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Biomedical subjects

Jie Yang

Publications and source records attributed to Jie Yang.

At least 145 records · Page 8Linked to original sources
PubMed2004

The effect of ovariectomy on mandibular cortical thickness in the rat.

OBJECTIVES: The purpose of this study was to investigate the effects of long-term oestrogen deficiency on mandibular cortical thickness in ovariectomized rats. METHODS: Twelve female rats either underwent ovariectomy or received a sham-operation. One year later images of the left side of the mandible were made using a standardized radiographic protocol. Manual measurements were made of the lower mandibular cortical thickness at three locations. The mean cortical thickness was also assessed using a specially developed image analysis program by placing points at three positions, identical to those used for the manual measurements, and additionally at 20 points evenly distributed along the mandibular cortex. RESULTS: The mean mandibular cortical thickness of the ovariectomized mandibles was significantly less than that of the sham-operated rats, measured using the computer image analysis (p=0.016, 95% CI=0.125, 0.016) and measured manually (p=0.011, 95% CI=0.0218, 0.1309). When 20 computational points were used, the mean mandibular cortical width of the ovariectomized rats was significantly less than that for the control rats (p=0.016, 95% CI=0.127, 0.018). CONCLUSIONS AND CLINICAL IMPLICATIONS: Long-term oestrogen deficiency in ovariectomized rats decreased the mandibular cortical thickness. If our result is applicable to human studies, a considerable duration of oestrogen deficiency may be necessary before a reduction of mandibular cortical bone loss can be observed. Because mandibular cortical bone is resistant to resorption, the value of clinically determined mandibular cortical thickness measurements as a method of detecting patients at risk of osteoporosis may have a reduced importance in younger postmenopausal patients.

Animals↗
PubMed2004

Enhancement of antibody production and expression of c-Fos in the insular cortex in response to a conditioned stimulus after a single-trial learning paradigm.

Immune responses can be modulated by Pavlovian conditioning techniques. In this study, to evaluate the conditionability of antibody response via a single-trial conditioning paradigm, we used a protein antigen ovalbumin as an unconditioned stimulus (UCS) that was paired with a novel taste of saccharin in a single-trial learning protocol. A significant enhancement of anti-ovalbumin antibody production was observed in the conditioned rats at Days 15, 20 and 25 after re-exposure to the conditioned stimulus. The pattern of conditioned antibody response is similar to that of antigen-induced antibody response. Furthermore, to identify the involvement of a limbic brain structure in the expression of conditioned antibody response, immediate-early gene c-fos expression was used as a marker of neuronal activation to detect the functional activation in the insular cortex (IC) in response to the conditioned stimulus. The re-exposure of conditioned rats to the conditioned stimulus resulted in a significant increase of c-Fos immunoreactivity in all three areas of the IC including the agranular, dysgranular, and granular areas, suggesting that IC is involved in the neural mechanism of expression of conditioned immune response.

Analysis of Variance↗
PubMed2004

Ferulic acid inhibits vascular smooth muscle cell proliferation induced by angiotensin II.

The aim of this study was to determine the effects of ferulic acid on the proliferation and molecular mechanism in cultured vascular smooth muscle cell (VSMC) induced by angiotensin II. It was shown that ferulic acid significantly inhibited angiotensin II-induced VSMC proliferation in a dose-dependent manner. Western blotting analyses suggest that the antiproliferative effect of ferulic acid was involved in the mitogen-activated protein kinases (MAPKs) pathway. While no effect on p38, ferulic acid markedly inactivated the extracellular signal-regulated kinases (ERK1/2) and c-Jun N-terminal kinases (JNK), indicating that the inhibition of ferulic acid on VSMC proliferation was associated with ERK1/2 and JNK rather than p38 pathway. On the expression of cell cycle regulatory proteins, ferulic acid elevated the protein content of p21(waf1/cip1), decreased expression of cyclin D1 and inhibited phosphorylation of retinoblastoma protein, suggesting that ferulic acid inhibited VSMC proliferation by regulating the cell progression from G1 to S phase. The inactivation of MAPKs and modulation of cell cycle proteins of ferulic acid may be of importance in preventing cardiovascular disease.

Angiotensin II↗
PubMed2004

Protective effect of Ligusticum chuanxiong and Angelica sinensis on endothelial cell damage induced by hydrogen peroxide.

Ligusticum chuanxiong and Angelica sinensis have been widely used in traditional Chinese medicine to treat some pathological settings such as atherosclerosis and hypertension. We determined the protective effect of the extract of Ligusticum chuanxiong and Angelica sinensis (ELCAS) on human umbilical vein endothelial cells (ECV304) damage induced by hydrogen peroxide. ECV304 cells were pre-treated with ELCAS and exposed to 5 mM hydrogen peroxide. The results show that ELCAS dose- and time-dependently protected ECV304 cells against hydrogen peroxide damage and suppressed the production of reactive oxygen species (ROS). The decrement of ROS may be associated with increased activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX). Western blot analysis revealed that ELCAS significantly increased the phosphorylation of ERK and promoted eNOS expression. These observations indicate that ELCAS protected ECV304 cells against hydrogen peroxide damage by enhancing the antioxidative ability, activating ERK and eNOS signaling pathway. Our data also provide new evidence of Ligusticum chuanxiong and Angelica sinensis in preventing both cardiovascular and cerebrovascular diseases.

Analysis of Variance↗
PubMed2004

Weighted-support vector machines for predicting membrane protein types based on pseudo-amino acid composition.

Membrane proteins are generally classified into the following five types: (1) type I membrane proteins, (2) type II membrane proteins, (3) multipass transmembrane proteins, (4) lipid chain-anchored membrane proteins and (5) GPI-anchored membrane proteins. Prediction of membrane protein types has become one of the growing hot topics in bioinformatics. Currently, we are facing two critical challenges in this area: first, how to take into account the extremely complicated sequence-order effects, and second, how to deal with the highly uneven sizes of the subsets in a training dataset. In this paper, stimulated by the concept of using the pseudo-amino acid composition to incorporate the sequence-order effects, the spectral analysis technique is introduced to represent the statistical sample of a protein. Based on such a framework, the weighted support vector machine (SVM) algorithm is applied. The new approach has remarkable power in dealing with the bias caused by the situation when one subset in the training dataset contains many more samples than the other. The new method is particularly useful when our focus is aimed at proteins belonging to small subsets. The results obtained by the self-consistency test, jackknife test and independent dataset test are encouraging, indicating that the current approach may serve as a powerful complementary tool to other existing methods for predicting the types of membrane proteins.

Algorithms↗
PubMed2004

IL-9-mediated induction of eotaxin1/CCL11 in human airway smooth muscle cells.

Recent work has shown the potential importance of IL-9 in allergic diseases. The development of transgenic mice overexpressing IL-9 has suggested a key role for this cytokine in the development of the asthmatic phenotype including airway eosinophilia. In this study, we evaluated the expression of the IL-9R and the effects of IL-9 on human ASM cells by examining the release of Th2-associated chemokines (eotaxin1/CCL11 and thymus- and activation-regulated chemokine (TARC)/CCL17). IL-9R alpha-chain mRNA and surface expression were detected in cultured human airway smooth muscle (ASM) cells. In addition, primary cultured ASM cells, as well as bronchial smooth muscle cells within biopsies of asthmatics and not control subjects, revealed IL-9R protein expression. IL-9 stimulation of human ASM cells resulted in release of eotaxin1/CCL11, but had no effect on the release of TARC/CCL17, in time- and dose-dependent manner. Moreover, in vitro chemotaxis assay demonstrated that conditioned medium from IL-9-stimulated ASM cells attracted human eosinophils. Neutralizing Abs to IL-9, but not to IL-4 or IL-13, reduced significantly IL-9-induced production of eotaxin1/CCL11 from ASM cells. Interestingly, real-time RT-PCR showed that IL-9 up-regulated eotaxin1/CCL11 mRNA expression, but had no effect on TARC/CCL17. Treatment with Act D abrogates IL-9-induced eotaxin1/CCL11 mRNA and protein release by ASM cells. Finally, transfection study using eotaxin1/CCL11 promoter luciferase construct confirmed that IL-9 induced eotaxin1/CCL11 at the transcriptional level. Taken together, these data provide new evidence demonstrating that IL-9-dependent activation of ASM cells contributes to eosinophilic inflammation observed in asthma.

Asthma↗
PubMed2004

Immunohistochemical localization of inducible and endothelial nitric oxide synthase in porcine ovaries and effects of NO on antrum formation and oocyte meiotic maturation.

The present study is to investigate the immunolocalization of endothelial and inducible nitric oxide synthase (eNOS, iNOS) in porcine ovary and the effect of nitric oxide (NO) on antrum formation and oocyte meiotic resumption. In Experiment 1, preantral follicles (250-300 microm in diameter) were cultured in 0 (Control), 0.1, 0.3, 0.5 or 1 mM sodium nitroprusside (SNP), a NO donor. In Experiment 2, the cumulus-oocyte complexes (COCs) aspirated from medium follicles (3-6 mm in diameter) were incubated in 0.1mM SNP or two inhibitors for NOS, 10 mM aminoguanidine bicarbonate salt (AG) or 1 mM Nomega-nitro-l-arginine methyl ester (L-NAME), alone or concomitantly. In Experiment 3, ovarian tissues, corpus luteum (CL), corpus albican (CA) and COCs from small (1-2 mm in diameter), medium (3-6 mm) and large follicles (7-10 mm) were isolated, rinsed, fixed, paraffin embedded and stained by the conventional avidin-biotin complex method for the detection of eNOS and iNOS production. The results showed that 0.1mM SNP had no effect on antrum formation (P > 0.05) while 0.3, 0.5 or 1 mM significantly inhibited the antrum formation (P < 0.05). AG markedly inhibited porcine oocyte meiotic resumption (P < 0.05) while L-NAME inhibited first polar body (PB1) extrusion (P < 0.05). The immunoreactivity of eNOS in early antral follicles was restricted to oocyte and it increased from small, medium to large follicle-enclosed oocytes. Cumulus cells from large follicles showed weak eNOS immunoreactivity but those from small or medium follicles not. In CL, eNOS-positive staining was shown in granulosa lutein cells. In CA, it was in some parenchymal cells. In contrast, no immunoreactivity for iNOS was found in primordial, early antral follicle or the COCs aspirated from small and medium follicles. The large follicle-enclosed oocyte showed weak immunoreactivity. In CL, some granulosa lutein cells showed iNOS-positive cytoplasm. Such immunostaining was not found in CA. The results demonstrate that porcine ovaries have distinct cell-specific expression of both eNOS and iNOS, and that NO derived from both NOS is actively involved in meiotic resumption. Nitric oxide is not involved in the antrum formation of preantral follicles but exogenous NO inhibits the antrum formation. Endothelial nitric oxide synthase and inducible nitric oxide synthase might be differently functional in CL development and regression.

Animals↗
PubMed2004

[Expression of germ cell nuclear factor in rat epididymis during postnatal development].

OBJECTIVE: To explore the expression and distribution of germ cell nuclear factor (GCNF), an orphan receptor of the nuclear receptor superfamily which is supposed to have multifunction including spermatogenesis, neurogenesis and embryo development, in adult rat epididymis and young rats during postnatal development. METHODS: Whole epididymis was collected from SD rats' aged 7, 14, 28, 45, 60 and 90 days, and 18 months. The protein expression of GCNF during rat epididymal development and its cellular localizations were examined by Western blotting and immunohistochemistry respectively. RESULTS: GCNF was immunolocalized in the nuclei of epididymal epithelial cells with negatively stained cytoplasm in rats during postnatal development. Study of postnatal development revealed that the density of GCNF protein (about 55000) was age-dependent. GCNF protein was first detected in the rats aged day 14. The number and intensity of positive cells increased along with differentiation and proliferation of the epithelium, and peaked when the rats were aged 45 days and then decreased gradually. The results of Western-blotting confirmed those of immunohistochemistry. In adult rats, basal cell, apical cell, narrow cell, and clear cell and halo cell. GCNF in the principal cells exhibited a region-specific and cell-specific expression pattern that was observed from the age of 14 days. The GCNF expression was gradually decreased from the initial segment to proximal cauda epididymis. There was a predominant expression in the proximal caput region. The principal cells in the same segment also displayed a variable staining pattern, with the nucleus being intensely, moderately, or weekly reactive. In the distal cauda epididymis, only the nuclei of clear cells displayed an intensive staining, as compared with very weak staining in the principal cells. CONCLUSION: The expression of GCNF may be concerned with the differentiation and development of epididymal epithelium, and its expression pattern is epididymal segment-specific and cell-specific.

Age Factors↗
PubMed2004

Inhibition of insulin-like growth factor I receptor autophosphorylation by novel 6-5 ring-fused compounds.

The insulin-like growth factor 1 receptor (IGF1R) plays an important role in cell transformation, and it has emerged as a target for anti-cancer drug design. IGF1R is activated by autophosphorylation at three sites in the enzyme activation loop. We describe here a group of 6-5 ring-fused compounds that are the first reported inhibitors selective for the unphosphorylated (0P) form of IGF1R. These compounds do not significantly inhibit the fully activated, triply phosphorylated (3P) form. IGF1R was produced from baculovirus-infected Spodoptera frugiperda (Sf9) cells, and the 0P and 3P forms were purified to homogeneity. We used a continuous spectrophotometric assay to measure inhibition of the 0P and 3P forms. Analysis by native gel electrophoresis confirmed that the step inhibited in the autoactivation process was the transition between the 0P and IP forms of IGF1R. The compounds were also active against IGF1R autophosphorylation in intact Chinese hamster ovary (CHO) cells. Most of the compounds also inhibited the closely related insulin receptor to varying degrees, although some compounds showed selectivity for IGF1R or insulin receptor. This class of compounds could form the basis of design efforts to selectively block the autoinhibited conformation of IGF1R.

Animals↗
PubMed2004

A novel missense mutation of the ATP2A2 gene in a Chinese family with Darier's disease.

Darier's disease (DD) is an autosomal dominant skin disorder that is characterized by multiple keratotic papules, focal loss of adhesion and abnormal keratinization. Mutations in the ATP2A2 gene encoding sarco/endoplasmic reticulum calcium pumping ATPase type 2 have been identified as the molecular basis of DD. We report here a three-generation family with DD, and examined ATP2A2 gene mutations in this family by direct sequencing. A novel missense mutation A-->G was identified in exon 12, nucleotide 1704, which leads to the substitution of lysine by arginine at codon 514 (K514R). This study contributes to the database on ATP2A2 in DD, and further illustrates the extensive diversity of mutational events that lead to the different phenotypes of DD.

Adenine↗
PubMed2004

Natural product glycorandomization.

glycorandomization is a chemoenzymatic strategy that overcomes the limitations in natural product derivatization associated with both solely chemistry-based approaches or in vivo engineering. In this article we present the basic strategies for glycorandomization development as a next-generation tool in drug discovery.

Carbohydrate Sequence↗
PubMed2004

Crystal structure of a cAMP-dependent protein kinase mutant at 1.26A: new insights into the catalytic mechanism.

The catalytic subunit of cAMP-dependent protein kinase has served as a paradigm for the entire kinase family. In the course of studying the structure-function relationship of the P+1 loop (Leu198-Leu205) of the kinase, we have solved the crystal structure of the Tyr204 to Ala mutant in complexes with Mg.ATP and an inhibitory peptide at 1.26A, with overall structure very similar to that of the wild-type protein. However, at the nucleotide binding site, ATP was found largely hydrolyzed, with the products ADP-PO(4) retained in the structure. High-resolution refinement suggests that 26% of the molecules contain the intact ATP, whereas 74% have the hydrolyzed products. The observation of the substrate and product states in the same structure adds significant information to our understanding of the phosphoryl transfer process. Structural examination of the mutation site substantiates and extends the emerging concept that the hydrophobic core in the large lobe of the kinase might serve as a stable platform for anchoring key segments involved in catalysis. We propose that Tyr204 is critical for anchoring the P+1 loop to the core. Further analysis has highlighted two major connections between the P+1 loop and the catalytic loop (Arg165-Asn171). One emphasizes the hydrophobic packing of Tyr204 and Leu167 mediated through residues from the alphaF-helix, recently recognized as a signal integration motif, which together with the alphaE-helix forms the center of the hydrophobic core network. The other connection is mediated by the hydrogen bond interaction between Thr201 and Asp166, in a substrate-dependent manner. We speculate that the latter interaction may be important for the kinase to sense the presence of substrate and prepare itself for the catalytic reaction. Thus, the P+1 loop is not merely involved in substrate binding; it mediates the communication between substrate and catalytic residues.

Adenosine Triphosphatases↗
PubMed2004

Zero kinetic energy photoelectron study of SO2+(X2A1) using coherent extreme ultraviolet radiation.

Using our newly built extreme ultraviolet (XUV) photoelectron and photoion spectrometer, we have obtained the pulsed field ionization zero kinetic energy (ZEKE) photoelectron spectra of SO2+(X2A1)<--SO2(X1A1) by coherent XUV radiation in the energy range of 12.29-12.82 eV. The adiabatic ionization potential (IP) of SO2 is 12.3458+/-0.0002 (eV), which was determined by comparing the partially resolved rotational branch contour with the simulated one. Besides the bending vibrational mode (upsilon2) which was found to be exclusive in the photoelectron spectra (PE) reported previously, we also observed the other two modes: the symmetric stretching (upsilon1) and the antisymmetric stretching (upsilon3) vibrations. The fundamental of the symmetric stretching (upsilon(1)) is 1057 cm(-1) and the overtone of the antisymmetric stretching (2upsilon(3)) is 2494 cm(-1). The new vibrational progressions (upsilon(1)00)+, (1upsilon(2)0)+, (2upsilon(2)0)+, and (0upsilon(2)2)+ have also been observed, and these new observations suggested that the irregular structure of (0upsilon(2)0)+ assigned to the previous PE spectra should be reconsidered. The comparison of the intensities of these vibrational bands with the calculated Franck-Condon factors with harmonic approximation was also made.

Journal Article↗
PubMed2004

Emodin enhances arsenic trioxide-induced apoptosis via generation of reactive oxygen species and inhibition of survival signaling.

Although arsenic trioxide (As(2)O(3)) induces apoptosis in a relatively wide spectrum of tumors, the sensitivity of different cell types to this treatment varies to a great extent. Because reactive oxygen species (ROS) are critically involved in As(2)O(3)-induced apoptosis, we attempted to explore the possibility that elevating the cellular ROS level might be an approach to facilitate As(2)O(3)-induced apoptosis. Emodin, a natural anthraquinone derivative, was selected because its semiquinone structure is likely to increase the generation of intracellular ROS. Its independent and synergistic effects with As(2)O(3) in cytotoxicity were studied, and the plausible signaling mechanism was investigated in HeLa cells. Cell Proliferation Assay and flow cytometry were used to assess cell viability and apoptosis. Electrophoretic mobility shift assay, luciferase reporter assay, and Western blotting were performed to analyze signaling alteration. The results demonstrated that coadministration of emodin, at low doses of 0.5-10 micro M, with As(2)O(3) enhanced As(2)O(3)-rendered cytotoxicity on tumor cells, whereas these treatments caused no detectable proproliferative or proapoptotic effects on nontumor cells. ROS generation was increased, and activation of nuclear factor kappaB and activator protein 1 was suppressed by coadministration. All enhancements by emodin could be abolished by the antioxidant N-acetyl-L-cysteine. Therefore, we concluded that emodin sensitized HeLa cells to As(2)O(3) via generation of ROS and ROS-mediated inhibition on two major prosurvival transcription factors, nuclear factor kappaB and activator protein 1. This result allows us to propose a novel strategy in chemotherapy that uses mild ROS generators to facilitate apoptosis-inducing drugs whose efficacy depends on ROS.

Apoptosis↗
PubMed2004

Natural killer T cells contribute to airway eosinophilic inflammation induced by ragweed through enhanced IL-4 and eotaxin production.

Although NKT cells have been found to be capable of modulating immune responses in several model systems, the role of NKT cells in allergy remains unclear. Using CD1 gene knockout (KO) mice, which lack NKT cells, we examined the function of NKT cells in the development of allergic inflammation induced by a common airborne human allergen, ragweed. The data showed that airway eosinophilia and mucus overproduction induced by ragweed were significantly reduced in CD1 KO mice, which was correlated with significantly lower allergen-driven IL-4 production and lower eotaxin responses in the airways of CD1 KO mice. Moreover, both ragweed-specific and total serum IgE levels in CD1 KO mice were significantly lower than those in control BALB/c mice. The reduced allergic reaction in CD1 KO mice is not due to intrinsic deficiency because they showed normal levels of immune cells and function. In addition, in vivo stimulation of NKT cells using their natural ligand, alpha-galactosylceramide, enhanced ragweed-induced airway eosinophilia, IL-4, and eotaxin production in control, but not CD1 KO mice. These data provide in vivo evidence for the involvement of NKT cells in the allergic mechanisms responsible for allergen-driven cytokine and chemokine production and airway inflammation.

Ambrosia↗
PubMed2004

Dendritic cells from Chlamydia-infected mice show altered Toll-like receptor expression and play a crucial role in inhibition of allergic responses to ovalbumin.

Our previous study has shown that Chlamydia lung infection can inhibit local eosinophilic inflammation induced by allergen sensitization and challenge, which is correlated with altered cytokine production. In the present study, we examined the role played by dendritic cells (DC) in chlamydial infection-mediated modulation of allergic responses. The results showed that DC freshly isolated from Chlamydia-infected mice (iIDC), unlike those from naive control mice (iNDC), could efficiently modulate immune responses to ovalbumin in vitro and in vivo. Co-culture of freshly isolated DC with naive CD4 cells from T cell receptor transgenic mice (DO11.10) showed that iIDC directed Th1-dominant, while iNDC directed Th2-dominant, allergen-specific CD4 T cell responses. Moreover, adoptive transfer of iIDC, but not iNDC, could inhibit systemic and local eosinophilia induced by allergen exposure. The reduction of eosinophilia was associated with a decrease in IL-5 receptor expression on bone marrow cells and the production of IL-5 and IL-13 by T lymphocytes. Analysis of the DC showed that iIDC expressed significantly higher levels of mRNA for Toll-like receptor 9 and produced more IL-12 compared to iNDC. The data demonstrate a critical role played by DC in infection-mediated inhibition of allergic responses.

Animals↗
PubMed2004

Specific gene expression and therapy for pancreatic cancer using the cytosine deaminase gene directed by the rat insulin promoter.

Suicide gene therapy has been shown to be an effective means of destroying pancreatic cancer cells, but cell-specific delivery of the gene is required to limit host toxicity. The objective of this study is to determine whether the rat insulin promoter (RIP) will permit cell-specific gene delivery and subsequent cell death in human pancreatic cancer cells. The RIP DNA was amplified using polymerase chain reaction (PCR), and the purified fragment was inserted into pCR-Blunt II-TOPO plasmid at the SpeI site, which contains the coding sequence of yeast cytosine deaminase (CD). Transfection assays were carried out using both RIP-lacZ and RIP-CD DNA constructs in two human pancreatic cancer cell lines, PANC-1 and MIA PaCa-2. Reporter assays using X-gal staining were performed, and the in vitro cytotoxicity was examined in RIP-CD-transfected cells treated with 5-flucytosine for 5 days. The expression levels of CD protein in the transfected cells were determined 2 days after transfection by Western blot analysis. The expression levels of insulin promoter factor (IPF-1/PDX-1) in these human pancreatic cell lines, as well as in freshly isolated human pancreatic cancer specimens, were determined using in situ immunohistochemistry analysis. After transfection with RIP-lacZ, only PANC-1 cells, but not MIA PaCa-2 cells, were positive for RIP-lacZ expression, indicating that RIP-directed reporter gene expression occurred only in PANC-1 cells. After transfection with RIP-CD and treatment with 5-flucytosine, PANC-1 cells had a significantly increased cell death rate compared with that of MIA PaCa-2 cells, suggesting that RIP-directed suicide gene expression occurred only in PANC-1 cells. Western blot analysis demonstrated that only PANC-1 cells were able to express the CD protein and that significantly increased levels of PDX-1 were found in PANC-1 but not in Mia PaCa-2 cells. In situ immunohistochemical analysis of both cell lines showed that PDX-1 was only expressed in the nuclei of PANC-1 cells and not in MIA PaCa-2 cells. Furthermore, two freshly isolated human pancreatic cancer specimens had significantly increased levels of PDX-1. The RIP is activated in PANC-1 cells, but not in Mia PaCa-2 cells, and the mechanism of activation is via PDX-1. Pancreatic cancer-specific cytotoxicity can be achieved with the use of RIP-CD and 5-flucytosine treatment in vitro. Significantly increased levels of PDX-1 have been found in human pancreatic cancer specimens. These results suggest that RIP could be used for cell-specific suicide gene therapy to target human pancreatic tumors.

Antimetabolites↗