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1.
Clinics (Sao Paulo) ; 79: 100415, 2024.
Article En | MEDLINE | ID: mdl-38897099

INTRODUCTION: Patients with Human Papillomavirus (HPV+)-associated Laryngeal Squamous Cell Carcinoma (LSCC) exhibit dramatically improved survival relative to those with HPV-Negative (HPV-) tumors. In this study, the authors aimed to investigate the radiosensitivity of all available confirmed HPV+ and HPV-LSCC cells in vitro and in vivo. METHODS: Primary LSCC cells were generated from tumor specimens obtained from patients. Real-time PCR was performed to confirm HPV infection and the expression of HPV-related genes (E6 and E7), p53, and pRB. Clonogenic survival assays, western blotting, and flow cytometry were used to assess radiation sensitivity, apoptosis, and the expression of p53 and pRB. p53 and pRB knockout cells were generated using CRISPR/Cas9 technology. RESULTS: HPV+ LSCC cells displayed enhanced radiation sensitivity compared to HPV- cells. Radiation-induced apoptosis in HPV+ LSCC cells, accompanied by increased levels of p53 and pRB. Knockout of p53 or pRB led to radiation resistance and attenuated radiation-induced apoptosis in HPV+ LSCC cells. In vivo experiments showed similar results, where knockout of p53 or pRB decreased radiosensitivity in tumor-bearing mice. CONCLUSION: The present findings demonstrated that HPV+ LSCC cells displayed obvious inherent radiation sensitivity, corresponding to increased apoptosis following radiation exposure. Mechanism study showed that the expression of p53 and pRB in HPV+ cells are required for radiation sensitivity. These findings highlight a novel mechanism by which p53 and pRB play key roles in the radiation sensitivity of HPV+ LSCC compared to HPV-LSCC.


Apoptosis , Carcinoma, Squamous Cell , Laryngeal Neoplasms , Papillomavirus Infections , Radiation Tolerance , Tumor Suppressor Protein p53 , Humans , Laryngeal Neoplasms/radiotherapy , Laryngeal Neoplasms/virology , Carcinoma, Squamous Cell/radiotherapy , Carcinoma, Squamous Cell/virology , Tumor Suppressor Protein p53/metabolism , Papillomavirus Infections/radiotherapy , Papillomavirus Infections/virology , Papillomavirus Infections/complications , Apoptosis/radiation effects , Animals , Cell Line, Tumor , Real-Time Polymerase Chain Reaction , Male , Mice , Flow Cytometry , Blotting, Western , Retinoblastoma Protein/metabolism
2.
Zhonghua Bing Li Xue Za Zhi ; 53(6): 546-551, 2024 Jun 08.
Article Zh | MEDLINE | ID: mdl-38825898

Objective: To investigate the clinical and pathological characteristics of primary mucinous gland lesions of the fallopian tubes. Methods: The clinical data, pathomorphological characteristics and immunophenotype of 14 cases of primary mucinous gland lesions of the fallopian tube diagnosed at Obstetrics and Gynecology Hospital of Fudan University from 2015 to 2023 were analyzed retrospectively. In addition, a comprehensive review of relevant literature was conducted. Results: The age of 14 patients ranged from 53 to 83 years, with an average of 65 years. Among them, 13 cases exhibited unilateral involvement while one case showed bilateral presentation. Nine cases were mucinous metaplasia of the fallopian tube, four cases were invasive mucinous adenocarcinoma and one case was mucinous carcinoma in situ. Morphologically, mucinous metaplasia of the fallopian tube was focal, with or without inflammation. The cells of mucinous adenocarcinoma or mucinous carcinoma in situ exhibited characteristics indicative of gastrointestinal differentiation. Immunohistochemical analysis revealed diffuse positive expression of CK7, and negative expression of SATB2. CDX2 demonstrated positive staining in two cases. One case exhibited diffuse and strongly positive mutant expression of p53, whereas the remaining cases displayed wild-type expression. MUC6 showed diffuse or focally positive staining in mucinous gland lesions characterized by gastric differentiation. Some cases of mucinous adenocarcinoma of fallopian tube were subject to AB-PAS staining, resulting in red to purple cytoplasmic staining. Conclusions: Primary mucinous lesions of the fallopian tube are exceedingly uncommon. All cases of mucinous adenocarcinoma of fallopian tubes in this study exhibit the morphology and immunohistochemical characteristics of gastrointestinal differentiation. Mucinous metaplasia of the fallopian tube is a benign lesion of incidental finding, which is closely related to inflammation or gastric differentiation. Mucinous lesions of cervix, ovary and digestive tract are excluded in all patients, confirming the independent existence of mucinous lesions within fallopian tubes.


Adenocarcinoma, Mucinous , Fallopian Tube Neoplasms , Fallopian Tubes , Metaplasia , Tumor Suppressor Protein p53 , Humans , Female , Fallopian Tube Neoplasms/pathology , Fallopian Tube Neoplasms/metabolism , Adenocarcinoma, Mucinous/pathology , Adenocarcinoma, Mucinous/metabolism , Aged , Middle Aged , Retrospective Studies , Fallopian Tubes/pathology , Aged, 80 and over , Tumor Suppressor Protein p53/metabolism , Metaplasia/pathology , Keratin-7/metabolism , CDX2 Transcription Factor/metabolism , CDX2 Transcription Factor/genetics , Mucin-6/metabolism , Matrix Attachment Region Binding Proteins/metabolism , Matrix Attachment Region Binding Proteins/genetics , Transcription Factors/metabolism , Transcription Factors/genetics , Carcinoma in Situ/pathology , Immunohistochemistry
3.
Zhonghua Bing Li Xue Za Zhi ; 53(6): 541-545, 2024 Jun 08.
Article Zh | MEDLINE | ID: mdl-38825897

Objective: To investigate the clinicopathological features, diagnosis and differential diagnosis of pseudocarcinomatous hyperplasia of the fallopian tubes. Methods: Sixteen cases of pseudocarcinomatous hyperplasia of the fallopian tubes diagnosed at Obstetrics and Gynecology Hospital of Fudan University from January 2011 to January 2024 were collected.The pathological sections were reviewed, the clinical and pathological data were consulted, and immunohistochemical examination was conducted along with follow-up. Results: The patients were aged from 19 to 57 years, with an average age of 41 and a median age of 38. Among the 16 cases, 4 were located in the right fallopian tubes, 6 in the left fallopian tubes, while the remaining cases presented bilaterally. The general manifestations were tubal edema, crispness and purulent secretion in the lumen. Morphologically, the fallopian tube mucosa exhibited a significant infiltration of neutrophils, lymphocytes and plasma cells. The epithelial cells of the fallopian tube displayed evident proliferation, stratification and disorganized arrangement leading to formation of small glandular cavity with back-to-back, fissure-like and sieve-like structures. Immunohistochemical analysis revealed positivity for CK7 and WT1, along with wild-type p53 expression, Ki-67 index ranged from 5% to 20%. During the follow-up period ranging from 1 to 156 months, all the patients remained free of disease. Conclusions: Pseudocarcinomatous hyperplasia of the fallopian tube is a rare non-neoplastic lesion, which can lead to epithelial hyperplasia and atypical hyperplasia. The most important significance of recognizing this lesion lies in avoiding misdiagnosis of fallopian tube cancer during intraoperative and postoperative pathological examination. This ensures that clinicians can administer correct clinical interventions.


Fallopian Tubes , Hyperplasia , Humans , Female , Adult , Hyperplasia/pathology , Middle Aged , Fallopian Tubes/pathology , Fallopian Tubes/metabolism , Diagnosis, Differential , Tumor Suppressor Protein p53/metabolism , Keratin-7/metabolism , Fallopian Tube Neoplasms/pathology , Fallopian Tube Neoplasms/metabolism , Fallopian Tube Neoplasms/surgery , Fallopian Tube Neoplasms/diagnosis , Ki-67 Antigen/metabolism , WT1 Proteins/metabolism , Young Adult , Epithelial Cells/pathology , Epithelial Cells/metabolism , Immunohistochemistry , Fallopian Tube Diseases/pathology , Fallopian Tube Diseases/metabolism , Fallopian Tube Diseases/diagnosis
4.
Ren Fail ; 46(2): 2365408, 2024 Dec.
Article En | MEDLINE | ID: mdl-38874119

Podocyte loss in glomeruli is a fundamental event in the pathogenesis of chronic kidney diseases. Currently, mitotic catastrophe (MC) has emerged as the main cause of podocyte loss. However, the regulation of MC in podocytes has yet to be elucidated. The current work aimed to study the role and mechanism of p53 in regulating the MC of podocytes using adriamycin (ADR)-induced nephropathy. In vitro podocyte stimulation with ADR triggered the occurrence of MC, which was accompanied by hyperactivation of p53 and cyclin-dependent kinase (CDK1)/cyclin B1. The inhibition of p53 reversed ADR-evoked MC in podocytes and protected against podocyte injury and loss. Further investigation showed that p53 mediated the activation of CDK1/cyclin B1 by regulating the expression of Wee1. Restraining Wee1 abolished the regulatory effect of p53 inhibition on CDK1/cyclin B1 and rebooted MC in ADR-stimulated podocytes via p53 inhibition. In a mouse model of ADR nephropathy, the inhibition of p53 ameliorated proteinuria and podocyte injury. Moreover, the inhibition of p53 blocked the progression of MC in podocytes in ADR nephropathy mice through the regulation of the Wee1/CDK1/cyclin B1 axis. Our findings confirm that p53 contributes to MC in podocytes through regulation of the Wee1/CDK1/Cyclin B1 axis, which may represent a novel mechanism underlying podocyte injury and loss during the progression of chronic kidney disorder.


CDC2 Protein Kinase , Cell Cycle Proteins , Cyclin B1 , Doxorubicin , Mitosis , Podocytes , Protein-Tyrosine Kinases , Tumor Suppressor Protein p53 , Podocytes/metabolism , Podocytes/pathology , Animals , CDC2 Protein Kinase/metabolism , Tumor Suppressor Protein p53/metabolism , Mice , Protein-Tyrosine Kinases/metabolism , Protein-Tyrosine Kinases/antagonists & inhibitors , Doxorubicin/pharmacology , Cyclin B1/metabolism , Cell Cycle Proteins/metabolism , Disease Models, Animal , Humans , Male
5.
Nat Commun ; 15(1): 4871, 2024 Jun 13.
Article En | MEDLINE | ID: mdl-38871738

The phenomenon of mixed/heterogenous treatment responses to cancer therapies within an individual patient presents a challenging clinical scenario. Furthermore, the molecular basis of mixed intra-patient tumor responses remains unclear. Here, we show that patients with metastatic lung adenocarcinoma harbouring co-mutations of EGFR and TP53, are more likely to have mixed intra-patient tumor responses to EGFR tyrosine kinase inhibition (TKI), compared to those with an EGFR mutation alone. The combined presence of whole genome doubling (WGD) and TP53 co-mutations leads to increased genome instability and genomic copy number aberrations in genes implicated in EGFR TKI resistance. Using mouse models and an in vitro isogenic p53-mutant model system, we provide evidence that WGD provides diverse routes to drug resistance by increasing the probability of acquiring copy-number gains or losses relative to non-WGD cells. These data provide a molecular basis for mixed tumor responses to targeted therapy, within an individual patient, with implications for therapeutic strategies.


Chromosomal Instability , ErbB Receptors , Lung Neoplasms , Mutation , Tumor Suppressor Protein p53 , Humans , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , Animals , Mice , Lung Neoplasms/genetics , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , ErbB Receptors/genetics , ErbB Receptors/metabolism , ErbB Receptors/antagonists & inhibitors , Drug Resistance, Neoplasm/genetics , Cell Line, Tumor , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Adenocarcinoma of Lung/genetics , Adenocarcinoma of Lung/drug therapy , Adenocarcinoma of Lung/pathology , Molecular Targeted Therapy/methods , Female , DNA Copy Number Variations , Male
6.
J Cell Mol Med ; 28(11): e18442, 2024 Jun.
Article En | MEDLINE | ID: mdl-38842135

Epithelial-mesenchymal transition (EMT) and its reversal process are important potential mechanisms in the development of HCC. Selaginella doederleinii Hieron is widely used in Traditional Chinese Medicine for the treatment of various tumours and Amentoflavone is its main active ingredient. This study investigates the mechanism of action of Amentoflavone on EMT in hepatocellular carcinoma from the perspective of bioinformatics and network pharmacology. Bioinformatics was used to screen Amentoflavone-regulated EMT genes that are closely related to the prognosis of HCC, and a molecular prediction model was established to assess the prognosis of HCC. The network pharmacology was used to predict the pathway axis regulated by Amentoflavone. Molecular docking of Amentoflavone with corresponding targets was performed. Detection and evaluation of the effects of Amentoflavone on cell proliferation, migration, invasion and apoptosis by CCK-8 kit, wound healing assay, Transwell assay and annexin V-FITC/propidium iodide staining. Eventually three core genes were screened, inculding NR1I2, CDK1 and CHEK1. A total of 590 GO enrichment entries were obtained, and five enrichment results were obtained by KEGG pathway analysis. Genes were mainly enriched in the p53 signalling pathway. The outcomes derived from both the wound healing assay and Transwell assay demonstrated significant inhibition of migration and invasion in HCC cells upon exposure to different concentrations of Amentoflavone. The results of Annexin V-FITC/PI staining assay showed that different concentrations of Amentoflavone induces apoptosis in HCC cells. This study revealed that the mechanism of Amentoflavone reverses EMT in hepatocellular carcinoma, possibly by inhibiting the expression of core genes and blocking the p53 signalling pathway axis to inhibit the migration and invasion of HCC cells.


Apoptosis , Biflavonoids , Carcinoma, Hepatocellular , Cell Movement , Cell Proliferation , Epithelial-Mesenchymal Transition , Gene Expression Regulation, Neoplastic , Liver Neoplasms , Signal Transduction , Tumor Suppressor Protein p53 , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/genetics , Epithelial-Mesenchymal Transition/drug effects , Humans , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , Liver Neoplasms/drug therapy , Liver Neoplasms/genetics , Biflavonoids/pharmacology , Tumor Suppressor Protein p53/metabolism , Tumor Suppressor Protein p53/genetics , Signal Transduction/drug effects , Cell Movement/drug effects , Cell Proliferation/drug effects , Apoptosis/drug effects , Gene Expression Regulation, Neoplastic/drug effects , Cell Line, Tumor , Molecular Docking Simulation , Computational Biology/methods
7.
Vopr Virusol ; 69(2): 127-133, 2024 May 06.
Article En | MEDLINE | ID: mdl-38843019

OBJECTIVES: The HTLV-1 infection persists for life, remaining as asymptomatic viral reservoirs in most patients, ensuring the chain of transmission, but around 4% develop adult T-cell leukemia/lymphoma (ATLL). HTLV-1 is an oncogenic retrovirus that transforms CD4+ T lymphocytes and deregulates the lymphoproliferative pathways that contribute to the development of ATLL. To achieve cell transformation, most oncogenic retroviruses use proto-oncogene capture transduction, with proviral integration disrupting the expression of tumor suppressors or proto-oncogenes. THE AIM: We conducted this study on the prevalence of HTLV-1 infection in blood donors to expand the HTLV-1 database, assess the risk of transmission via blood products, as well as evaluate the risk of persistent infection or development of neoplastic diseases in HTLV-1 carriers. MATERIALS AND METHODS: This is a cross-sectional study of blood donors of all categories. For this study, 265 blood donors were recruited at the Centre National de Transfusion Sanguine in Brazzaville. After testing for HTLV-1 antibodies by ELISA, proviral DNA was extracted from all ELISA-positive samples for detection by nested PCR, followed by RT qPCR using specific primers p53 and c-myc for gene expression. RESULTS: 20/265 were positive for anti-HTLV-1 antibody, 5 donors were positive for proviral DNA. The prevalence of HTLV-1 was 1.8%. All HTLV-1-positive donors were male (1.8%), with a positive correlation (p = 0.05); the 1.1% of positive donors were regular, with the majority aged between 31 and 45 years (1.5%), and concubine donors were the most frequent (1.1%). All samples showed normal expression of the p53 and c-myc genes. CONCLUSION: The prevalence, though low, remains a serious problem. No abnormal p53 or c-myc gene expression was detected in HTLV-1-positive donors, which could mean that none of the T lymphocytes in these donors had been transformed by HTLV-1.


Blood Donors , HTLV-I Infections , Human T-lymphotropic virus 1 , Proto-Oncogene Proteins c-myc , Tumor Suppressor Protein p53 , Humans , Human T-lymphotropic virus 1/genetics , Male , HTLV-I Infections/epidemiology , HTLV-I Infections/virology , HTLV-I Infections/genetics , HTLV-I Infections/blood , Adult , Female , Tumor Suppressor Protein p53/genetics , Middle Aged , Proto-Oncogene Proteins c-myc/genetics , Proto-Oncogene Mas , Cross-Sectional Studies , Gene Expression Profiling , Leukemia-Lymphoma, Adult T-Cell/virology , Leukemia-Lymphoma, Adult T-Cell/epidemiology , Leukemia-Lymphoma, Adult T-Cell/genetics , Leukemia-Lymphoma, Adult T-Cell/blood , Proviruses/genetics , Adolescent
8.
Life Sci Alliance ; 7(8)2024 Aug.
Article En | MEDLINE | ID: mdl-38843934

RNA-binding proteins are frequently deregulated in cancer and emerge as effectors of the DNA damage response (DDR). The non-POU domain-containing octamer-binding protein NONO/p54nrb is a multifunctional RNA-binding protein that not only modulates the production and processing of mRNA, but also promotes the repair of DNA double-strand breaks (DSBs). Here, we investigate the impact of Nono deletion in the murine KP (KRas G12D , Trp53 -/- ) cell-based lung cancer model. We show that the deletion of Nono impairs the response to DNA damage induced by the topoisomerase II inhibitor etoposide or the radiomimetic drug bleomycin. Nono-deficient KP (KPN) cells display hyperactivation of DSB signalling and high levels of DSBs. The defects in the DDR are accompanied by reduced RNA polymerase II promoter occupancy, impaired nascent RNA synthesis, and attenuated induction of the DDR factor growth arrest and DNA damage-inducible beta (Gadd45b). Our data characterise Gadd45b as a putative Nono-dependent effector of the DDR and suggest that Nono mediates a genome-protective crosstalk of the DDR with the RNA metabolism via induction of Gadd45b.


DNA Damage , DNA Repair , RNA-Binding Proteins , Animals , Mice , RNA-Binding Proteins/metabolism , RNA-Binding Proteins/genetics , DNA Breaks, Double-Stranded , Antigens, Differentiation/metabolism , Antigens, Differentiation/genetics , Bleomycin/pharmacology , DNA-Binding Proteins/metabolism , DNA-Binding Proteins/genetics , Etoposide/pharmacology , Signal Transduction , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Tumor Suppressor Protein p53/metabolism , Tumor Suppressor Protein p53/genetics , Cell Line, Tumor , RNA Polymerase II/metabolism , Humans , GADD45 Proteins
9.
Breast Cancer Res ; 26(1): 91, 2024 Jun 04.
Article En | MEDLINE | ID: mdl-38835038

BACKGROUND: The aberrant amplification of mammary luminal progenitors is at the origin of basal-like breast cancers associated with BRCA1 mutations. Integrins mediate cell-matrix adhesion and transmit mechanical and chemical signals that drive epithelial stem cell functions and regulate tumor progression, metastatic reactivation, and resistance to targeted therapies. Consistently, we have recently shown that laminin-binding integrins are essential for the expansion and differentiation of mammary luminal progenitors in physiological conditions. As over-expression of the laminin-binding α6 integrin (Itgα6) is associated with poor prognosis and reduced survival in breast cancer, we here investigate the role of Itgα6 in mammary tumorigenesis. METHODS: We used Blg-Cre; Brca1F/F; Trp53F/F mice, a model that phenocopies human basal-like breast cancer with BRCA1 mutations. We generated mutant mice proficient or deficient in Itgα6 expression and followed tumor formation. Mammary tumors and pretumoral tissues were characterized by immunohistochemistry, flow cytometry, RT-qPCR, Western blotting and organoid cultures. Clonogenicity of luminal progenitors from preneoplastic glands was studied in 3D Matrigel cultures. RESULTS: We show that Itga6 deletion favors activation of p16 cell cycle inhibitor in the preneoplastic tissue. Subsequently, the amplification of luminal progenitors, the cell of origin of Brca1-deficient tumors, is restrained in Itgα6-deficient gland. In addition, the partial EMT program operating in Brca1/p53-deficient epithelium is attenuated in the absence of Itgα6. As a consequence of these events, mammary tumor formation is delayed in Itgα6-deficient mice. After tumor formation, the lack of Itgα6 does not affect tumor growth but rather alters their differentiation, resulting in reduced expression of basal cell markers. CONCLUSIONS: Our data indicate that Itgα6 has a pro-tumorigenic role in Blg-Cre; Brca1F/F; Trp53F/F mice developing basal-like mammary tumors. In particular, we reveal that Itgα6 is required for the luminal progenitor expansion and the aberrant partial EMT program that precedes the formation of BRCA1 deficient tumors.


BRCA1 Protein , Breast Neoplasms , Integrin alpha6 , Tumor Suppressor Protein p53 , Animals , Integrin alpha6/metabolism , Integrin alpha6/genetics , Female , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , Mice , BRCA1 Protein/genetics , BRCA1 Protein/metabolism , Breast Neoplasms/pathology , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Humans , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/pathology , Cell Proliferation , Stem Cells/metabolism , Gene Deletion , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/metabolism
10.
Biochem Biophys Res Commun ; 723: 150186, 2024 Sep 03.
Article En | MEDLINE | ID: mdl-38830298

The aim of this study was to investigate the anti-cancer effects of resveratrol (RES) against gastric cancer (GC) and explore the potential mechanisms. We first measured the anti-cancer effects of RES on GC cell lines (i.e. AGS and HGC-27). Then protein-protein interaction (PPI) network was constructed, followed by GO and KEGG analysis to screen the possible targets. Molecular docking analysis was given to visualize the pharmacological effects of RES on GC cell lines. For the in vivo experiments, xenograft tumor model was established, and Western blot analysis was performed to determine the expression of protein screened by network pharmacology. Our results showed that RES could promote the apoptosis of GC cells. Five hub targets were identified by network pharmacology, including AKT1, TP53, JUN, ESR1 and MAPK14. GO and KEGG analyses revealed the PI3K/Akt/P53 signaling pathway was the most related signaling pathway. Molecular docking analysis indicated that RES could form 3 hydrogen bonds with AKT1 and 3 hydrogen bonds with TP53. The inhibitory effects of RES on the proliferation and promoting effects of RES on the apoptosis of AGS and HGC-27 cells were significantly reversed when blocking the PI3K-Akt signaling pathway using the LY294002. In vivo results showed that RES induced significant decrease of tumor volume and tumor weight without changing the body weight, or inducing significant cytotoxicities. Western blot analysis proved that RES could induce down-regulation of p-Akt and up-regulation of P53 in vivo. In conclusion, RES showed anti-cancer effects in GC by regulating the PI3K/Akt/P53 signaling pathway.


Phosphatidylinositol 3-Kinases , Proto-Oncogene Proteins c-akt , Resveratrol , Stomach Neoplasms , Tumor Suppressor Protein p53 , Animals , Humans , Mice , Antineoplastic Agents, Phytogenic/pharmacology , Apoptosis , Cell Line, Tumor , Cell Proliferation , Mice, Inbred BALB C , Mice, Nude , Molecular Docking Simulation , Phosphatidylinositol 3-Kinases/metabolism , Protein Interaction Maps , Proto-Oncogene Proteins c-akt/metabolism , Resveratrol/pharmacology , Signal Transduction , Stilbenes/pharmacology , Stomach Neoplasms/metabolism , Stomach Neoplasms/pathology , Stomach Neoplasms/drug therapy , Tumor Suppressor Protein p53/metabolism , Xenograft Model Antitumor Assays
11.
Cell Death Dis ; 15(6): 426, 2024 Jun 18.
Article En | MEDLINE | ID: mdl-38890278

Radiation therapy (RT) remains a common treatment for cancer patients worldwide, despite the development of targeted biological compounds and immunotherapeutic drugs. The challenge in RT lies in delivering a lethal dose to the cancerous site while sparing the surrounding healthy tissues. Low linear energy transfer (low-LET) and high linear energy transfer (high-LET) radiations have distinct effects on cells. High-LET radiation, such as alpha particles, induces clustered DNA double-strand breaks (DSBs), potentially inducing cell death more effectively. However, due to limited range, alpha-particle therapies have been restricted. In human cancer, mutations in TP53 (encoding for the p53 tumor suppressor) are the most common genetic alteration. It was previously reported that cells carrying wild-type (WT) p53 exhibit accelerated senescence and significant rates of apoptosis in response to RT, whereas cells harboring mutant p53 (mutp53) do not. This study investigated the combination of the alpha-emitting atoms RT based on internal Radium-224 (224Ra) sources and systemic APR-246 (a p53 reactivating compound) to treat tumors with mutant p53. Cellular models of colorectal cancer (CRC) or pancreatic ductal adenocarcinoma (PDAC) harboring mutant p53, were exposed to alpha particles, and tumor xenografts with mutant p53 were treated using 224Ra source and APR-246. Effects on cell survival and tumor growth, were assessed. The spread of alpha emitters in tumors was also evaluated as well as the spatial distribution of apoptosis within the treated tumors. We show that mutant p53 cancer cells exhibit radio-sensitivity to alpha particles in vitro and to alpha-particles-based RT in vivo. APR-246 treatment enhanced sensitivity to alpha radiation, leading to reduced tumor growth and increased rates of tumor eradication. Combining alpha-particles-based RT with p53 restoration via APR-246 triggered cell death, resulting in improved therapeutic outcomes. Further preclinical and clinical studies are needed to provide a promising approach for improving treatment outcomes in patients with mutant p53 tumors.


Alpha Particles , Radiation-Sensitizing Agents , Tumor Suppressor Protein p53 , Alpha Particles/therapeutic use , Humans , Tumor Suppressor Protein p53/metabolism , Tumor Suppressor Protein p53/genetics , Animals , Mice , Radiation-Sensitizing Agents/pharmacology , Mutation , Quinuclidines/pharmacology , Cell Line, Tumor , Mice, Nude , Xenograft Model Antitumor Assays , Apoptosis/drug effects , Apoptosis/radiation effects , Neoplasms/radiotherapy , Neoplasms/genetics , Neoplasms/pathology
12.
Blood Cancer J ; 14(1): 99, 2024 Jun 18.
Article En | MEDLINE | ID: mdl-38890297

Current therapies for high-grade TP53-mutated myeloid neoplasms (≥10% blasts) do not offer a meaningful survival benefit except allogeneic stem cell transplantation in the minority who achieve a complete response to first line therapy (CR1). To identify reliable pre-therapy predictors of complete response to first-line therapy (CR1) and outcomes, we assembled a cohort of 242 individuals with TP53-mutated myeloid neoplasms and ≥10% blasts with well-annotated clinical, molecular and pathology data. Key outcomes examined were CR1 & 24-month survival (OS24). In this elderly cohort (median age 68.2 years) with 74.0% receiving frontline non-intensive regimens (hypomethylating agents +/- venetoclax), the overall cohort CR1 rate was 25.6% (50/195). We additionally identified several pre-therapy factors predictive of inferior CR1 including male gender (P = 0.026), ≥2 autosomal monosomies (P < 0.001), -17/17p (P = 0.011), multi-hit TP53 allelic state (P < 0.001) and CUX1 co-alterations (P = 0.010). In univariable analysis of the entire cohort, inferior OS24 was predicated by ≥2 monosomies (P = 0.004), TP53 VAF > 25% (P = 0.002), TP53 splice junction mutations (P = 0.007) and antecedent treated myeloid neoplasm (P = 0.001). In addition, mutations/deletions in CUX1, U2AF1, EZH2, TET2, CBL, or KRAS ('EPI6' signature) predicted inferior OS24 (HR = 2.0 [1.5-2.8]; P < 0.0001). In a subgroup analysis of HMA +/-Ven treated individuals (N = 144), TP53 VAF and monosomies did not impact OS24. A risk score for HMA +/-Ven treated individuals incorporating three pre-therapy predictors including TP53 splice junction mutations, EPI6 and antecedent treated myeloid neoplasm stratified 3 prognostic distinct groups: intermediate, intermediate-poor, and poor with significantly different median (12.8, 6.0, 4.3 months) and 24-month (20.9%, 5.7%, 0.5%) survival (P < 0.0001). For the first time, in a seemingly monolithic high-risk cohort, our data identifies several baseline factors that predict response and 24-month survival.


Mutation , Tumor Suppressor Protein p53 , Humans , Male , Female , Aged , Tumor Suppressor Protein p53/genetics , Middle Aged , Aged, 80 and over , Adult , Prognosis , Treatment Outcome
13.
Sci Rep ; 14(1): 14087, 2024 06 18.
Article En | MEDLINE | ID: mdl-38890407

Canine liposarcoma is an uncommon tumor that shares morphological similarities with its human counterpart. In dogs, the genetic features of this tumor are unknown and, based on immunohistochemical studies, amplification of the gene MDM2 and the mutation of TP53 are suspected. In this study 51 cases of primary liposarcomas were immunohistochemically stained for MDM2 and p53 and subjected to fluorescent in situ hybridization and next-generation sequencing to detect MDM2 amplification and TP53 mutations, respectively. MDM2 and p53 were expressed in 21 and 6 cases, respectively. MDM2 amplification and TP53 mutations were identified in 10 and 15 cases, respectively. Statistical analysis revealed an association of the myxoid subtype and the mitotic count with p53 expression and TP53 mutation. No association was found between MDM2 amplification and MDM2 expression or tumor subtype. These results suggest that despite morphological similarities, canine liposarcoma differs from its human counterpart, for which MDM2 amplification is diagnostic for well differentiated and de-differentiated variants, and TP53 mutations are more common in pleomorphic liposarcoma rather than the myxoid one as occur in our cases. Furthermore, canine myxoid liposarcoma likely represents a distinct disease rather than a mere morphological variant.


Dog Diseases , Liposarcoma , Proto-Oncogene Proteins c-mdm2 , Tumor Suppressor Protein p53 , Proto-Oncogene Proteins c-mdm2/genetics , Proto-Oncogene Proteins c-mdm2/metabolism , Dogs , Animals , Liposarcoma/genetics , Liposarcoma/veterinary , Liposarcoma/pathology , Liposarcoma/metabolism , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , Dog Diseases/genetics , Dog Diseases/pathology , Mutation , Female , Male , In Situ Hybridization, Fluorescence , High-Throughput Nucleotide Sequencing , Gene Amplification , Immunohistochemistry
14.
Neurosurg Rev ; 47(1): 283, 2024 Jun 21.
Article En | MEDLINE | ID: mdl-38904885

This study examined the risk factors for short-term outcomes, focusing particularly on the associations among molecular subgroups. The analysis focused on the data of pediatric patients with medulloblastoma between 2013 and 2023, as well as operative complications, length of stay from surgery to adjuvant treatment, 30-day unplanned reoperation, unplanned readmission, and mortality. 148 patients were included. Patients with the SHH TP53-wildtype exhibited a lower incidence of complications (45.2% vs. 66.0%, odds ratio [OR] 0.358, 95% confidence interval [CI] 0.160 - 0.802). Female sex (0.437, 0.207 - 0.919) was identified as an independent protective factor for complications, and brainstem involvement (1.900, 1.297 - 2.784) was identified as a risk factor. Surgical time was associated with an increased risk of complications (1.004, 1.001 - 1.008), duration of hospitalization (1.006, 1.003 - 1.010), and reoperation (1.003, 1.001 - 1.006). Age was found to be a predictor of improved outcomes, as each additional year was associated with a 14.1% decrease in the likelihood of experiencing a prolonged length of stay (0.859, 0.772 - 0.956). Patients without metastasis exhibited a reduced risk of reoperation (0.322, 0.133 - 0.784) and readmission (0.208, 0.074 - 0.581). There is a significant degree of variability in the occurrence of operative complications in pediatric patients with medulloblastoma. SHH TP53-wildtype medulloblastoma is commonly correlated with a decreased incidence of complications. The short-term outcomes of patients are influenced by various unmodifiable endogenous factors. These findings could enhance the knowledge of onconeurosurgeons and alleviate the challenges associated with patient/parent education through personalized risk communication. However, the importance of a dedicated center with expertise surgical team and experienced neurosurgeon in improving neurosurgical outcomes appears self-evident.


Cerebellar Neoplasms , Medulloblastoma , Neurosurgical Procedures , Postoperative Complications , Humans , Medulloblastoma/surgery , Female , Male , Child , Cerebellar Neoplasms/surgery , Neurosurgical Procedures/methods , Child, Preschool , Postoperative Complications/epidemiology , Treatment Outcome , Adolescent , Cohort Studies , Length of Stay , Reoperation , Hedgehog Proteins/genetics , Risk Factors , Tumor Suppressor Protein p53/genetics
15.
Med Oncol ; 41(7): 167, 2024 Jun 04.
Article En | MEDLINE | ID: mdl-38831079

Cancer stem cells (CSCs) are mainly responsible for tumorigenesis, chemoresistance, and cancer recurrence. CSCs growth and progression are regulated by multiple signaling cascades including Wnt/ß-catenin and Hh/GLI-1, which acts independently or via crosstalk. Targeting the crosstalk of signaling pathways would be an effective approach to control the CSC population. Both Wnt/ß-catenin and Hh/GLI-1 signaling cascades are known to be regulated by p53/p21-dependent mechanism. However, it is interesting to delineate whether p21 can induce apoptosis in a p53-independent manner. Therefore, utilizing various subtypes of oral CSCs (SCC9-PEMT p53+/+p21+/+, SCC9-PEMT p53-/-p21+/+, SCC9-PEMT p53+/+p21-/- and SCC9-PEMT p53-/-p21-/-), we have examined the distinct roles of p53 and p21 in Resveratrol nanoparticle (Res-Nano)-mediated apoptosis. It is interesting to see that, besides the p53/p21-mediated mechanism, Res-Nano exposure also significantly induced apoptosis in oral CSCs through a p53-independent activation of p21. Additionally, Res-Nano-induced p21-activation deregulated the ß-catenin-GLI-1 complex and consequently reduced the TCF/LEF and GLI-1 reporter activities. In agreement with in vitro data, similar experimental results were obtained in in vivo mice xenograft model.


Apoptosis , Cyclin-Dependent Kinase Inhibitor p21 , Mouth Neoplasms , Nanoparticles , Neoplastic Stem Cells , Resveratrol , Tumor Suppressor Protein p53 , Zinc Finger Protein GLI1 , beta Catenin , Apoptosis/drug effects , Neoplastic Stem Cells/drug effects , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/pathology , Resveratrol/pharmacology , Zinc Finger Protein GLI1/metabolism , Zinc Finger Protein GLI1/genetics , beta Catenin/metabolism , Tumor Suppressor Protein p53/metabolism , Humans , Mouth Neoplasms/pathology , Mouth Neoplasms/drug therapy , Mouth Neoplasms/metabolism , Animals , Cyclin-Dependent Kinase Inhibitor p21/metabolism , Cyclin-Dependent Kinase Inhibitor p21/genetics , Mice , Cell Line, Tumor , Xenograft Model Antitumor Assays
16.
BMC Cancer ; 24(1): 673, 2024 Jun 03.
Article En | MEDLINE | ID: mdl-38825709

Hepatocellular carcinoma (HCC) genomic research has discovered actionable genetic changes that might guide treatment decisions and clinical trials. Nonetheless, due to a lack of large-scale multicenter clinical validation, these putative targets have not been converted into patient survival advantages. So, it's crucial to ascertain whether genetic analysis is clinically feasible, useful, and whether it can be advantageous for patients. We sequenced tumour tissue and blood samples (as normal controls) from 111 Chinese HCC patients at Qingdao University Hospital using the 508-gene panel and the 688-gene panel, respectively. Approximately 95% of patients had gene variations related to targeted treatment, with 50% having clinically actionable mutations that offered significant information for targeted therapy. Immune cell infiltration was enhanced in individuals with TP53 mutations but decreased in patients with CTNNB1 and KMT2D mutations. More notably, we discovered that SPEN, EPPK1, and BRCA2 mutations were related to decreased median overall survival, although MUC16 mutations were not. Furthermore, we found mutant MUC16 as an independent protective factor for the prognosis of HCC patients after curative hepatectomy. In conclusion, this study connects genetic abnormalities to clinical practice and potentially identifies individuals with poor prognoses who may benefit from targeted treatment or immunotherapy.


Carcinoma, Hepatocellular , Liver Neoplasms , Mutation , Humans , Liver Neoplasms/genetics , Liver Neoplasms/therapy , Liver Neoplasms/mortality , Liver Neoplasms/pathology , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/therapy , Carcinoma, Hepatocellular/mortality , Carcinoma, Hepatocellular/pathology , Male , Female , Prognosis , Middle Aged , Aged , Adult , Biomarkers, Tumor/genetics , Genomics/methods , BRCA2 Protein/genetics , Molecular Targeted Therapy , Hepatectomy , Gene Expression Profiling , Tumor Suppressor Protein p53/genetics , DNA-Binding Proteins , Neoplasm Proteins , beta Catenin
17.
PLoS One ; 19(6): e0303134, 2024.
Article En | MEDLINE | ID: mdl-38837975

In recent years, a cancer research trend has shifted towards identifying novel therapeutic compounds from natural assets for the management of cancer. In this study, we aimed to assess the cytotoxic activity of Kigelia Africana (KA) extracts on breast cancer (MDA-MB-231 and MCF-7) and noncancerous kidney cells (HEK-293T) to develop an efficient anticancer medication. We used gas chromatography mass spectrometry (GC-MS to analyze the constituents of EKA and HKA extracts meanwhile the crystal violet and the MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) assays were used to examine the possible cytotoxic effects of plant extracts on our cancer cell lines along with non-cancerous control. The quantitative real-time PCR (RT-PCR) was run on cell samples to evaluate the differential expression of cell proliferative markers of cancer (BCL-2 and TP53). These phytochemicals have been reported to have binding affinity for some other growth factors and receptors as well which was evaluated by the in-silico molecular docking against Bcl2, EGFR, HER2, and TP53. Our Morphological observation showed a significant difference in the cell morphology and proliferation potential which was decreased under the effect of plant extracts treatment as compared to the control samples. The ethanol extract exhibited a marked antiproliferative activity towards MDA-MB-231 and MCF-7 cell lines with IC50 = 20 and 32 µg/mL, respectively. Quantitative RT-PCR gene expression investigation revealed that the IC50 concentration of ethanolic extract regulated the levels of mRNA expression of apoptotic genes. With the target and active binding site amino acids discovered in the molecular docking investigation, TP53/Propanoic acid, 3-(2, 3, 6-trimethyl-1, 4-dioxaspiro [4.4] non-7-yl)-, methyl ester (-7.1 kcal/mol) is the best-docked ligand. The use of this plant in folk remedies justifies its high in vitro anti-cancer capabilities. This work highlights the role of phytochemicals in the inhibition of cancer proliferation. Based on all these findings, it can be concluded that EKA extract has promising anti-proliferative effect on cancerous cells but more study is required in future to further narrow down the active ingredients of total crude extract with specific targets in cancer cells.


Molecular Docking Simulation , Plant Extracts , Tumor Suppressor Protein p53 , Humans , Plant Extracts/pharmacology , Plant Extracts/chemistry , MCF-7 Cells , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , Cell Proliferation/drug effects , Cell Line, Tumor , Antineoplastic Agents, Phytogenic/pharmacology , Antineoplastic Agents, Phytogenic/chemistry , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Breast Neoplasms/metabolism , Gene Expression Regulation, Neoplastic/drug effects , Female , HEK293 Cells , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-bcl-2/metabolism
18.
Sci Rep ; 14(1): 13058, 2024 06 06.
Article En | MEDLINE | ID: mdl-38844774

The incidence of vulvar carcinoma varies by race; however, it is a rare disease, and its genomic profiles remain largely unknown. This study examined the characteristics of vulvar squamous cell carcinoma (VSCC) in Japanese patients, focusing on genomic profiles and potential racial disparities. The study included two Japanese groups: the National Cancer Center Hospital (NCCH) group comprised 19 patients diagnosed between 2015 and 2023, and the Center for Cancer Genomics and Advanced Therapeutics group comprised 29 patients diagnosed between 2019 and 2022. Somatic mutations were identified by targeted or panel sequencing, and TP53 was identified as the most common mutation (52-81%), followed by HRAS (7-26%), CDKN2A (21-24%), and PIK3CA (5-10%). The mutation frequencies, except for TP53, were similar to those of Caucasian cohorts. In the NCCH group, 16 patients of HPV-independent tumors were identified by immunohistochemistry and genotyping. Univariate analysis revealed that TP53-mutated patients were associated with a poor prognosis (log-rank test, P = 0.089). Japanese VSCC mutations resembled those of Caucasian vulvar carcinomas, and TP53 mutations predicted prognosis regardless of ethnicity. The present findings suggest potential molecular-targeted therapies for select VSCC patients.


Carcinoma, Squamous Cell , Mutation , Tumor Suppressor Protein p53 , Vulvar Neoplasms , Humans , Female , Vulvar Neoplasms/genetics , Vulvar Neoplasms/pathology , Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/pathology , Middle Aged , Aged , Tumor Suppressor Protein p53/genetics , Japan/epidemiology , Aged, 80 and over , Cyclin-Dependent Kinase Inhibitor p16/genetics , Class I Phosphatidylinositol 3-Kinases/genetics , Prognosis , Adult , Asian People/genetics , Genomics/methods , Proto-Oncogene Proteins p21(ras)/genetics , East Asian People
19.
PeerJ ; 12: e17532, 2024.
Article En | MEDLINE | ID: mdl-38873643

Background: Hepatocellular carcinoma (HCC) is an aggressive malignancy with limited effective treatment options. Phenethyl isothiocyanate (PEITC) is a bioactive substance present primarily in the cruciferous vegetables. PEITC has exhibited anti-cancer properties in various cancers, including lung, bile duct, and prostate cancers. It has been demonstrated that PEITC can inhibit the proliferation, invasion, and metastasis of SK-Hep1 cells, while effectively inducing apoptosis and cell cycle arrest in HepG2 cells. However, knowledge of its anti-carcinogenic effects on Huh7.5.1 cells and its underlying mechanism remains elusive. In the present study, we aim to evaluate the anti-carcinogenic effects of PEITC on human HCC Huh7.5.1 cells. Methods: MTT assay and colony formation assay was performed to investigate the anti-proliferative effects of PEITC against Huh7.5.1 cells. The pro-apoptosis effects of PEITC were determined by Annexin V-FITC/PI double staining assay by flow cytometry (FCM), mitochondrial transmembrane potential (MMP) measurement, and Caspase-3 activity detection. A DAPI staining and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay was conducted to estimate the DNA damage in Huh7.5.1 cells induced by PEITC. Cell cycle progression was determined by FCM. Transwell invasion assay and wound healing migration assay were performed to investigate the impact of PEITC on the migration and invasion of Huh7.5.1 cells. In addition, transcriptome sequencing and gene set enrichment analysis (GSEA) were used to explore the potential molecular mechanisms of the inhibitory effects of PEITC on HCC. Quantitative real-time PCR (qRT-PCR) analysis was performed to verify the transcriptome data. Results: MTT assay showed that treatment of Huh7.5.1 cells with PEITC resulted in a dose-dependent decrease in viability, and colony formation assay further confirmed its anti-proliferative effect. Furthermore, we found that PEITC could induce mitochondrial-related apoptotic responses, including a decrease of mitochondrial transmembrane potential, activation of Caspase-3 activity, and generation of intracellular reactive oxygen species. It was also observed that PEITC caused DNA damage and cell cycle arrest in the S-phase in Huh7.5.1 cells. In addition, the inhibitory effect of PEITC on the migration and invasion ability of Huh7.5.1 cells was assessed. Transcriptome sequencing analysis further suggested that PEITC could activate the typical MAPK, PI3K-Akt, and p53 signaling pathways, revealing the potential mechanism of PEITC in inhibiting the carcinogenic properties of Huh7.5.1 cells. Conclusion: PEITC exhibits anti-carcinogenic activities against human HCC Huh7.5.1 cells by activating MAPK/PI3K-Akt/p53 signaling pathways. Our results suggest that PEITC may be useful for the anti-HCC treatment.


Apoptosis , Carcinoma, Hepatocellular , Cell Proliferation , Isothiocyanates , Liver Neoplasms , Proto-Oncogene Proteins c-akt , Signal Transduction , Humans , Isothiocyanates/pharmacology , Isothiocyanates/therapeutic use , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/metabolism , Liver Neoplasms/drug therapy , Liver Neoplasms/pathology , Liver Neoplasms/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Cell Line, Tumor , Signal Transduction/drug effects , Apoptosis/drug effects , Cell Proliferation/drug effects , Phosphatidylinositol 3-Kinases/metabolism , Tumor Suppressor Protein p53/metabolism , Tumor Suppressor Protein p53/genetics
20.
J Cancer Res Clin Oncol ; 150(6): 303, 2024 Jun 11.
Article En | MEDLINE | ID: mdl-38861187

BACKGROUND: Human MARCH5 is a mitochondria-localized E3 ubiquitin-protein ligase that is essential for the regulation of mitochondrial dynamics. A large body of evidence suggests that imbalances in mitochondrial dynamics are strongly associated with cancer. However, the expression, biological function and prognostic significance of MARCH5 in hepatocellular carcinoma (HCC) have not been determined. MATERIALS AND METHODS: The mRNA and protein expression of MARCH5 in HCC cell lines and tumor tissues was assessed by real-time quantitative PCR, Western blot analysis and immunohistochemistry. The clinical prognostic significance of MARCH5 was evaluated in 135 HCC patients. Knockdown or overexpression of MARCH5 in HCC cells was determined by in vitro cell proliferation, migration and invasion assays, and in vivo tumor growth and metastasis assays. In addition, the intrinsic mechanisms by which MARCH5 regulates HCC cell growth and metastasis were explored. RESULTS: MARCH5 was significantly overexpressed in HCC cells and was closely associated with patients' poor postoperative prognosis. In vivo and in vitro experiments revealed that MARCH5 significantly promoted the increase and invasive and migratory ability of hepatocellular carcinoma cells, which was mainly due to the promotion of autophagy by MARCH5. Mechanistic studies revealed that MARCH5 promoted autophagy through ubiquitination degradation of p53 leading to malignant progression of hepatocellular carcinoma. CONCLUSION: Our findings suggest that MARCH5 plays a critical oncogenic role in HCC cells, which provides experimental evidence for the use of MARCH5 as a potential target for HCC therapy.


Carcinoma, Hepatocellular , Disease Progression , Liver Neoplasms , Mice, Nude , Tumor Suppressor Protein p53 , Ubiquitin-Protein Ligases , Ubiquitination , Humans , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/genetics , Liver Neoplasms/pathology , Liver Neoplasms/metabolism , Liver Neoplasms/genetics , Ubiquitin-Protein Ligases/metabolism , Ubiquitin-Protein Ligases/genetics , Tumor Suppressor Protein p53/metabolism , Tumor Suppressor Protein p53/genetics , Male , Animals , Mice , Female , Prognosis , Cell Proliferation , Middle Aged , Cell Line, Tumor , Mice, Inbred BALB C , Cell Movement
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