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Scientific Reports Jan 2021Retinoic acid and retinoid acid receptor (RA-RAR) signaling exhibits suppressive functions in the progression of hepatocellular carcinoma (HCC) through multiple...
Retinoic acid and retinoid acid receptor (RA-RAR) signaling exhibits suppressive functions in the progression of hepatocellular carcinoma (HCC) through multiple mechanisms. However, whether RA-RAR signaling induces autophagy that contributes its anti-tumor activity in HCC remains elusive. In the current study, the effects of RA-RAR pathway on autophagy were investigated in two HCC cell lines: alpha-fetoprotein (AFP) positive PLC/PRF/5 and AFP negative HLE cells. Cell autophagy was analyzed with western blot for detection of LC3 conversion and p62/SQSTM1 degradation while autophagy flux was assayed using the mRFP-GFP-LC3 reporter. Cell apoptosis and viability were analyzed by caspase-3 activity, TdT-mediated dUTP nick end labeling (TUNEL) assay, and Cell Counting Kit (CCK)-8, respectively. Chromatin immunoprecipitation (ChIP) was employed to detect the binding of RAR onto the promoter of autophagy-relevant 7 (ATG7), and co-immunoprecipitation (CoIP) was used to analyze the interaction of AFP and RAR. The results showed that ATRA dosage and time-dependently induced high levels of cell autophagy in both the PLC/PRF/5 and HLE cells, which was accompanied with up-regulation of ATG7. ChIP assay showed that RAR was able to bind to its responsive elements on ATG7 promoter. Impairment of ATG7 induction or blockade of autophagy with chloroquine aggravated ATRA induced apoptosis of HCC cells. Furthermore, intracellular AFP was able to complex with RAR in PLC/PRF/5 cells. Knockdown of AFP in PLC/PRF/5 cells augmented the up-regulation of ATG7 by ATRA while overexpression of AFP in HLE cells attenuated ATRA induced ATG7 expression and autophagy. Thus, ATRA induced ATG7 and autophagy participated in its cytotoxicity on HCC cells and AFP interfere with the induction of ATG7 and autophagy through forming complex with RAR.
Topics: Autophagy; Autophagy-Related Protein 7; Carcinoma, Hepatocellular; Cell Line, Tumor; Humans; Intracellular Space; Liver Neoplasms; Protein Binding; Receptors, Retinoic Acid; Signal Transduction; Transcription, Genetic; Tretinoin; alpha-Fetoproteins
PubMed: 33495541
DOI: 10.1038/s41598-021-81678-7 -
Frontiers in Immunology 2022Postpartum hemorrhage (PPH) is one of the leading causes of maternal mortality. Promptly recovering blood loss is critical for PPH. Intraoperative cell salvage (ICS) is... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Postpartum hemorrhage (PPH) is one of the leading causes of maternal mortality. Promptly recovering blood loss is critical for PPH. Intraoperative cell salvage (ICS) is a method to collect and process red blood cells (RBCs) from the blood lost during surgery and transfuse them to the patient's circulation during or immediately after surgery. Its effectiveness in reducing the demand for allogeneic blood transfusion has been proven, but its effectiveness and safety as a sole treatment for PPH during Cesarean sections are unclear. This is particularly important for patients who cannot or do not want to accept allogeneic blood transfusion.
MATERIALS AND METHODS
In this prospective randomized controlled study, patients with high risks of PPH were randomized into the ICS group or the control group, receiving ICS or allogeneic RBC transfusion if their hemoglobin level was less than 80 g/L during operation. Data collected include clinical examination, blood cell count, hemoglobin level, coagulation function, and plasma levels of fetal hemoglobin, tissue factor, and alpha-fetoprotein before and after fetal delivery and 0, 2, and 12 h after treatment. Adverse events were recorded.
RESULTS
A total of 130 patients were enrolled, aged 33 ± 1 years with a mean gestation period of 37 ± 1 week. The most common cause of Cesarean section was placenta previa, followed by twin pregnancy, scarred uterus, preeclampsia, placental abruption, fetal distress, and placenta accreta spectrum. Bleeding amount was similar between the two groups. The ICS group, compared to controls, had more efficient increases in levels of hemoglobin, RBC, and hematocrit (all p < 0.05). Coagulation function was maintained in the ICS group but reduced in controls 24 h after transfusion, indicated by significantly reduced fibrinogen level and prolonged prothrombin time (PT), thrombin time (TT), and activated partial thromboplastin time (aPTT) (all p < 0.05). There was a transient but significant decrease in plasma tissue factor and alpha-fetoprotein levels and an increase in plasma fetal hemoglobin level with ICS treatment in the postpartum period. No adverse event occurred with ICS intervention.
CONCLUSION
ICS is an effective and safe intervention for patients with a high risk of PPH during elective or emergency Cesarean section. It can effectively clear tissue factors and alpha-fetoprotein but not fetal hemoglobin.
Topics: Humans; Female; Pregnancy; Postpartum Hemorrhage; alpha-Fetoproteins; Cesarean Section; Prospective Studies; Thromboplastin; Placenta; Hemoglobins; Fibrinogen
PubMed: 36300123
DOI: 10.3389/fimmu.2022.953334 -
Taiwanese Journal of Obstetrics &... Nov 2023To evaluate the correlation of high levels [>2.0 multiples of median (MoM)] of amniotic fluid alpha-fetoprotein (AFAFP) in midtrimester with abnormal fetal outcome.
OBJECTIVE
To evaluate the correlation of high levels [>2.0 multiples of median (MoM)] of amniotic fluid alpha-fetoprotein (AFAFP) in midtrimester with abnormal fetal outcome.
MATERIALS AND METHODS
We retrospectively studied 6245 pregnant women with singleton pregnancy who had undergone amniocentesis between 15 and 27 weeks' gestation at Mackay Memorial Hospital between January 2014 and June 2020. Fifty-five cases had high AFAFP levels (>2.0 MoM). We investigated the abnormal fetal outcomes.
RESULTS
Among the fifty-five cases with high AFAFP levels (>2.0 MoM), thirty (54.5%) had fetal chromosomal abnormalities, major structural abnormalities, and/or adverse obstetric events. Eight cases (14.5%) had chromosomal abnormalities including trisomy 21 (3 cases), trisomy 18 (3 cases), mosaic trisomy 18 (1 cases), and mosaic ring 13 (1 case). Seventeen cases (30.9%) had major structural abnormalities including abdominal wall defect (6 cases) and central nervous system (5 cases), gastrointestinal tract (3 cases), cardiovascular (2 cases), and genitourinary tract (2 cases) abnormalities. Fifteen cases (27%) had adverse obstetric events, including preterm delivery (5 cases), intrauterine fetal demise (4 cases), small for gestational age (4 cases), preeclampsia (4 cases), gestational diabetes mellitus (2 cases), gestational hypertension (1 case), preterm prelabor rupture of membrane (1 case), prolonged labor (1 case), and preterm uterine contraction (1 case).
CONCLUSION
A high AFAFP level (>2.0 MoM) in midtrimester can be associated with abnormal fetal outcome, including chromosomal abnormalities, major structural abnormalities, and adverse obstetric events. Women with a prenatal diagnosis of high AFAFP levels (>2.0 MoM) should be alerted of the possibility of abnormal fetal outcomes, and further detailed genetic studies and serial sonographic examinations are recommended.
Topics: Infant, Newborn; Pregnancy; Female; Humans; Amniotic Fluid; alpha-Fetoproteins; Trisomy 18 Syndrome; Retrospective Studies; Chromosome Aberrations; Pregnancy Trimester, Second
PubMed: 38008506
DOI: 10.1016/j.tjog.2022.12.013 -
World Journal of Gastroenterology Jul 2021Diagnostic accuracy of various tumor markers and their combinations for hepatocellular carcinoma (HCC) was not fully investigated.
BACKGROUND
Diagnostic accuracy of various tumor markers and their combinations for hepatocellular carcinoma (HCC) was not fully investigated.
AIM
To evaluate the diagnostic accuracy of alpha-fetoprotein (AFP), the agglutinin-reactive fraction of AFP (AFP-L3), and protein induced by vitamin K absence or antagonist-II (PIVKA-II) and their combination for HCC diagnosis.
METHODS
Patients with newly detected liver mass or elevated serum AFP levels were considered eligible. Serum AFP level, AFP-L3 fraction, and PIVKA-II level were measured at the first visit.
RESULTS
In total, 622 patients were included; 355 patients (57.1%) had chronic liver disease, and 208 (33.4%) had liver cirrhosis. HCC was diagnosed in 160 patients (25.7%). The area under the receiver operating characteristics curves (AUROCs) of the serum AFP, AFP-L3 fraction, AFP-L3, and PIVKA-II levels for the diagnosis of HCC were 0.775, 0.792, 0.814, and 0.834, respectively. A novel diagnostic model was developed by classifying patients in a 1:1 ratio into training and validation sets. Using the binary regression analysis of the training cohort, the AFP, AFP-L3 fraction, and PIVKA-II (ALPs) score was calculated as follows: ALPs score = 3.8 × [serum AFP level (ng/mL) × AFP-L3 fraction (%) × 0.01] + 0.2 × PIVKA-II level (mAU/mL). The AUROC of the ALPs score for diagnosis of HCC was 0.878, significantly higher than that of serum AFP level ( < 0.001), AFP-L3 fraction ( < 0.001), PIVKA-II level ( = 0.036), and AFP-L3 level ( = 0.006). The optimal ALPs score cut-off was 5.3 (sensitivity, 85.0%, specificity 80.1%). The validation cohort showed similar results.
CONCLUSION
The ALPs score calculated using serum AFP level, AFP-L3 fraction, and PIVKA-II level showed improved accuracy in HCC diagnosis.
Topics: Biomarkers; Biomarkers, Tumor; Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Plant Lectins; Protein Precursors; Prothrombin; alpha-Fetoproteins
PubMed: 34366629
DOI: 10.3748/wjg.v27.i28.4687 -
The Oncologist Dec 2022Ramucirumab is indicated for patients with advanced hepatocellular carcinoma (HCC) and α-fetoprotein (AFP) ≥400 ng/mL following sorafenib. Here, we prospectively...
BACKGROUND
Ramucirumab is indicated for patients with advanced hepatocellular carcinoma (HCC) and α-fetoprotein (AFP) ≥400 ng/mL following sorafenib. Here, we prospectively studied ramucirumab following non-sorafenib systemic therapies.
MATERIALS AND METHODS
This open-label, non-comparative cohort of REACH-2 enrolled patients with advanced HCC, Child-Pugh class-A liver disease, and AFP ≥400 ng/mL who had received 1-2 lines of therapy, excluding sorafenib or chemotherapy. Ramucirumab was administered 8 mg/kg intravenously Q2W. The primary endpoint was safety. Secondary endpoints were overall survival, progression-free survival, objective response rate (RECIST v1.1), time to progression, pharmacokinetics, and patient-reported outcomes. Final analysis occurred after all enrolled patients completed ≥3 treatment cycles or discontinued treatment.
RESULTS
Between April 27, 2018, and March 29, 2021, 47 patients were treated at 21 investigative sites in Asia, Europe, and USA. The most frequently reported grade ≥3 adverse events, regardless of causality, were hypertension (11%), proteinuria (6%), hyponatremia (6%), and AST increased (6%). Two patients died from adverse events (myocardial infarction and upper gastrointestinal hemorrhage), deemed related to treatment. Median progression-free survival, time to progression, and overall survival were 1.7 months, 2.8 months, and 8.7 months, respectively. The objective response rate was 10.6% with a median duration response of 8.3 months. Median time to deterioration in FHSI-8 total score was 4.4 months.
CONCLUSION
Ramucirumab demonstrated consistent and meaningful clinical activity with no new safety signals following non-sorafenib therapies in patients with advanced HCC and AFP ≥400 ng/mL. This represents one of the first sequencing studies for patients with advanced HCC not treated with sorafenib.
Topics: Humans; Sorafenib; Carcinoma, Hepatocellular; alpha-Fetoproteins; Liver Neoplasms; Europe
PubMed: 36190331
DOI: 10.1093/oncolo/oyac183 -
The International Journal of Biological... Oct 2017Hepatocellular carcinoma (HCC) has one of the highest death rates of any cancer in the world, and its incidence is increasing worldwide. Early-stage diagnosis of HCC is... (Review)
Review
Hepatocellular carcinoma (HCC) has one of the highest death rates of any cancer in the world, and its incidence is increasing worldwide. Early-stage diagnosis of HCC is thus crucial for medical treatment. Detection of tumor biomarkers is one of the main methods for the early diagnosis of HCC. At present, α-fetoprotein (AFP) is the most practical serum biomarker for HCC diagnosis. However, the diagnostic accuracy of HCC with serum AFP exhibits both sensitivity and specificity far below satisfaction, especially with small sizes of HCC. As a result, the discovery of new biomarkers and/or their combination to enhance both the sensitivity and specificity for laboratory diagnosis of HCC is a crucial goal. With the development of new technology and advances in research, a number of new and specific biomarkers of HCC have been discovered. These biomarkers and their applications for the diagnosis, treatment monitoring and prognosis prediction of HCC, are reviewed in this article.
Topics: Biomarkers, Tumor; Carcinoma, Hepatocellular; Early Detection of Cancer; Humans; Liver Neoplasms; Prognosis; alpha-Fetoproteins
PubMed: 28967065
DOI: 10.5301/ijbm.5000299 -
BioMed Research International 2022The present study was aimed at evaluating the antitumor effects of royal jelly (RJ) obtained from compared with cyclophosphamide against the Ehrlich solid tumors (EST)...
OBJECTIVE
The present study was aimed at evaluating the antitumor effects of royal jelly (RJ) obtained from compared with cyclophosphamide against the Ehrlich solid tumors (EST) in mice.
METHODS
Tumor growth inhibition, body weight, the serum level of alpha-fetoprotein (AFP) and carcinoembryonic antigen tumor (CAE), liver and kidney enzymes, tumor lipid peroxidation (LPO), nitric oxide (NO), antioxidant enzymes (glutathione peroxidase (GPx), catalase enzyme (CAT), and superoxide dismutase enzyme activity (SOD)), tumor necrosis factor alpha level (TNF-), and the apoptosis-regulatory genes expression were assessed in EST mice treated with RJ (200 and 400 mg/kg orally once a day for 2 weeks).
RESULTS
The results showed that treatment of EST-suffering mice with RJ at the doses of 200 and 400 mg/kg causes significant reduction in tumor volume and inhibition rate, body weight, tumor markers (AFP and CEA), serum level of liver and kidney, LPO and NO, TNF- level, as well as the expression level of Bcl-2 in comparison with the EST mice receiving the normal saline; whereas RJ at the doses of 200 and 400 mg/kg/day significantly increased ( < 0.05) the level of antioxidant enzymes of GPx, CAT, and SOD and the expression level of caspase-3 and Bax genes.
CONCLUSION
The findings revealed that oral administration of royal jelly especially at the doses of 200 and 400 mg/kg exhibited promising antitumor effects against EST in mice through induction of apoptosis as well as its antioxidant and anti-inflammatory effects, which suggest it as a novel anticancer agent against tumor; however, additional surveys especially in clinical setting are necessary to approve these findings.
Topics: Animals; Antioxidants; Bees; Body Weight; Fatty Acids; Mice; Neoplasms; Oxidative Stress; Superoxide Dismutase; Tumor Necrosis Factor-alpha; alpha-Fetoproteins
PubMed: 35528154
DOI: 10.1155/2022/7233997 -
Journal of Cancer Research and... Sep 2018To explore the biological roles of alpha-fetoprotein (AFP), a tumor-associated antigen in human hepatocellular carcinoma (HCC).
AIMS
To explore the biological roles of alpha-fetoprotein (AFP), a tumor-associated antigen in human hepatocellular carcinoma (HCC).
MATERIALS AND METHODS
After knockdown of AFP in HepG2 cells by transfection of specific Stealth™ RNAi, the expression of AFP were detected by reverse transcription polymerase chain reaction at mRNA level and by enzyme-linked immunosorbent assay at the protein level. Then, the effect of silenced AFP on cell proliferation was assessed by dimethylthiazolyl-2,5-diphenyl-tetrazolium bromide assay, and apoptosis assessment with Hoechst33258 and flow cytometry (double stain with fluorescein isothiocyanate/propidium iodide), the roles of AFP in the cell cycle regulation were assessed by flow cytometry. We also detected the expression of some key proteins related to apoptosis pathway by Western immunoblot analysis.
RESULTS
After the transfection for 48 h, the expression of AFP gene was almost abolished, the cell proliferation was inhibited by 47.61%, the number of cells undergoing early apoptosis was significantly increased to 59.47%; cell cycle was arrested with the increase of G0/G1 phase cells from 45.3% to 58.4%. Inhibition of AFP expression also results in decreasing of transforming growth factor-β (TGF-β), mutant P53 expression, and increasing of Bax/Bcl-2 ratio, activation of caspase-3.
CONCLUSIONS
The results suggest that AFP may positively regulate cell proliferation by enhancing the apoptosis resistance via effect on TGF-β and p53/Bax/caspase-3 signaling pathway in HepG2 cells. As such, the knockdown of AFP gene should be further investigated in vivo as a novel approach to HCC treatment.
Topics: Carcinoma, Hepatocellular; Caspase 3; Cell Proliferation; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Hep G2 Cells; Humans; Liver Neoplasms; Signal Transduction; Transforming Growth Factor beta; Tumor Suppressor Protein p53; alpha-Fetoproteins; bcl-2-Associated X Protein
PubMed: 30249880
DOI: 10.4103/0973-1482.180681 -
Fertility and Sterility Aug 2021To determine if high alpha-fetoprotein (AFP) level in vaginal blood collected on a sanitary pad can assist with detecting an active miscarriage.
OBJECTIVE
To determine if high alpha-fetoprotein (AFP) level in vaginal blood collected on a sanitary pad can assist with detecting an active miscarriage.
DESIGN
A prospective cohort study.
SETTING
Academic medical center.
PATIENT(S)
Five groups were evaluated: women with active miscarriage, pregnancy of unknown location, completed miscarriage or extrauterine pregnancy (EUP), ongoing pregnancy, and undergoing elective dilation and curettage (D&C).
INTERVENTION(S)
None.
MAIN OUTCOME MEASURE(S)
For each patient, AFP level in the vaginal blood collected on a sanitary pad was quantified.
RESULT(S)
The vaginal blood AFP median levels (and their ranges) were 3.7 IU/mL (0.5-739.2) and 4,542 IU/mL (15.6-100,000) in the active miscarriage (n = 16) and the elective D&C (n = 24) groups, respectively. Alpha-fetoprotein was detected in all elective D&C and active miscarriage cases except in 1 case. In the ongoing pregnancy group (n = 35), only 2 of 35 specimens showed detectable AFP levels. In the pregnancy of unknown location (n = 12) and the completed miscarriage or EUP (n = 10) groups, no AFP was detected. Receiver operating characteristic analysis demonstrated 93.7% sensitivity and 97.8% specificity for the detection of an active miscarriage (cutoff 0.61 IU/mL; area under the curve 0.96).
CONCLUSION(S)
Alpha-fetoprotein can be extracted from vaginal blood collected on sanitary pads. A high level of vaginal AFP can assist with the same-day detection of an active miscarriage. This novel test is useful in differentiating active miscarriages from ongoing pregnancies, completed miscarriages, and EUPs and, therefore, it reduces uncertainty, anxiety level, and number of repeat office visits.
Topics: Abortion, Spontaneous; Adult; Female; Humans; Middle Aged; Pregnancy; Pregnancy Trimester, First; Vagina; Young Adult; alpha-Fetoproteins
PubMed: 33461753
DOI: 10.1016/j.fertnstert.2020.10.006 -
PLoS Neglected Tropical Diseases Jan 2024Extensive evidence links Clonorchis sinensis (C. sinensis) to cholangiocarcinoma; however, its association with hepatocellular carcinoma (HCC) is less acknowledged, and...
BACKGROUND
Extensive evidence links Clonorchis sinensis (C. sinensis) to cholangiocarcinoma; however, its association with hepatocellular carcinoma (HCC) is less acknowledged, and the underlying mechanism remains unclear. This study was designed to investigate the association between C. sinensis infection and HCC and reveal the relationship between C. sinensis infection and cancer stemness.
METHODS
A comprehensive analysis of 839 HCC patients categorized into C. sinensis (-) HCC and C. sinensis (+) HCC groups was conducted. Chi-square and Mann-Whitney U tests were used to assess the association between C. sinensis infection and clinical factors. Kaplan-Meier and Cox regression analyses were used to evaluate survival outcomes. Immunohistochemistry was used to determine CK19 and EpCAM expression in HCC specimens.
RESULTS
Compared to C. sinensis (-) HCC patients, C. sinensis (+) HCC patients exhibited advanced Barcelona Clinic Liver Cancer (BCLC) stage, higher male prevalence and more liver cirrhosis as well as elevated alpha-fetoprotein (AFP), carbohydrate antigen 19-9 (CA19-9), eosinophil, complement 3 (C3), and complement 4 (C4) values. C. sinensis infection correlated with shorter overall survival (OS) (p < 0.05) and recurrence-free survival (RFS) (p < 0.05). Furthermore, Cox multivariate analysis revealed that C. sinensis infection was an independent prognostic factor for OS in HCC patients. Importantly, C. sinensis infection upregulated the expression of HCC cancer stem cell markers CK19 and EpCAM.
CONCLUSION
HCC patients with C. sinensis infection exhibit a poor prognosis following hepatectomy. Moreover, C. sinensis infection promotes the acquisition of cancer stem cell-like characteristics, consequently accelerating the malignant progression of HCC.
AUTHOR SUMMARY
Clonorchis sinensis (C. sinensis) is a prominent food-borne parasite prevalent in regions such as China, particularly in Guangxi. C. sinensis has been associated with various hepatobiliary system injuries, encompassing inflammation, periductal fibrosis, cholangiocarcinoma and even hepatocellular carcinoma (HCC). A substantial body of evidence links C. sinensis to cholangiocarcinoma, However, the connection between C. sinensis and HCC and the intricate mechanisms underlying its contribution to HCC development remain incompletely elucidated. Our study demonstrates clear clinicopathological associations between C. sinensis and HCC, such as gender, BCLC stage, liver cirrhosis, MVI, AFP, CA19-9, circulating eosinophils and complements. Furthermore, we found that the co-occurrence of C. sinensis exhibited a significant association with shorter OS and RFS in patients diagnosed with HCC. A major finding was that C. sinensis infection promotes the acquisition of cancer stem cell-like characteristics, consequently accelerating the malignant progression of HCC. Our results provide a more comprehensive comprehension of the interplay between C. sinensis and HCC, shedding fresh light on the carcinogenic potential of C. sinensis.
Topics: Animals; Humans; Male; Carcinoma, Hepatocellular; Liver Neoplasms; Epithelial Cell Adhesion Molecule; Clonorchiasis; alpha-Fetoproteins; CA-19-9 Antigen; Neoplasm Staging; China; Prognosis; Clonorchis sinensis; Cholangiocarcinoma; Bile Ducts, Intrahepatic; Bile Duct Neoplasms; Liver Cirrhosis; Retrospective Studies
PubMed: 38285640
DOI: 10.1371/journal.pntd.0011906