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Frontiers in Immunology 2024Resection of colorectal liver metastasis is the standard of care for patients with Stage IV CRC. Despite undoubtedly improving the overall survival of patients, pHx for...
BACKGROUND
Resection of colorectal liver metastasis is the standard of care for patients with Stage IV CRC. Despite undoubtedly improving the overall survival of patients, pHx for colorectal liver metastasis frequently leads to disease recurrence. The contribution of this procedure to metastatic colorectal cancer at a molecular level is poorly understood. We designed a mouse model of orthograde metastatic colorectal cancer (CRC) to investigate the effect of partial hepatectomy (pHx) on tumor progression.
METHODS
CRC organoids were implanted into the cecal walls of wild type mice, and animals were screened for liver metastasis. At the time of metastasis, 1/3 partial hepatectomy was performed and the tumor burden was assessed longitudinally using MRI. After euthanasia, different tissues were analyzed for immunological and transcriptional changes using FACS, qPCR, RNA sequencing, and immunohistochemistry.
RESULTS
Mice that underwent pHx presented significant liver hypertrophy and an increased overall metastatic load compared with SHAM operated mice in MRI. Elevation in the metastatic volume was defined by an increase in liver metastasis without any effect on the growth of each metastasis. Concordantly, the livers of pHx mice were characterized by neutrophil and bacterial infiltration, inflammatory response, extracellular remodeling, and an increased abundance of tight junctions, resulting in the formation of a premetastatic niche, thus facilitating metastatic seeding.
CONCLUSIONS
Regenerative pathways following pHx accelerate colorectal metastasis to the liver by priming a premetastatic niche.
Topics: Animals; Colorectal Neoplasms; Hepatectomy; Mice; Liver Neoplasms; Liver; Tumor Microenvironment; Disease Models, Animal; Humans; Mice, Inbred C57BL; Inflammation; Male
PubMed: 38919609
DOI: 10.3389/fimmu.2024.1388272 -
Iranian Journal of Public Health Mar 2024Gastrointestinal cancers can cause major health problems globally since their burden is increasing in many countries. We aimed to investigate the trend of years of life...
BACKGROUND
Gastrointestinal cancers can cause major health problems globally since their burden is increasing in many countries. We aimed to investigate the trend of years of life lost due to gastrointestinal cancers in Fars Province, southern Iran during the 2004-2019.
METHODS
In this cross-sectional survey study, we obtained the information regarding all deaths due to gastrointestinal cancers in Fars Province from the electronic population-based death registration system (EDRS). Years of Life Lost (YLL) was calculated using the YLL template of 2015 by the WHO. To examine the trend for different years, join point regression based on the log-linear model was used. Joinpoint regression analysis describes changing trends over successive periods of time and the increasing or decreasing rate within each period.
RESULTS
During the years of 2004-2019, 9742 deaths due to gastrointestinal cancers occurred in Fars Province. 6013 (61.72%) cases were male and 3729 (38.28%) cases were female (Male / Female Sex Ratio: 1.61). Overall, 4152 cases (42.63%) were due to gastric cancer and 2112 cases (21.68%) were due to liver cancer. Total years of life lost due to premature death from gastrointestinal cancers during the 16-year study period was 73565 yr (2.33 per 1000 persons) in men, 52766 yr (1.71 per 1000 persons) in women, and 126331 yr (2.02 per 1000 persons) in both sexes.
CONCLUSION
Among all cancers, the highest mortality rates in both sexes belong to gastric cancer. This study showed the trend of YLL rate of malignant neoplasms of liver and intrahepatic bile ducts, esophagus, oral cavity, and colon cancer were increasing in both sexes, however, the trend of YLL rate for malignant neoplasms of the small intestine was decreasing in both sexes. Variation of GI cancers patterns and trends around the Fars Province indicated that a more comprehensive control plan is needed to control these variations.
PubMed: 38919300
DOI: 10.18502/ijph.v53i3.15149 -
Journal of Translational Medicine Jun 2024Sorafenib resistance is becoming increasingly common and disadvantageous for hepatocellular carcinoma (HCC) treatment. Ferroptosis is an iron dependent programmed cell...
BACKGROUND
Sorafenib resistance is becoming increasingly common and disadvantageous for hepatocellular carcinoma (HCC) treatment. Ferroptosis is an iron dependent programmed cell death underlying the mechanism of sorafenib. Iron is crucial for synthesis of cofactors essential to mitochondrial enzymes and necessary for HCC proliferation, while mitochondrial iron overload and oxidative stress are associated with sorafenib induced ferroptosis. However, the crosstalk among iron homeostasis and sorafenib resistance is unclear.
METHODS
We conducted bioinformatics analysis of sorafenib treated HCC datasets to analyze GCN5L1 and iron related gene expression with sorafenib resistance. GCN5L1 deleted HCC cell lines were generated by CRISPR technology. Sorafenib resistant HCC cell line was established to validate dataset analysis and evaluate the effect of potential target.
RESULTS
We identified GCN5L1, a regulator of mitochondrial acetylation, as a modulator in sorafenib-induced ferroptosis via affecting mitochondrial iron homeostasis. GCN5L1 deficiency significantly increased sorafenib sensitivity in HCC cells by down-regulating mitochondrial iron transporters CISD1 expression to induce iron accumulation. Mitochondrial iron accumulation leads to an acceleration in cellular and lipid ROS. Sorafenib resistance is related to CISD1 overexpression to release mitochondrial iron and maintaining mitochondrial homeostasis. We combined CISD1 inhibitor NL-1 with sorafenib, which significantly enhanced sorafenib-induced ferroptosis by promoting mitochondrial iron accumulation and lipid peroxidation. The combination of NL-1 with sorafenib enhanced sorafenib efficacy in vitro and in vivo.
CONCLUSIONS
Our findings demonstrate that GCN5L1/CISD1 axis is crucial for sorafenib resistance and would be a potential therapeutic strategy for sorafenib resistant HCC.
Topics: Sorafenib; Carcinoma, Hepatocellular; Liver Neoplasms; Iron; Humans; Homeostasis; Mitochondria; Cell Line, Tumor; Animals; Ferroptosis; Drug Resistance, Neoplasm; Mice, Nude; Reactive Oxygen Species; Mice; Gene Expression Regulation, Neoplastic
PubMed: 38918793
DOI: 10.1186/s12967-024-05404-3 -
BMC Cancer Jun 2024Clinically significant portal hypertension (CSPH) seriously affects the feasibility and safety of surgical treatment for hepatocellular carcinoma (HCC) patients. The aim...
OBJECTIVE
Clinically significant portal hypertension (CSPH) seriously affects the feasibility and safety of surgical treatment for hepatocellular carcinoma (HCC) patients. The aim of this study was to establish a new surgical scheme defining risk classification of post-hepatectomy liver failure (PHLF) to facilitate the surgical decision-making and identify suitable candidates for individual hepatectomy among HCC patients with CSPH.
BACKGROUNDS
Hepatectomy is the preferred treatment for HCC. Surgeons must maintain a balance between the expected oncological outcomes of HCC removal and short-term risks of severe PHLF and morbidity. CSPH aggravates liver decompensation and increases the risk of severe PHLF thus complicating hepatectomy for HCC.
METHODS
Multivariate logistic regression and stochastic forest algorithm were performed, then the independent risk factors of severe PHLF were included in a nomogram to determine the risk of severe PHLF. Further, a conditional inference tree (CTREE) through recursive partitioning analysis validated supplement the misdiagnostic threshold of the nomogram.
RESULTS
This study included 924 patients, of whom 137 patients (14.8%) suffered from mild-CSPH and 66 patients suffered from (7.1%) with severe-CSPH confirmed preoperatively. Our data showed that preoperative prolonged prothrombin time, total bilirubin, indocyanine green retention rate at 15 min, CSPH grade, and standard future liver remnant volume were independent predictors of severe PHLF. By incorporating these factors, the nomogram achieved good prediction performance in assessing severe PHLF risk, and its concordance statistic was 0.891, 0.850 and 0.872 in the training cohort, internal validation cohort and external validation cohort, respectively, and good calibration curves were obtained. Moreover, the calculations of total points of diagnostic errors with 95% CI were concentrated in 110.5 (range 76.9-178.5). It showed a low risk of severe PHLF (2.3%), indicating hepatectomy is feasible when the points fall below 76.9, while the risk of severe PHLF is extremely high (93.8%) and hepatectomy should be rigorously restricted at scores over 178.5. Patients with points within the misdiagnosis threshold were further examined using CTREE according to a hierarchic order of factors represented by the presence of CSPH grade, ICG-R15, and sFLR.
CONCLUSION
This new surgical scheme established in our study is practical to stratify risk classification in assessing severe PHLF, thereby facilitating surgical decision-making and identifying suitable candidates for individual hepatectomy.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Hepatectomy; Male; Female; Middle Aged; Hypertension, Portal; Nomograms; Aged; Risk Factors; Postoperative Complications; Liver Failure; Retrospective Studies; Adult
PubMed: 38918786
DOI: 10.1186/s12885-024-12535-9 -
Asian Pacific Journal of Cancer... Jun 2024Standard tools are not sensitive enough for hepatocellular carcinoma (HCC) early detection. This study aimed to evaluate the accuracy of dickkopf-1 (DKK1) and soluble...
BACKGROUND
Standard tools are not sensitive enough for hepatocellular carcinoma (HCC) early detection. This study aimed to evaluate the accuracy of dickkopf-1 (DKK1) and soluble Axl (sAxl) and their combined for early differentiating of HCC from premalignant benign liver diseases.
METHODS
A total of 210 chronic hepatitis C (CHC) patients (55 fibrotic, 45 cirrhotic and 110 HCC) were enrolled. Both DKK1 and sAxl were tested using ELISA for all participants.
RESULTS
HCC patients were accompanied by a significant increase (P<0.05) in DKK1 (5.38±2.05 ng/mL) and sAxl (178.02±49.39 ng/mL) compared to patients with fibrosis (2.16±0.6, 97.63±19.71 ng/mL, respectively) and cirrhosis (2.62±0.8, 121.84±34.66 ng/mL, respectively). Both DKK1 (AUC=0.852) and sAxl (AUC=0.882) had a good diagnostic accuracy in separating HCC from all non-HCC patients. Multiplying DKK1 with sAXL yielded values that significantly (P=0.0001) increased in patients who developed HCC (674.3 (434.2-1413.9)) versus fibrotic (204.9 (161.7-262)) and cirrhotic (254.4 (205.4-343.7)) patients. This model improves HCC diagnostic performances [AUC=0.921; sensitivity 90.9%, specificity 87%, PPV 88.5%, NPV 89.7% and efficiency 89.1%]. Elevated DKK1×sAxl values were associated with aggressive tumor features including multiple nodules, large size, Child-Pugh and BCLC late stages.
CONCLUSIONS
combined use of DKK1×sAxl is simple and feasible HCC diagnostic model that could enhance HCC diagnostic accuracy and could replace AFP in follow up of patients with premalignant diseases.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Intercellular Signaling Peptides and Proteins; Male; Axl Receptor Tyrosine Kinase; Female; Middle Aged; Receptor Protein-Tyrosine Kinases; Biomarkers, Tumor; Proto-Oncogene Proteins; Hepatitis C, Chronic; Prognosis; Liver Cirrhosis; Follow-Up Studies; Adult; Hepacivirus; Early Detection of Cancer; Aged
PubMed: 38918682
DOI: 10.31557/APJCP.2024.25.6.2185 -
Asian Pacific Journal of Cancer... Jun 2024The aim of this study was to evaluate the expression profiles of PIWI-like protein- 2 (PIWIL2), and HepPar1 and their immunohistochemical (IHC) characteristics in...
OBJECTIVE
The aim of this study was to evaluate the expression profiles of PIWI-like protein- 2 (PIWIL2), and HepPar1 and their immunohistochemical (IHC) characteristics in Hepatocellular Carcinoma (HCC), and determine their correlation with clinicopathological parameters of this type of cancer to determine their diagnostic value in combination.
METHODS
Seventy-five patients with HCC were assessed for the expression of PIWIL2 in serum and tissue using real-time polymerase chain reaction (RT-PCR) and IHC was performed for PIWIL2 and HepPar1 was performed on all patients.
RESULTS
A statistically significantly higher level of PIWIL2 was found in HCC compared to controls (p≤0.001). Both HepPar1 and PIWIL2 were detected in 84% of HCC cases, the diagnostic and prognostic factors for PIWIL2 were found to be significant in liver tumour tissue samples and non-tumorous sections p<0.001, and the same was observed for serum samples and results of healthy serum controls (p<0.001) when compared to AFP.
CONCLUSION
Our results affirm the hypothesis that reactivation of PIWI expression in various caner types is crucial for cancer development, and that a possible panel maybe used for these markers HCC diagnosis.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Argonaute Proteins; Biomarkers, Tumor; Male; Female; Middle Aged; Prognosis; Case-Control Studies; Follow-Up Studies; Adult; alpha-Fetoproteins; Aged
PubMed: 38918675
DOI: 10.31557/APJCP.2024.25.6.2123 -
Endoscopy Dec 2024
Topics: Humans; Liver Transplantation; Endoscopic Ultrasound-Guided Fine Needle Aspiration; Male; Mediastinal Neoplasms; Endosonography; Mediastinum; Female; Image-Guided Biopsy
PubMed: 38917969
DOI: 10.1055/a-2336-3197 -
Human Genomics Jun 2024To investigate the association between liver enzymes and ovarian cancer (OC), and to validate their potential as biomarkers and their mechanisms in OC. Methods...
Elucidating the role of liver enzymes as markers and regulators in ovarian cancer: a synergistic approach using Mendelian randomization, single-cell analysis, and clinical evidence.
OBJECTIVE
To investigate the association between liver enzymes and ovarian cancer (OC), and to validate their potential as biomarkers and their mechanisms in OC. Methods Genome-wide association studies for OC and levels of enzymes such as Alkaline phosphatase (ALP), Aspartate aminotransferase (AST), Alanine aminotransferase, and gamma-glutamyltransferase were analyzed. Univariate and multivariate Mendelian randomization (MR), complemented by the Steiger test, identified enzymes with a potential causal relationship to OC. Single-cell transcriptomics from the GSE130000 dataset pinpointed pivotal cellular clusters, enabling further examination of enzyme-encoding gene expression. Transcription factors (TFs) governing these genes were predicted to construct TF-mRNA networks. Additionally, liver enzyme levels were retrospectively analyzed in healthy individuals and OC patients, alongside the evaluation of correlations with cancer antigen 125 (CA125) and Human Epididymis Protein 4 (HE4).
RESULTS
A total of 283 single nucleotide polymorphisms (SNPs) and 209 SNPs related to ALP and AST, respectively. Using the inverse-variance weighted method, univariate MR (UVMR) analysis revealed that ALP (P = 0.050, OR = 0.938) and AST (P = 0.017, OR = 0.906) were inversely associated with OC risk, suggesting their roles as protective factors. Multivariate MR (MVMR) confirmed the causal effect of ALP (P = 0.005, OR = 0.938) on OC without reverse causality. Key cellular clusters including T cells, ovarian cells, endothelial cells, macrophages, cancer-associated fibroblasts (CAFs), and epithelial cells were identified, with epithelial cells showing high expression of genes encoding AST and ALP. Notably, TFs such as TCE4 were implicated in the regulation of GOT2 and ALPL genes. OC patient samples exhibited decreased ALP levels in both blood and tumor tissues, with a negative correlation between ALP and CA125 levels observed.
CONCLUSION
This study has established a causal link between AST and ALP with OC, identifying them as protective factors. The increased expression of the genes encoding these enzymes in epithelial cells provides a theoretical basis for developing novel disease markers and targeted therapies for OC.
Topics: Humans; Female; Ovarian Neoplasms; Polymorphism, Single Nucleotide; Mendelian Randomization Analysis; Single-Cell Analysis; Genome-Wide Association Study; Alkaline Phosphatase; Biomarkers, Tumor; WAP Four-Disulfide Core Domain Protein 2; Aspartate Aminotransferases; Liver; Alanine Transaminase; gamma-Glutamyltransferase; CA-125 Antigen; Gene Expression Regulation, Neoplastic; Transcription Factors; Membrane Proteins; Middle Aged
PubMed: 38915066
DOI: 10.1186/s40246-024-00642-4 -
BMC Medicine Jun 2024To assess the largely undetermined separate and joint effects of sleep and liver function biomarkers on liver cancer.
BACKGROUND
To assess the largely undetermined separate and joint effects of sleep and liver function biomarkers on liver cancer.
METHODS
Data of 356,894 participants without cancer at baseline in the UK Biobank were analyzed. Sleep score was evaluated using five sleep traits (sleep duration, chronotype, insomnia, snoring, and excessive daytime sleepiness) and dichotomized into healthy or unhealthy sleep. Circulating liver function biomarkers were measured. Cox proportional hazard model was performed to investigate the independent and joint associations of sleep and liver function biomarkers with liver cancer incidence.
RESULTS
After a median follow-up time of 13.1 years, 394 cases of incident liver cancer were documented. The multivariable-adjusted hazard ratio (HR) for liver cancer was 1.46 (95% confidence interval: 1.15-1.85) associated with unhealthy sleep (vs. healthy sleep), and was 1.17 (1.15-1.20), 1.20 (1.18-1.22), 1.69 (1.47-1.93), 1.06 (1.06-1.07), 1.08 (1.07-1.09), 1.81 (1.37-2.39), or 0.29 (0.18-0.46) associated with each 10-unit increase in alanine transaminase (ALT), aspartate transaminase (AST), total bilirubin (TBIL), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), total protein (TP), or albumin (ALB), respectively. Individuals with unhealthy sleep and high (≥ median) ALT, AST, TBIL, GGT, ALP, or TP or low (< median) ALB level had the highest HR of 3.65 (2.43-5.48), 4.03 (2.69-6.03), 1.97 (1.40-2.77), 4.69 (2.98-7.37), 2.51 (1.75-3.59), 2.09 (1.51-2.89), or 2.22 (1.55-3.17) for liver cancer, respectively. Significant additive interaction of unhealthy sleep with high TP level on liver cancer was observed with relative excess risk due to an interaction of 0.80 (0.19-1.41).
CONCLUSIONS
Unhealthy sleep was associated with an increased risk of liver cancer, especially in participants with lower ALB levels or higher levels of ALT, AST, TBIL, GGT, ALP, or particularly TP.
Topics: Humans; Male; Female; Middle Aged; Liver Neoplasms; Prospective Studies; Sleep; Biomarkers; Aged; United Kingdom; Adult; Incidence; Liver Function Tests; Risk Factors; Liver
PubMed: 38915009
DOI: 10.1186/s12916-024-03440-w -
BMC Gastroenterology Jun 2024Hepatocellular carcinoma (HCC) represents a significant global health challenge with high incidence and mortality rates. T cells and natural killer (NK) cells are...
BACKGROUND
Hepatocellular carcinoma (HCC) represents a significant global health challenge with high incidence and mortality rates. T cells and natural killer (NK) cells are pivotal in this context, yet HCC can evade immune surveillance. CD161 (KLRB1), a C-type lectin receptor, modulates immune responses and is expressed on NK cells and a subset of T cells. Its relevance in HCC remains poorly understood, with conflicting findings regarding its impact on patient prognosis.
METHODS
Utilizing TCGA data and single-cell analysis, we investigated the biological functions of KLRB1 in HCC. Peripheral blood samples from 126 HCC patients were collected to assess KLRB1 expression on NK and T cells. The diagnostic performance of KLRB1 on NK and CD8 + T cells was evaluated using receiver operating characteristic curve (ROC) analysis, while its prognostic significance was assessed using Kaplan-Meier analysis and COX regression models.
RESULTS
Analysis of TCGA data revealed a significant correlation between KLRB1 expression and immune activation, particularly T cell activation. Single-cell data further demonstrated elevated KLRB1 expression in tissue-resident NK and T cells within HCC, which co-expressed markers of immune activation. Clinical data showed downregulated KLRB1 expression on NK and T cells in HCC patients compared to health individuals, with lower expression levels correlating with poorer prognosis.
CONCLUSION
KLRB1 emerges as a promising biomarker in HCC, with its downregulation on peripheral blood NK and T cells suggesting potential prognostic value. Further elucidation of KLRB1's role in HCC may pave the way for the development of targeted immunotherapies and the improvement of patient outcomes.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Killer Cells, Natural; Prognosis; Male; Female; Middle Aged; Biomarkers, Tumor; NK Cell Lectin-Like Receptor Subfamily B; CD8-Positive T-Lymphocytes; Kaplan-Meier Estimate; Aged; Single-Cell Analysis; ROC Curve; Lymphocyte Activation; Down-Regulation
PubMed: 38914941
DOI: 10.1186/s12876-024-03299-4