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1.
Transl Oncol ; 40: 101851, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38042137

ABSTRACT

Colorectal cancer (CRC) is the third most prevalent cancer in the world. The PD-1/PD-L1 pathway plays a crucial role in modulating immune response to cancer, and PD-L1 expression has been observed in tumor and immune cells within the tumor microenvironment of CRC. Thus, immunotherapy drugs, specifically checkpoint inhibitors, have been developed to target the PD-1/PD-L1 signaling pathway, thereby inhibiting the interaction between PD-1 and PD-L1 and restoring T-cell function in cancer cells. However, the emergence of resistance mechanisms can reduce the efficacy of these treatments. To counter this, monoclonal antibodies (mAbs) have been used to improve the efficacy of CRC treatments. mAbs such as nivolumab and pembrolizumab are currently approved for CRC treatment. These antibodies impede immune checkpoint receptors, including PD-1/PD-L1, and their combination therapy shows promise in the treatment of advanced CRC. This review presents a concise overview of the use of the PD-1/PD-L1 blockade as a therapeutic strategy for CRC using monoclonal antibodies and combination therapies. Additionally, this article outlines the function of PD-1/PD-L1 as an immune response suppressor in the CRC microenvironment as well as the potential advantages of administering inflammatory agents for CRC treatment. Finally, this review analyzes the outcomes of clinical trials to examine the challenges of anti-PD-1/PD-L1 therapeutic resistance.

2.
Clin Chim Acta ; 543: 117305, 2023 Mar 15.
Article in English | MEDLINE | ID: mdl-36966964

ABSTRACT

Colorectal cancer (CRC) is the third leading cause of cancer-related death in men and women worldwide. As early detection is associated with lower mortality, novel biomarkers are urgently needed for timely diagnosis and appropriate management of patients to achieve the best therapeutic response. Long noncoding RNAs (lncRNAs) have been reported to play essential roles in CRC progression. Accordingly, the regulatory roles of lncRNAs should be better understood in general and for identifying diagnostic, prognostic and predictive biomarkers in CRC specifically. In this review, the latest advances on the potential diagnostic and prognostic lncRNAs as biomarkers in CRC samples were highlighted, Current knowledge on dysregulated lncRNAs and their potential molecular mechanisms were summarized. The potential therapeutic implications and challenges for future and ongoing research in the field were also discussed. Finally, novel insights on the underlying mechanisms of lncRNAs were examined as to their potential role as biomarkers and therapeutic targets in CRC. This review may be used to design future studies and advanced investigations on lncRNAs as biomarkers for the diagnosis, prognosis and therapy in CRC.


Subject(s)
Colorectal Neoplasms , RNA, Long Noncoding , Humans , Female , Colorectal Neoplasms/diagnosis , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , RNA, Long Noncoding/genetics , Prognosis , Biomarkers, Tumor/genetics , Gene Expression Regulation, Neoplastic
4.
Heart Surg Forum ; 22(3): E215-E217, 2019 05 22.
Article in English | MEDLINE | ID: mdl-31237546

ABSTRACT

BACKGROUND: This study aims to investigate the correlation between premature coronary heart disease (pCHD) and both serum homocysteine (Hcy) and hypersensitive C-reactive protein (hs-CRP). METHODS: A total of 170 patients with pCHD were enrolled in this study from June 2014 to April 2016 (including 52 patients with stable angina pectoris [SAP], 70 patients with unstable angina pectoris [UAP], and 48 patients with acute myocardial infarction [AMI]), together with 105 healthy controls (CON) selected at the same period, to observe the changes of Hcy and hs-CRP in CHD patients and those with different types of CHD. RESULTS: The levels of serum Hcy and hs-CRP in group pCHD were significantly higher than in group CON (P < .05). The levels of Hcy and hs-CRP in group AMI were significantly higher than in group UAP and group SAP (P < .05). The changes of serum Hcy and hs-CRP were significantly higher in patients with multi-vascular lesions and dual-vascular lesions than in those with single-vascular lesion (P < .05). CONCLUSION: The levels of serum Hcy and hs-CRP in CHD patients are positively correlated with the severity of CHD, which increase with the increase of lesion count. The combined detection of Hcy and hs-CRP can initially reflect the severity of coronary artery, thus better guiding treatment and predicting prognosis.


Subject(s)
C-Reactive Protein/metabolism , Coronary Artery Disease/blood , Homocysteine/blood , Age Factors , Aged , Case-Control Studies , Coronary Artery Disease/diagnosis , Coronary Artery Disease/etiology , Female , Humans , Male , Middle Aged , Predictive Value of Tests , Severity of Illness Index
5.
Exp Cell Res ; 380(1): 80-89, 2019 07 01.
Article in English | MEDLINE | ID: mdl-31002815

ABSTRACT

CSTP1, a recently identified protein phosphotase, is frequently repressed in bladder cancers. Previous results showed that CSTP1 over-expression inhibited cell cycle progression and promoted apoptosis through dephosphorylating Akt kinase at Ser473 site in bladder cancer cells, but the mechanisms how CSTP1 exerted tumor suppressive activity remains unclear. In this study, we analyzed the gene expression profile changes that affected by CSTP1 overexpression by microarray, and reported that CSTP1 decreased IL-6 expression/secretion in bladder cancer cells and re-expression of IL-6 abrogated CSTP1's tumor suppressive activity. We also found that FoxO3a occupy IL-6 gene promoter and repressed IL mRNA transcription. Further results showed that decreased expression of IL-6 in CSTP1-overexpressing cells inactivated Stat3 transcriptional factor, which resulted in the down-regulation of cyclin D1, Bcl-xl expression. Spearman correlation analysis revealed that the mRNA level of CSTP1 correlated inversely with that of IL-6 in bladder cancer tissues. In conclusion, our studies revealed that protein phosphotase CSTP1 inhibited IL-6 expression through targeting Akt/FoxO3a signaling pathway and IL-6 inactivated Stat3 was necessary for CSTP1's tumor suppressive function.


Subject(s)
Calcineurin/genetics , Interleukin-6/genetics , STAT3 Transcription Factor/genetics , Urinary Bladder Neoplasms/genetics , Apoptosis/genetics , Cell Line, Tumor , Cell Proliferation/genetics , Forkhead Box Protein O3/genetics , Gene Expression Regulation, Neoplastic/genetics , Humans , Oncogene Protein v-akt/genetics , Signal Transduction/genetics , Urinary Bladder Neoplasms/pathology
6.
Mol Oncol ; 13(4): 811-828, 2019 04.
Article in English | MEDLINE | ID: mdl-30585695

ABSTRACT

Polybromo-1 (PBRM1) is an important tumor suppressor in kidney cancer. It contains six tandem bromodomains (BDs), which are specialized structures that recognize acetyl-lysine residues. While BD2 has been found to bind acetylated histone H3 lysine 14 (H3K14ac), it is not known whether other BDs collaborate with BD2 to generate strong binding to H3K14ac, and the importance of H3K14ac recognition for the molecular and tumor suppressor function of PBRM1 is also unknown. We discovered that full-length PBRM1, but not its individual BDs, strongly binds H3K14ac. BDs 2, 4, and 5 were found to collaborate to facilitate strong binding to H3K14ac. Quantitative measurement of the interactions between purified BD proteins and H3K14ac or nonacetylated peptides confirmed the tight and specific association of the former. Interestingly, while the structural integrity of BD4 was found to be required for H3K14ac recognition, the conserved acetyl-lysine binding site of BD4 was not. Furthermore, simultaneous point mutations in BDs 2, 4, and 5 prevented recognition of H3K14ac, altered promoter binding and gene expression, and caused PBRM1 to relocalize to the cytoplasm. In contrast, tumor-derived point mutations in BD2 alone lowered PBRM1's affinity to H3K14ac and also disrupted promoter binding and gene expression without altering cellular localization. Finally, overexpression of PBRM1 variants containing point mutations in BDs 2, 4, and 5 or BD2 alone failed to suppress tumor growth in a xenograft model. Taken together, our study demonstrates that BDs 2, 4, and 5 of PBRM1 collaborate to generate high affinity to H3K14ac and tether PBRM1 to chromatin. Mutations in BD2 alone weaken these interactions, and this is sufficient to abolish its molecular and tumor suppressor functions.


Subject(s)
Histones/metabolism , Lysine/metabolism , Nuclear Proteins/chemistry , Nuclear Proteins/metabolism , Transcription Factors/chemistry , Transcription Factors/metabolism , Tumor Suppressor Proteins/chemistry , Tumor Suppressor Proteins/metabolism , Acetylation , Amino Acid Sequence , Animals , Cell Line , DNA-Binding Proteins , Gene Expression Regulation, Neoplastic , Mice, Nude , Nuclear Proteins/genetics , Point Mutation/genetics , Promoter Regions, Genetic/genetics , Protein Binding , Protein Domains , Structure-Activity Relationship , Transcription Factors/genetics , Tumor Suppressor Proteins/genetics
7.
Heart Surg Forum ; 21(5): E337-E340, 2018 Aug 13.
Article in English | MEDLINE | ID: mdl-30311881

ABSTRACT

BACKGROUND: This study aims to investigate the relationship between polymorphism of adiponectin (ADIPOQ) gene SNPS+276 and the severity of coronary heart disease (CHD) and coronary artery disease (CAD). METHODS: A total of 582 inpatients were enrolled and divided into Group CHD (342 cases) and the control group (CON, 240 cases), according to their angiographic results from June 2014 to April 2016 for the genotype (G/T) analysis of ADIPOQ SNPs+276 by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: Group CHD: GG 110 (32%), GT 205 (59%), and TT27 (8%); Group CON: GG 36 (15%), GT 161 (67%), and TT 43 (18%) (P < .05). The frequency of allele G in group CHD was 62.1% and 48.5% in group CON (P < .05). The frequencies of genotype GG, GT, and TT were 67 (33.3%), 107 (53.2%), and 27 (13.5%), respectively, in the group with single vascular lesion, and 64 (45.4%), 53 (37.6%), and 24 (17%), respectively, in the group with multiple vascular lesions. There was statistical significance between the two groups (P < .05). CONCLUSIONS: The 276G gene of adiponectin may be a susceptibility gene of CHD, and the genotype GG may be related to the severity of this disease.


Subject(s)
Adiponectin/genetics , Coronary Stenosis/genetics , Coronary Vessels/diagnostic imaging , DNA/genetics , Genetic Predisposition to Disease , Polymorphism, Genetic , Adiponectin/blood , Aged , China/epidemiology , Coronary Angiography , Coronary Stenosis/blood , Coronary Stenosis/epidemiology , Female , Follow-Up Studies , Humans , Incidence , Male , Polymerase Chain Reaction , Retrospective Studies , Severity of Illness Index
8.
Elife ; 72018 10 25.
Article in English | MEDLINE | ID: mdl-30355451

ABSTRACT

Whereas VHL inactivation is a primary event in clear cell renal cell carcinoma (ccRCC), the precise mechanism(s) of how this interacts with the secondary mutations in tumor suppressor genes, including PBRM1, KDM5C/JARID1C, SETD2, and/or BAP1, remains unclear. Gene expression analyses reveal that VHL, PBRM1, or KDM5C share a common regulation of interferon response expression signature. Loss of HIF2α, PBRM1, or KDM5C in VHL-/-cells reduces the expression of interferon stimulated gene factor 3 (ISGF3), a transcription factor that regulates the interferon signature. Moreover, loss of SETD2 or BAP1 also reduces the ISGF3 level. Finally, ISGF3 is strongly tumor-suppressive in a xenograft model as its loss significantly enhances tumor growth. Conversely, reactivation of ISGF3 retards tumor growth by PBRM1-deficient ccRCC cells. Thus after VHL inactivation, HIF induces ISGF3, which is reversed by the loss of secondary tumor suppressors, suggesting that this is a key negative feedback loop in ccRCC.


Subject(s)
Basic Helix-Loop-Helix Transcription Factors/metabolism , Carcinoma, Renal Cell/pathology , Gene Expression Regulation , Genes, Tumor Suppressor , Interferon-Stimulated Gene Factor 3, gamma Subunit/metabolism , Kidney Neoplasms/pathology , Von Hippel-Lindau Tumor Suppressor Protein/metabolism , Animals , Cell Line, Tumor , Disease Models, Animal , Feedback, Physiological , Gene Expression Profiling , Heterografts , Humans , Mice, Nude , Neoplasm Transplantation
9.
Exp Cell Res ; 350(1): 1-8, 2017 Jan 01.
Article in English | MEDLINE | ID: mdl-27756608

ABSTRACT

Androgens (AR) play an important role in initiation and progression of prostate cancer. It has been shown that AR exert their effects mainly through the androgen-activated AR which binds to androgen response elements (AREs) in the regulatory regions of target genes to regulate the transcription of androgen-responsive genes, thus, identification of AR downstream target gene is critical to understand androgen function in prostate cancer. In this study, our results showed that androgen treatment of LNCaP cells induced PTTG1 expression, which was blocked by the androgen receptor antagonist, Casodex. Bioinformatics analysis and experiments using PTTG1 promoter deletion mutants showed that the PTTG1 promoter contains a putative androgen response element (ARE), which localizes in the -851 to -836 region of the promoter. Androgen activated androgen receptor (AR) binding to this ARE was confirmed by Chromatin immunoprecipitation (ChIP) assay. Furthermore, Knockdown of PTTG1 expression using short hairpin RNA significantly reduced androgen-induced LNCaP cell growth and invasion. In addition, we showed PTTG1 is highly expressed in metastasis prostate cancer tissue. These results suggest that PTTG1 is a novel downstream target gene of androgen receptor and take part in prostate cancer proliferation and metastasis.


Subject(s)
Cell Proliferation , Gene Expression Regulation, Neoplastic , Prostate/metabolism , Prostatic Neoplasms/genetics , Receptors, Androgen/metabolism , Securin/genetics , Animals , Cell Line, Tumor , Cell Proliferation/genetics , Humans , Male , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Receptors, Androgen/genetics , Securin/metabolism
10.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 24(6): 1863-1868, 2016 Dec.
Article in Chinese | MEDLINE | ID: mdl-28024509

ABSTRACT

OBJECTIVE: To investigate the in vitro effects of different culture systems on hematopoietic differentiation ability of induced pluripotent stem (iPS) cells. METHOD: Two culture systems including E8 and mTESR(freeder-free medium), and the classical ES culture medium were chosen for culture of iPS cells. The iPS cells maintaining in above mentioning culcure systems were co-cultured with OP9 cells(murine bone marrow stromal cells) in vitro to be induced to differentiate into hematopoietic stem/progenitor cells. Flow cytometry and real-time quantitative PCR were used to detect the expression of specific hematopoietic markers and the effects of different culture systems on the differentiation of iPS in vitro. RESULT: iPS cultured in the 3 selected medium could be differentiated into hematopoietic stem cells. Efficiency of hematopoietic differentiation was up to 28.4% in classical ES culture system, which was significantly higher than that in E8 and mTESR system. CONCLUSION: Under the co-culture with OP9, iPS can differentiate into hematopoietic stem/progenitor cells, which shows higher efficiency when iPS maintained in the ES medium.


Subject(s)
Cell Differentiation , Induced Pluripotent Stem Cells , Animals , Cells, Cultured , Coculture Techniques , Flow Cytometry , Hematopoietic Stem Cells , Mesenchymal Stem Cells , Mice
11.
Biomed Res Int ; 2016: 6701793, 2016.
Article in English | MEDLINE | ID: mdl-27847820

ABSTRACT

Spinocerebellar ataxia-3 (SCA3) is the most common dominant inherited ataxia worldwide and is caused by an unstable CAG trinucleotide expansion mutation within the ATXN3 gene, resulting in an expanded polyglutamine tract within the ATXN3 protein. Many in vitro studies have examined the role of autophagy in neurodegenerative disorders, including SCA3, using transfection models with expression of pathogenic proteins in normal cells. In the current study, we aimed to develop an improved model for studying SCA3 in vitro using patient-derived cells. The patient-derived iPS cells presented a phenotype similar to that of human embryonic stem cells and could be differentiated into neurons. Additionally, these cells expressed abnormal ATXN3 protein without changes in the CAG repeat length during culture for at least 35 passages as iPS cells, up to 3 passages as neural stem cells, and after 4 weeks of neural differentiation. Furthermore, we demonstrated that neural differentiation in these iPS cells was accompanied by autophagy and that rapamycin promoted autophagy through degradation of mutant ATXN3 proteins in neurally differentiated spinocerebellar ataxia-3 human induced pluripotent stem cells (p < 0.05). In conclusion, patient-derived iPS cells are a good model for studying the mechanisms of SCA3 and may provide a tool for drug discovery in vitro.


Subject(s)
Ataxin-3/metabolism , Autophagy/genetics , Induced Pluripotent Stem Cells/metabolism , Machado-Joseph Disease/metabolism , Repressor Proteins/metabolism , Ataxin-3/genetics , Cell Differentiation/genetics , Cell Line , Gene Expression Regulation , Humans , Induced Pluripotent Stem Cells/pathology , Karyotype , Machado-Joseph Disease/genetics , Machado-Joseph Disease/pathology , Neural Stem Cells/metabolism , Neural Stem Cells/pathology , Proteolysis , Repressor Proteins/genetics , Trinucleotide Repeats/genetics
12.
Sci Rep ; 6: 32463, 2016 09 01.
Article in English | MEDLINE | ID: mdl-27581487

ABSTRACT

ß-thalassemia results from point mutations or small deletions in the ß-globin (HBB) gene that ultimately cause anemia. The generation of induced pluripotent stem cells (iPSCs) from the somatic cells of patients in combination with subsequent homologous recombination-based gene correction provides new approaches to cure this disease. CRISPR/Cas9 is a genome editing tool that is creating a buzz in the scientific community for treating human diseases, especially genetic disorders. Here, we reported that correction of ß-thalassemia mutations in patient-specific iPSCs using the CRISPR/Cas9 tool promotes hematopoietic differentiation in vivo. CRISPR/Cas9-corrected iPSC-derived hematopoietic stem cells (HSCs) were injected into sublethally-irradiated NOD-scid-IL2Rg-/- (NSI) mice. HBB expression was observed in these HSCs after hematopoietic differentiation in the NSI mice. Importantly, no tumor was found in the livers, lungs, kidneys, or bone marrow at 10 weeks in the NSI mice after implantation with these HSCs. Collectively, our findings demonstrated that CRISPR/Cas9 successfully corrects ß-thalassemia mutations in patient-specific iPSCs. These CRISPR/Cas9-corrected iPSC-derived HSCs express normal HBB in mice without tumorigenic potential, suggesting a safe strategy for personalized treatment of ß-thalassemia.


Subject(s)
CRISPR-Cas Systems , Genetic Therapy/methods , Hematopoietic Stem Cells/metabolism , Induced Pluripotent Stem Cells/metabolism , beta-Globins/genetics , beta-Thalassemia/therapy , Animals , Cell Differentiation , Female , Gene Editing/methods , Gene Expression , Hematopoietic Stem Cell Transplantation , Hematopoietic Stem Cells/cytology , Homologous Recombination , Humans , Induced Pluripotent Stem Cells/pathology , Interleukin Receptor Common gamma Subunit/deficiency , Interleukin Receptor Common gamma Subunit/genetics , Mice , Mice, Inbred NOD , Mice, SCID , Mutation , Whole-Body Irradiation , beta-Globins/deficiency , beta-Thalassemia/genetics , beta-Thalassemia/metabolism , beta-Thalassemia/pathology
13.
J Biol Chem ; 291(32): 16576-85, 2016 08 05.
Article in English | MEDLINE | ID: mdl-27288406

ABSTRACT

ß-Thalassemia (ß-Thal) is one of the most common genetic diseases in the world. The generation of patient-specific ß-Thal-induced pluripotent stem cells (iPSCs), correction of the disease-causing mutations in those cells, and then differentiation into hematopoietic stem cells offers a new therapeutic strategy for this disease. Here, we designed a CRISPR/Cas9 to specifically target the Homo sapiens hemoglobin ß (HBB) gene CD41/42(-CTTT) mutation. We demonstrated that the combination of single strand oligodeoxynucleotides with CRISPR/Cas9 was capable of correcting the HBB gene CD41/42 mutation in ß-Thal iPSCs. After applying a correction-specific PCR assay to purify the corrected clones followed by sequencing to confirm mutation correction, we verified that the purified clones retained full pluripotency and exhibited normal karyotyping. Additionally, whole-exome sequencing showed that the mutation load to the exomes was minimal after CRISPR/Cas9 targeting. Furthermore, the corrected iPSCs were selected for erythroblast differentiation and restored the expression of HBB protein compared with the parental iPSCs. This method provides an efficient and safe strategy to correct the HBB gene mutation in ß-Thal iPSCs.


Subject(s)
CRISPR-Cas Systems , Genetic Therapy/methods , Hemoglobins/genetics , Induced Pluripotent Stem Cells , Mutation , Cell Line , Female , Humans
14.
Hepatology ; 64(2): 488-500, 2016 08.
Article in English | MEDLINE | ID: mdl-27015352

ABSTRACT

UNLABELLED: Hepatocellular carcinoma (HCC) is a major cause of cancer-related death worldwide and currently has the fastest rising incidence of all cancers. Sorafenib was originally identified as an inhibitor of multiple oncogenic kinases and remains the only approved systemic therapy for advanced HCC. However, acquired resistance to sorafenib has been found in HCC patients, which results in poor prognosis. Here, we show that metallothionein (MT)-1G is a critical regulator and promising therapeutic target of sorafenib resistance in human HCC cells. The expression of MT-1G messenger RNA and protein is remarkably induced by sorafenib but not other clinically relevant kinase inhibitors (e.g., erlotinib, gefitinib, tivantinib, vemurafenib, selumetinib, imatinib, masitinib, and ponatinib). Activation of the transcription factor nuclear factor erythroid 2-related factor 2, but not p53 and hypoxia-inducible factor 1-alpha, is essential for induction of MT-1G expression following sorafenib treatment. Importantly, genetic and pharmacological inhibition of MT-1G enhances the anticancer activity of sorafenib in vitro and in tumor xenograft models. The molecular mechanisms underlying the action of MT-1G in sorafenib resistance involve the inhibition of ferroptosis, a novel form of regulated cell death. Knockdown of MT-1G by RNA interference increases glutathione depletion and lipid peroxidation, which contributes to sorafenib-induced ferroptosis. CONCLUSION: These findings demonstrate a novel molecular mechanism of sorafenib resistance and suggest that MT-1G is a new regulator of ferroptosis in HCC cells. (Hepatology 2016;64:488-500).


Subject(s)
Antineoplastic Agents , Carcinoma, Hepatocellular/metabolism , Drug Resistance, Neoplasm , Liver Neoplasms/metabolism , Metallothionein/metabolism , Niacinamide/analogs & derivatives , Phenylurea Compounds , Animals , Cell Death , Hep G2 Cells , Humans , Mice, Nude , NF-E2-Related Factor 2/metabolism , Sorafenib
15.
Hepatology ; 63(1): 173-84, 2016 Jan.
Article in English | MEDLINE | ID: mdl-26403645

ABSTRACT

UNLABELLED: Ferroptosis is a recently recognized form of regulated cell death caused by an iron-dependent accumulation of lipid reactive oxygen species. However, the molecular mechanisms regulating ferroptosis remain obscure. Here, we report that nuclear factor erythroid 2-related factor 2 (NRF2) plays a central role in protecting hepatocellular carcinoma (HCC) cells against ferroptosis. Upon exposure to ferroptosis-inducing compounds (e.g., erastin, sorafenib, and buthionine sulfoximine), p62 expression prevented NRF2 degradation and enhanced subsequent NRF2 nuclear accumulation through inactivation of Kelch-like ECH-associated protein 1. Additionally, nuclear NRF2 interacted with transcriptional coactivator small v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog proteins such as MafG and then activated transcription of quinone oxidoreductase-1, heme oxygenase-1, and ferritin heavy chain-1. Knockdown of p62, quinone oxidoreductase-1, heme oxygenase-1, and ferritin heavy chain-1 by RNA interference in HCC cells promoted ferroptosis in response to erastin and sorafenib. Furthermore, genetic or pharmacologic inhibition of NRF2 expression/activity in HCC cells increased the anticancer activity of erastin and sorafenib in vitro and in tumor xenograft models. CONCLUSION: These findings demonstrate novel molecular mechanisms and signaling pathways of ferroptosis; the status of NRF2 is a key factor that determines the therapeutic response to ferroptosis-targeted therapies in HCC cells.


Subject(s)
Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/pathology , Cell Death/physiology , Intracellular Signaling Peptides and Proteins/physiology , Iron/physiology , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , NF-E2-Related Factor 2/physiology , RNA-Binding Proteins/physiology , Signal Transduction , Animals , Humans , Kelch-Like ECH-Associated Protein 1 , Mice , Mice, Inbred C57BL , Tumor Cells, Cultured
16.
World J Surg Oncol ; 13: 278, 2015 Sep 17.
Article in English | MEDLINE | ID: mdl-26381239

ABSTRACT

BACKGROUNDS: Radioactive tracer-based detection has been proposed as a standard procedure in identifying sentinel nodes for cN0 oral/oropharyngeal carcinoma. However, access to radioactive isotopes may be limited in some surgical centers, and there is potential risk of the radioactive tracers to the operators. This study was designed to evaluate the feasibility of near-infrared fluorescence imaging with indocyanine green combined with blue dye mapping in sentinel node biopsy for cN0 oral/oropharyngeal carcinoma. METHODS: Twenty-six cases of previously untreated oral/oropharyngeal carcinoma staged cT1-2N0M0 were enrolled in this study. One milliliter of indocyanine green (5 mg/ml) and 1.5 ml of methylene blue (1 mg/ml) were injected sequentially around the primary tumor in a four-quadrant pattern before skin incision. After elevation of the platysma flap and posterior retraction of the sternocleidomastoid muscle, fluorescence images were taken with a near-infrared detector, with special attention paid to any blue-dyed lymph nodes. Lymph nodes identified first with fluorescent hot spots with or without blue dye were defined as sentinel nodes, and they were harvested and sent for pathologic study. RESULTS: Sentinel nodes were successfully harvested in all 26 cases. The number of sentinel nodes (SNs) per case varied from 1 to 9, with an average of 3.4. Routine pathology demonstrated occult metastasis exclusively in SNs in four cases (15.4 %). No tracer-associated side effects occurred in this series. CONCLUSIONS: Near-infrared imaging using indocyanine green combined with methylene blue mapping is a feasible and reliable new method for SN biopsy in cN0 oral/oropharyngeal carcinoma.


Subject(s)
Carcinoma, Squamous Cell/secondary , Indocyanine Green , Mouth Neoplasms/pathology , Oropharyngeal Neoplasms/pathology , Radioactive Tracers , Radiopharmaceuticals , Sentinel Lymph Node Biopsy , Adult , Aged , Carcinoma, Squamous Cell/diagnostic imaging , Carcinoma, Squamous Cell/surgery , Coloring Agents , Female , Follow-Up Studies , Humans , Lymphatic Metastasis , Male , Middle Aged , Mouth Neoplasms/diagnostic imaging , Mouth Neoplasms/surgery , Neoplasm Staging , Oropharyngeal Neoplasms/diagnostic imaging , Oropharyngeal Neoplasms/surgery , Prognosis , Radionuclide Imaging
17.
Stem Cells Dev ; 24(9): 1053-65, 2015 May 01.
Article in English | MEDLINE | ID: mdl-25517294

ABSTRACT

The generation of beta-thalassemia (ß-Thal) patient-specific induced pluripotent stem cells (iPSCs), subsequent homologous recombination-based gene correction of disease-causing mutations/deletions in the ß-globin gene (HBB), and their derived hematopoietic stem cell (HSC) transplantation offers an ideal therapeutic solution for treating this disease. However, the hematopoietic differentiation efficiency of gene-corrected ß-Thal iPSCs has not been well evaluated in the previous studies. In this study, we used the latest gene-editing tool, clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9), to correct ß-Thal iPSCs; gene-corrected cells exhibit normal karyotypes and full pluripotency as human embryonic stem cells (hESCs) showed no off-targeting effects. Then, we evaluated the differentiation efficiency of the gene-corrected ß-Thal iPSCs. We found that during hematopoietic differentiation, gene-corrected ß-Thal iPSCs showed an increased embryoid body ratio and various hematopoietic progenitor cell percentages. More importantly, the gene-corrected ß-Thal iPSC lines restored HBB expression and reduced reactive oxygen species production compared with the uncorrected group. Our study suggested that hematopoietic differentiation efficiency of ß-Thal iPSCs was greatly improved once corrected by the CRISPR/Cas9 system, and the information gained from our study would greatly promote the clinical application of ß-Thal iPSC-derived HSCs in transplantation.


Subject(s)
CRISPR-Cas Systems , Embryonic Stem Cells/cytology , Hematopoiesis , Hematopoietic Stem Cells/cytology , Induced Pluripotent Stem Cells/cytology , beta-Globins/genetics , beta-Thalassemia/genetics , Cells, Cultured , Embryonic Stem Cells/metabolism , Genetic Therapy/methods , Hematopoietic Stem Cells/metabolism , Humans , Induced Pluripotent Stem Cells/metabolism , beta-Globins/metabolism , beta-Thalassemia/therapy
18.
PLoS One ; 8(11): e80544, 2013.
Article in English | MEDLINE | ID: mdl-24260413

ABSTRACT

Somatic mutations or loss of expression of tumor suppressor VHL happen in the vast majority of clear cell Renal Cell Carcinoma, and it's causal for kidney cancer development. Without VHL, constitutively active transcription factor HIF is strongly oncogenic and is essential for tumor growth. However, the contribution of individual HIF-responsive genes to tumor growth is not well understood. In this study we examined the contribution of important HIF-responsive genes such as VEGF, CCND1, ANGPTL4, EGLN3, ENO2, GLUT1 and IGFBP3 to tumor growth in a xenograft model using immune-compromised nude mice. We found that the suppression of VEGF or CCND1 impaired tumor growth, suggesting that they are tumor-promoting genes. We further discovered that the lack of ANGPTL4, EGLN3 or ENO2 expression did not change tumor growth. Surprisingly, depletion of GLUT1 or IGFBP3 significantly increased tumor growth, suggesting that they have tumor-inhibitory functions. Depletion of IGFBP3 did not lead to obvious activation of IGFIR. Unexpectedly, the depletion of IGFIR protein led to significant increase of IGFBP3 at both the protein and mRNA levels. Concomitantly, the tumor growth was greatly impaired, suggesting that IGFBP3 might suppress tumor growth in an IGFIR-independent manner. In summary, although the overall transcriptional activity of HIF is strongly tumor-promoting, the expression of each individual HIF-responsive gene could either enhance, reduce or do nothing to the kidney cancer tumor growth.


Subject(s)
Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/metabolism , Gene Expression Regulation, Neoplastic , Hypoxia-Inducible Factor 1/metabolism , Angiopoietin-Like Protein 4 , Angiopoietins/genetics , Angiopoietins/metabolism , Animals , Carcinoma, Renal Cell/pathology , Cell Line, Tumor , Cyclin D1/genetics , Cyclin D1/metabolism , Disease Models, Animal , Gene Knockout Techniques , Glucose Transporter Type 1/genetics , Glucose Transporter Type 1/metabolism , Humans , Hypoxia-Inducible Factor-Proline Dioxygenases/genetics , Hypoxia-Inducible Factor-Proline Dioxygenases/metabolism , Insulin-Like Growth Factor Binding Protein 3/genetics , Insulin-Like Growth Factor Binding Protein 3/metabolism , Mice , Phosphopyruvate Hydratase/genetics , Phosphopyruvate Hydratase/metabolism , Receptor, IGF Type 1/genetics , Receptor, IGF Type 1/metabolism , Transcriptional Activation , Tumor Burden/genetics , Vascular Endothelial Growth Factor A/genetics , Vascular Endothelial Growth Factor A/metabolism , Von Hippel-Lindau Tumor Suppressor Protein/genetics , Von Hippel-Lindau Tumor Suppressor Protein/metabolism , Xenograft Model Antitumor Assays
19.
J Asian Nat Prod Res ; 11(4): 365-70, 2009.
Article in English | MEDLINE | ID: mdl-19431018

ABSTRACT

By introducing octyloxy to C-3 and alkyl groups to C-8 of jatrorrhizine, a series of 3-octyloxy-8-alkyljatrorrhizine derivatives were synthesized and their antimicrobial activities were evaluated in vitro. The results indicated that the derivatives exhibited high antimicrobial activities, especially against Gram-positive bacteria. The 3-octyloxy-8-butyljatrorrhizine displayed the highest antimicrobial activity in all compounds. Their structure-activity relationships were discussed.


Subject(s)
Bacteria/drug effects , Berberine , Candida tropicalis/drug effects , Drugs, Chinese Herbal , Berberine/analogs & derivatives , Berberine/chemical synthesis , Berberine/chemistry , Berberine/pharmacology , Drugs, Chinese Herbal/chemical synthesis , Drugs, Chinese Herbal/chemistry , Drugs, Chinese Herbal/pharmacology , Microbial Sensitivity Tests , Molecular Structure , Ranunculaceae/chemistry
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