HCC. More extensive multi-center prospective investigations must confirm this association.
Topics: Humans; Carcinoma, Hepatocellular; X-ray Repair Cross Complementing Protein 1; Liver Neoplasms; Male; Case-Control Studies; Egypt; Female; Polymorphism, Single Nucleotide; Genetic Predisposition to Disease; Middle Aged; Pilot Projects; Adult; Hepatitis C; Risk Factors; Genotype
PubMed: 38898405
DOI: 10.1177/03946320241265263