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Objective:Observing the effect of exosomes derived from hypoxic Bone marrow mesenchymal stem cells (BMSCs) on the function of chondrocytes, and exploring the role and mechanism of exosomal miR-196b-5p. Evaluating the application prospects of hypoxic BMSCs exosomes and miR-196b-5p for cartilage regeneration.Methods:Chondrocytes were cultured in the supernatant of BMSCs cultured under normoxia or hypoxia, respectively. The proliferation of chondrocytes was detected by CCK-8 assay and the expressions of Collagen type 2 (Col2), Col1, Aggrecan and SOX9 were detected by qPCR to evaluate the effect of hypoxic BMSCs paracrine on chondrocyte functions. Obtaining normoxic and hypoxic exosomes through ultracentrifugation, and testing their effects on the proliferation and anabolic-related genes of chondrocytes through CCK-8 assay and qPCR. Verifying the expression of miR-196b-5p in hypoxic exosomes based on exosomal miRNA array. Knocking out miR-196b-5p in hypoxic BMSCs, and detecting the effect of hypoxic exosomal miR-196b-5p on the functions of chondrocytes by loss-of-function assay. Predicting the downstream of miR-196b-5p through bioinformatics tools, and exploring the mechanism of hypoxic exosomal miR-196b-5p by gain-of-function assays. Hypoxic exosomes and miR-196b-5p-knockout hypoxic exosomes were loaded on silk fibroin hydrogel and subcutaneously into nude mice. After 4 weeks of culture, histological staining of saffron O, Masson and biochemical content of sGAG and collagen were performed to assess the application prospect of hypoxic exosomes and hypoxic exosomal miR-196b-5p on cartilage regeneration. Results:The results of CCK-8 assay and qPCR indicated that the supernatant of hypoxic BMSCs significantly promoted the proliferation of chondrocytes 1.20±0.07 and the expression of cartilage-related markers (Col2 2.95±0.17, Aggrecan 2.45±0.27, SOX9 2.92±0.29) compared to normoxic BMSCs (0.94±0.04, 1.89±0.09, 1.67±0.21, 1.76±0.16), the differences were statistically significant ( P<0.05). The result of CCK-8 assay showed that hypoxic exosomes (1.28±0.04) promoted the proliferation of chondrocytes compared to normoxic exosomes 1.05±0.06, the differences were statistically significant ( P<0.05). CCK-8 assay revealed that the down-regulation of miR-196b-5p in hypoxic exosomes 0.99±0.06 attenuated the proliferation of chondrocytes compared to control group 1.20±0.07, the differences were statistically significant ( P<0.05); the expression of Col2 0.56±0.04, Aggrecan 0.74±0.09, and SOX9 0.45±0.05 in chondrocytes was reduced in the miR-196b-5p knockdown group compared to the control group (1.00±0.09, 1.00±0.12, 1.00±0.07), the differences were statistically significant ( P<0.05). Co-transfection of pmirGLO-BACH1-WT reporter vector with miR-196b-5p mimics decreased the luciferase activity 0.73±0.06, the differences were statistically significant ( P<0.05). Co-transfection of pmirGLO-BACH1-MUT reporter vector with miR-196b-5p mimics showed no change in luciferase activity. BACH1 is the target of miR-196b-5p. Subcutaneous culture in nude mice showed that hypoxic exosomes significantly promoted the deposition of sGAG 383.2±21.54 and collagen 67.40±3.45, while reducing the expression of miR-196b-5p in hypoxic exosomes weakened the deposition of sGAG 258.4±19.50 and collagen 57.15±4.95, the differences were statistically significant ( P<0.05). Conclusion:Hypoxic exosomes promoted the functions of chondrocytes by inhibiting the expression of BACH1 through miR-196b-5p. Hypoxic exosomes can be applied in cartilage regeneration.
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Microribonucleic acid (miRNAs) is a widely existing endogenous single-stranded non-coding small RNA, which is stably expressed in tissues and body fluids. By complementing messenger RNA(mRNA) sequences, miRNAs degrade target mRNA and block the expression of protein-coding genes, playing a key role in post-transcriptional regulation and different biological processes. In recent years, more and more studies have shown that miRNAs are closely related to the occurrence and development of tumors. Among them, as a member of the miRNAs family, microribonucleic acid-196 (miR-196) is abnormally expressed in the serum, tissues and cells of patients with non-small cell lung cancer, participating in the occurrence and development of non-small cell lung cancer and playing an important regulatory role in various biological processes such as proliferation, invasion and metastasis, providing diagnostic evidence for early screening of non-small cell lung cancer.This paper reviews the progress of miR-196 in the development and diagnosis of non-small cell lung cancer.
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Objective:To investigate the expression and clinical significance of serum miR-193-5p and miR-196-5p in children with IgA nephropathy (IgAN).Methods:The 95 children with IgAN (IgAN group), 80 children with non IgAN nephritis (non IgAN group) and 50 normal subjects (control group) in Sanya Women and Children's Hospital of Shanghai Children's Medical Center and Sanya People's Hospital were selected to be included in this study. According to Oxford classification score (MEST), children with IgAN were divided into 35 cases with MEST≥3 points and 60 cases with MEST<3 points. The serum levels of miR-193-5p, miR-196-5p, IgA/C3 and galactose deficient IgA1 molecule (Gd-IgA1) in each group were compared. The receiver operating characteristic (ROC) curve was drawn to analyze the value of miR-193-5p, miR-196-5p, IgA/C3 and Gd-IgA1 in the diagnosis of IgAN. Pearson correlation analysis was used to analyze the correlation between the expression levels of miR-193-5p, miR-196-5p and IgA/C3 and Gd-IgA1.Results:The serum levels of miR-193-5p, miR-196-5p, IgA/C3 and Gd-IgA1 in IgAN group were significantly higher than those in non IgAN group and control group (all P<0.001). The levels of miR-193-5p, miR-196-5p, IgA/C3 and Gd-IgA1 in MEST≥3 group were significantly higher than those in MEST<3 group (all P<0.001). ROC curve analysis showed that the area under the curve for the combined diagnosis of IgAN by miR-193-5p, miR-196-5p, IgA/C3 and Gd-IgA1 was 0.958 (95% CI: 0.902-0.998), with sensitivity of 98.6% and specificity of 86.4%. Pearson correlation analysis showed that the expression levels of serum miR-193-5p and miR-196-5p in IgAN children were positively correlated with IgA/C3 and Gd-IgA1 (all P<0.001). Conclusions:The expression levels of serum miR-193-5p and miR-196-5p were significantly increased in children with IgAN, and the combined detection of IgA/C3 and Gd-IgA1 has high value for the diagnosis of IgAN in children.
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As a member of the miRNA family,microRNA-196a(miR-196a) has received much attention in recent years. MiR-196a not only plays an important regulatory role in various biological processes, but it also shows that miR-196a also func-tions as oncogene in the tumorigenesis and progression. In recent studies, miR-196a is high expression in the serum, tissues and cells of patients with cancer,and can promote tumor cell proliferation,invasion and metastasis,inhibit tumor cell apoptosis and en-hance tumor drug resistance. In this paper,we reviewed the research progress on the correlation between miR-196a and tumor based on the latest reports at domestics and abroad.
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Objective To construct miR-196b sponge lentiviral vector,and laid the foundation for studying the function of miR-196b in bone marrow stromal cells.Methods Based on the miR-196b mature sequence,a sequence consisting of 6 tandem repeats of the complementary sequence of miR-196b was designed,and which was cloned into pUC19 plasmid by using reverse PCR.Then the six-repeat sequence was cut and subcloned into pLVX-shRNA2 lentiviral vector.The lentivirus was packaged using 293T cells,and titer determination was done.The pLVX-shRNA2 lentivirus was used as the control group,and the 196b-sponge-pLVX lentivirus was the experimental group.Then ST2 cells were infected with the viruses,and the infection efficiency was calculated.The protein level of forkhead box O1 (FoxO1) was detected by Western blot assay.Results The identity of the sponge sequence was verified by sequencing.The titer of the sponge virus was 1 × 108 PFU/mL,and the infection efficiency reached 80％.Compared with the control group,the expression level of FoxO 1 protein was significantly increased (P ＜ 0.05).Conclusion The miR-196b sponge lentiviral vector is successfully constructed,and which has the capability to inhibit endogenous miR-196b.
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Objective To determine the effect of miR-196 on sensitivity of endocrine therapy for breast cancer and to explore its possible molecular mechanism.Methods The expression of miR-196 was detected by real-time quantitative PCR (RT-qPCR) in MCF7 (ER+) and BT549 (ER-).The sensitivity of tamoxifen on MCF7 cells was evaluated by MTT and colony formation.Dual-luciferase,RT-qPCR and western blot assays were used to determine the regulation of miR-196 on p27.Results The expression of miR-196 was up-regulated in BT549 compared to that in MCF7 cells.The cell viability and colony formation were increased in miR-196-overexpressed MCF7 cells compared to those in the control cells after treatment with tamoxifen.The luciferase activity and expression of p27 were decreased in miR-196-overexpressed MCF7 cells compared to those in the control cells.Overexpression of p27 eliminated the effect of miR-196-induced endocrine therapy resistance in MCF7 cell.Conclusion miR-196 promotes breast cancer endocrine resistance by targeting p27.
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Background and purpose:miR-196a2 functions as an oncogene during tumor initiation and pro-gression. The up-regulation promotes tumor cell proliferation, invasion and metastasis. Therefore, it is promising to be an important tumor biomarker. The aim of this study was to investigate whether rs11614913, a gene polymorphic site ofmiR-196a2, is associated with the risk of leukemia.Methods:A case-control analysis was employed. Bone marrow or periph-eral blood was collected from 210 leukemia patients diagnosed from Jan. 2009 to Jul. 2015 in Yantaishan Hospital (case group) as well as 250 healthy people who were physically examined during the same period (control group). Polymerase chain reaction-restriction fragment length polymorphism (PCR-PFLP) was used to detect the genotype of rs11614913. Application test was used to compare the difference in the frequency of each genotype between case group and control group. The odds ratio (OR) of SNP allelic genes was calculated using logistic regression analysis and 95%CI represented the risk of leukemia for each genotype.Results:The distribution differences in the frequency of T/T, C/C, C/T genotype of miR-196a2 rs11614913 between case group and control group were statistically significant (P<0.05). The risk of leukemia for individuals who carried mutant homozygous C/C was 2.661-fold higher than those carried wild-type homozygous T/T, and the difference was statistically significant (P<0.05).Conclusion:ThemiR-196a2 gene polymorphic site rs11614913 was associated with the risk of leukemia. Mutant homozygous C/C or C allelic gene carrying was probably a risk factor for leukemia.
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OBJECTIVE@#To explore the expression, biological function and possible mechanism of action of microRNA molecular-196a (miR-196a) in epithelial ovarian cancer.@*METHODS@#RT-PCR was used to detect the expression quantities of epithelial ovarian tissue, benign ovarian tissue, normal ovary epithelial tissue, ovarian cancer cell lines and miR-196a in normal ovarian epithelial cells to analyze the relationship between the expression of miR-196a and the clinical pathologic parameters of ovarian cancer. Among those cell lines, the cell line of which miR-196a expressed the most or least was selected and transfected the ovarian cancer cell line by using negative control plasma and miR-196a inhibitor. After transfection, RT-PCR was used to test the expression quantity of miR-196a, Transwell chamber method was applied to determine the migration and invasion abilities of ovarian carcinoma cells and Western blot was employed to detect the expression of HOXA10 protein.@*RESULTS@#The relative expression quantities of miR-196a in ovarian cancer tissue and benign ovarian tissue were significantly higher than that in normal ovarian epithelial tissue, and the expression quantity of miR-196a in ovarian cancer tissue was distinctively higher than that in benign ovarian tissue (P 0.05). Compared with normal ovarian epithelial cell line IOSE80, the expression quantities of miR-196a of all ovarian cancer cell lines increased obviously and differences were statistically significant (P < 0.05). Among them, the expression of miR-196a of ovarian cancer cell line SKOV3 was the highest, while it decreased significantly (4.678 ± 0.785 vs. 2.131 ± 0.345, t = 2.938, P < 0.05) after the ovarian cancer cell line SKOV3 was transfected by miR-196a inhibitor. The results of Transwell chamber method showed that the migration and invasion abilities of ovarian cancer cells SKOV3 were declined significantly after the expression of miR-196a was down-regulated and the difference showed statistical significance (P < 0.05). The results of Western blot revealed that the relative expression of HOXA10 decreased distinctly after the expression of miR-196a was down-regulated and also the difference showed statistical significance (P < 0.05).@*CONCLUSIONS@#The miR-196a might serve as a cancer-promoting gene to promote the migration and invasion of epithelial ovarian cancer by downstream target gene HOXA10.
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Objective To explore the expression, biological function and possible mechanism of action of microRNA molecular-196a (miR-196a) in epithelial ovarian cancer. Methods RT-PCR was used to detect the expression quantities of epithelial ovarian tissue, benign ovarian tissue, normal ovary epithelial tissue, ovarian cancer cell lines and miR-196a in normal ovarian epithelial cells to analyze the relationship between the expression of miR-196a and the clinical pathologic parameters of ovarian cancer. Among those cell lines, the cell line of which miR-196a expressed the most or least was selected and transfected the ovarian cancer cell line by using negative control plasma and miR-196a inhibitor. After transfection, RT-PCR was used to test the expression quantity of miR-196a, Transwell chamber method was applied to determine the migration and invasion abilities of ovarian carcinoma cells and Western blot was employed to detect the expression of HOXA10 protein. Results The relative expression quantities of miR-196a in ovarian cancer tissue and benign ovarian tissue were significantly higher than that in normal ovarian epithelial tissue, and the expression quantity of miR-196a in ovarian cancer tissue was distinctively higher than that in benign ovarian tissue (P 0.05). Compared with normal ovarian epithelial cell line IOSE80, the expression quantities of miR-196a of all ovarian cancer cell lines increased obviously and differences were statistically significant (P < 0.05). Among them, the expression of miR-196a of ovarian cancer cell line SKOV3 was the highest, while it decreased significantly (4.678 ± 0.785 vs. 2.131 ± 0.345, t = 2.938, P < 0.05) after the ovarian cancer cell line SKOV3 was transfected by miR-196a inhibitor. The results of Transwell chamber method showed that the migration and invasion abilities of ovarian cancer cells SKOV3 were declined significantly after the expression of miR-196a was down-regulated and the difference showed statistical significance (P < 0.05). The results of Western blot revealed that the relative expression of HOXA10 decreased distinctly after the expression of miR-196a was down-regulated and also the difference showed statistical significance (P < 0.05). Conclusions The miR-196a might serve as a cancer-promoting gene to promote the migration and invasion of epithelial ovarian cancer by downstream target gene HOXA10.
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BACKGROUND: Accumulating evidence has confirmed that miR-196a plays a critical role in tumorigenesis and tumor progression in a variety of cancers. It has been demonstrated that miR-196a is highly up-regulated in laryngeal cancer by miRNA profiling analysis. However, the functional mechanism of miR-196a in laryngeal cancer remains unclear. This study aims to explore the mechanism of miR-196a in laryngeal cancer METHODS: In the present study, we conducted qPCR analysis of miR-196a expression in human laryngeal cancer and showed that miR-196a was overexpressed in tumor-derived samples and laryngeal cancer cell lines compared with matched normal controls. Further functional analysis of miR-196a demonstrated that the inhibition of miR-196a could inhibit laryngeal cell-cycle progression and proliferation in vitro. Luciferase reporter assay and western blot confirmed that miR-196a directly targeted p27kip1. Moreover, in order to investigate whether miR-196a regulated cell growth in laryngeal cancer cells by targeting p27kip1, rescue studies were performed in laryngeal cancer cells RESULTS: Results showed that overexpression of p27kip1 rescue decreased cell proliferation caused by miR-196a inhibitors. A negative relation between miR-196a and p27kip1 expression in laryngeal cancer tissues were also noted by further analyses CONCLUSIONS: The present study showed that miR-196a was upregulated in laryngeal cancer and promoted cell proliferation by downregulating p27kip1 in laryngeal cancer. However, further studies are needed to verify this finding
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Objective: To evaluate the clinical value of the plasma microRNA-155 (miR-155), miR-196a, miR-21 and miR-210 in early diagnosis of patients with pancreatic cancer. Methods: The real-time fluorescent quantitative-PCR was performed to detect the levels of miR-155, miR-196a, miR-21 and miR-210 in plasma samples from sixty patients with pancreatic cancer, twenty patients with chronic pancreatitis, and ten healthy volunteers, as well as the levels of four miRNAs in cancer tissue specimens from ten patients with pancreatic cancer. The serum tumor markers carbohydrate antigen 199 (CA199), CA242 and carcino-embryonic antigen (CEA) were simultaneously detected. The relative expression levels of four miRNAs in plasma among these three groups were compared, and the relationship between miRNA levels in plasma and their levels in pancreatic cancer tissues were statistically analyzed. Finally, the diagnostic efficiency of plasma miR-155, miR-196a, miR-21 and miR-210 for pancreatic cancer was evaluated. Results: The relative expression levels of plasma miR-155, miR-196a, miR-21 and miR-210 in pancreatic cancer group were significantly higher than those in the chronic pancreatitis group and the healthy control group (all P 0.05). The area under receiver operating characteristic (AUC-ROC) curve of plasma miR-155, miR-196a, miR-21 and miR-210 in diagnosis of pancreatic cancer indicated that these four miRNAs had diagnostic value independently (all P < 0.01), in which miR-155 had the highest diagnostic efficiency. The binary Logistic regression model showed that combined detection of plasma miR-196a and miR-210 was more effective in diagnosis of stageI pancreatic cancer as compared with CA199. Conclusion: The plasma miR-155, miR-196a, miR-21 and miR-210 levels are effective to distinguish pancreatic cancer from non-pancreatic cancer. The combined detection of miR-196a and miR-210 may become a promising method for early diagnosis of pancreatic cancer.
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Objective To evaluate the expression of miR-196b in newly diagnosed pediatric acute myeloid leukemia (AML) and its clinical signiifcance. Methods Fifty-two AML children were enrolled in this study and 30 non-leukemia com-pared children were selected as controls. The expressions of miR-196b were detected in bone marrow samples by real-time quan-titative PCR (q-RT-PCR) and the results were expressed in 2-??Ct. Results miR-196b expressions were signiifcantly higher in M4-5 and lower in non-M4-5 of AML children than those in control (P<0.01), with a lowest level in t (15;17) and a highest level in MLL subtypes (P<0.01). The miR-196b expressions were signiifcantly different among different prognosis groups (P<0.01) and the level in the favorable prognostic group was lower than in poor prognosis group. It was also found that miR-196b expres-sion was lower in remission group than that in no-remission group after the ifrst induction remission therapy (P<0.05). Mean-while, the expression of miR-196b in the children with WBC≥100×109/L were statistically higher than that in the children with WBC<100×109/L (P<0.01), and miR-196b level was positively correlated with the platelet counts (r=0.302, P=0.030). Conclu-sions miR-196b expression is increased in poor prognosis group of AML children, and high expression of miR-196b is related with low response rate and poor prognosis. miR-1966 is expected to become a new target for the treatment of AML.
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Objective To study if 5-Aza-2’-deoxycytidine along or together with 4-phenylbutyric acid could affect miR-196b expression levels in chronic myeloid leukemia cells .Methods K562 cells were treated with DNA methylation inhibitor 5-Aza-2’-deoxycytidine, histone deacetylase inhibitors 4-phenylbutyric acid separately and the combined treatment with both of them, then expression levels of miR-196b were detected using Real-time PCR.Results The half inhibition concentration of 4-phenylbutyric acid was 1.58mmol/L.Comparing with the expression level of miR-196b in normal human bone marrow cells, the expression levels of miR-196b were significantly lower in Aza group , PBA group and negative control cells and nearly consistent among three groups , and as high as normal cells in combined treatment group . Conclusion The expression level of miR-196b in K562 cells could not return to normal treated with 5-Aza-2 ’-deoxycytidine or 4-phenylbutyric acid separately , while could restore normal when treated with both agents , indicating that miR-196b expression level in K562 cells is related with both DNA methylation and histone acetylation .
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Background and purpose: Colorectal cancer (CRC) is the most frequently occurring primary malignant tumor. Chemotherapy can reduce the risk of local and distant relapse. Therefore, it is very important to ifnd new biomarkers that can predict chemoresistant and help in treatment decisions. Methods:In this study, we examined the expression levels of 1 200 human miRNAs in 6 CRC tissues, using miRNA proifling assay arrays. A validation study was done to corroborate a subset of the results, including expression levels of miR-4299, miR-196b, miR-324-5p, miR-455-3p and miR-939, by analyzing 100 specimens of stageⅣcolorectal adenocarcinoma (not respond and respond to the chemotherapy) to quantitative real-time PCR. We modeled the relationship between the expression levels of these miRNAs and the survival rate of 100 CRC patients by Kaplan-Meier method. Results:Expression proifles in CRCs suggested that 5 miRNAs were candidate markers associated with the chemoresistance of colorectal cancer. We found that miR-4299 and-196b had signiifcant diagnostic value for chemoresistance CRC. miR-4299 yielded an AUC (the areas under the ROC curve) of 0.784 and miR-196b yielded an AUC of 0.647 in discriminating CRC from controls. Combined ROC analysis using these 2 miRNAs revealed an elevated AUC of 0.848 with 67.9%sensitivity and 90.9%speciifcity in discriminating chemoresistance CRC. The low level of miR-4299 expression and the high level of-196b expression are signiifcantly correlated with the good survival of CRC patients. Conclusion:These data suggest that miR-4299 and-196b have strong potential as novel biomarkers for chemoresistant detection of colorectal cancer.
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Obesity gives vent to many diseases such as type 2 diabetes, hypertension, and hyperlipidemia, being considered as the main causes of mortality and morbidity worldwide. The pathogenesis and pathophysiology of metabolic syndrome can well be understood by studying the molecular mechanisms that control the development and function of adipose tissue. In human body, exist two types of adipose tissue, the white and the brown one, which are reported to play various roles in energy homeostasis. The major and most efficient storage of energy occurs in the form of triglycerides in white adipose tissue while brown adipose tissue actively participates in both basal and inducible energy consumption in the form of thermogenesis. Recent years have observed a rapid and greater interest towards developmental plasticity and therapeutic potential of stromal cells those isolated from adipose tissue. The adipocyte differentiation involves a couple of regulators in the white or brown adipogenesis. Peroxisome proliferators-activated receptor-gamma actively participates in regulating carbohydrate and lipid metabolism, and also acts as main regulator of both white and brown adipogenesis. This review based on our recent research, seeks to highlight the adipocyte differentiation.
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Humans , Adipocytes , Adipocytes, Brown , Adipogenesis , Adipose Tissue , Adipose Tissue, Brown , Adipose Tissue, White , DNA-Directed DNA Polymerase , Genes, Homeobox , Homeostasis , Human Body , Hyperlipidemias , Hypertension , Lipid Metabolism , Obesity , Peroxisomes , Stromal Cells , Thermogenesis , TriglyceridesABSTRACT
BACKGROUND/AIMS: Intraductal papillary mucinous neoplasms (IPMN) are precursor lesions of fatal pancreatic cancer. Physiological function of microRNA is to regulate the stability and translation of mRNA. The aberrant microRNA expression is commonly observed in many cancers. The aim of this study was to analyze the expression pattern of microRNA in IPMN and evaluate the role of the microRNA. METHODS: Using two paraffin-embedded IPMN tissues, microRNA expression of normal tissue, IPMN adenoma and carcinoma were compared by cDNA-mediated annealing, selection, extension and ligation microarray assay. Using real time PCR, expression levels of aberrantly up-regulated microRNAs were assessed in another 20 IPMNs, four pancreatic cancer cell lines (Panc1, MiaPaCa-2, XPA-3, BxPC-3) and immortalized pancreatic ductal cell line (HPNE). Effect of suppressing highly over-expressed two microRNAs in pancreatic cancer cell lines with anti-microRNA inhibitors were evaluated using CCK-8 assay. RESULTS: Among aberrantly expressed 122 microRNAs in IPMN, miR-552, miR-25*, miR-183, miR-1300, miR-196a, miR-182*, and miR-30c-1* were consistently increased more than 3-fold. On average, miR-196a and miR-183 increased 10,824 folds and 26,519 folds in four pancreatic cancer cell lines compared with HPNE. These two microRNAs were also over-expressed in 20 IPMNs compared with HPNE. After applying anti-miRNA inhibitors, cell survival of four pancreatic cancer cell lines decreased by 24.5% with anti-miR-196a and by 14.2% with anti-miR-183 on average. CONCLUSIONS: Aberrant expression of 122 microRNAs was observed in IPMN. Two microRNAs, miR-196a and miR-183-increased in IPMN and pancreatic cancer cell lines compared with immortalized dancreatic ductal cell line. The inhibitions of these microRNAs repressed cell proliferation of pancreatic cancer cell lines.