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Results for “Enhancer mapping”

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PubMed2006

Direct contrast-enhanced 3D MR venography evaluation of upper extremity deep venous system.

PURPOSE: To investigate the diagnostic value of direct contrast-enhanced three dimensional magnetic resonance (3D MR) venography in mapping the deep venous system of the upper extremities and to plan potential interventional procedures. MATERIALS AND METHODS: Nineteen cases with the diagnoses of end-stage renal disease with multiple hemodialysis catheter access were examined. Direct contrast-enhanced 3D MR venograms were obtained with 1.5 Tesla device with 3D-FSPGR pulse sequence and using body coil following the manual injection of gadolinium solution prepared by diluting 20 ml of contrast substance in 200 ml saline with a proportion of 1:10 through intravenous access opened symmetrically in antecubital fossa. In the workstation, evaluation was performed on three-dimensional images, two-dimensional multiplanar reformats and maximum-intensity projection method obtained from the source images. Intravenous DSA was performed on all the patients, and two radiologists evaluated MR venograms and conventional angiograms independently from each other. Results of MR venography and conventional angiography were then compared. RESULTS: In all cases, the MR venograms obtained were capable of supporting the diagnoses. Venous pathologies were found in 16 cases. In three cases central veins were evaluated to be patent. Results of MR venography and conventional angiography were consistent with each other (100% sensitivity and 100% specificity). CONCLUSION: Direct contrast-enhanced 3D MR venography is a well-tolerated sensitive technique in explaining the cause of the malfunctioning arterio-venous fistulas and in pre-surgical planning before placing new catheters or creating fistulas. It is possible to obtain high-quality images with this technique as an alternative to invasive angiography.

Adult↗

PubMed2003

Simultaneous mapping of blood volume and endothelial permeability surface area product in gliomas using iterative analysis of first-pass dynamic contrast enhanced MRI data.

We describe a novel method for the calculation of endothelial permeability surface area product from dynamic contrast enhanced MRI. The technique uses iterative estimation to automatically decompose tissue residue function into intravascular and extravascular components, which are subsequently used to generate tumour blood volume, which is equal to relative cerebral blood volume calculated from T(1) weighted images and corrected for contamination by contrast agent leakage (rCBV(T1)(corrected), and endothelial permeability (k(fp)) maps. The technique was assessed in patients with cerebral glioma (n=5) by examining the reproducibility of endothelial permeability and rCBV(T1)(corrected) between two separate examinations conducted with a 2-day interval. The technique produces maps of endothelial permeability that appear to be free of any contribution from intravascular contrast agent. Maps of rCBV(T1)(corrected) show close correlation with maps of blood volume calculated from independently acquired dynamic susceptibility weighted MRI examinations, with no evidence of residual permeability effects. The results were highly reproducible with strong intra-class correlation between the two examinations for mean values and for 97.5 percentiles of endothelial permeability and rCBV(T1)(corrected). The excellent reproducibility of this technique and the ability to calculate endothelial permeability and rCBV(T1)(corrected) values from rapidly acquired data sets offer considerable advantages over conventional approaches and support the use of this methodology for therapeutic monitoring or trials of novel therapeutic agents.

Aged↗

PubMedDate not supplied

Detection of hepatic tumor perfusion following transcatheter arterial chemoembolization with dynamic susceptibility contrast-enhanced echoplanar imaging.

The aim of the study was to evaluate the usefulness of the magnetic resonance (MR) perfusion maps in the detection of liver tumor perfusion following transcatheter arterial chemoembolization (TACE). MR dynamic susceptibility contrast-enhanced imaging was performed in 12 patients with 10 confirmed hepatocellular carcinoma and 2 confirmed hepatic metastasis using single-shot echoplanar pulse sequence. Time-intensity curves for all hepatic tumors showed a transient signal drop and the hepatic blood volume (HBV) maps were reconstructed. On the HBV maps, most tumors (80%) demonstrated hyperperfusion before TACE and hypoperfusion following TACE. The site and the degree of residual hyperperfusion within the tumor on the HBV maps correlated well with the areas of hypervascularity on the angiograms. In conclusion, the MR perfusion maps can be a promising technique for detecting the perfusion of the residual tumor tissue following TACE.

Carcinoma, Hepatocellular↗

PubMed1995

Two distinct FUS breakpoint clusters in myxoid liposarcoma and acute myeloid leukemia with the translocations t(12;16) and t(16;21).

The FUS gene, which maps to 16p11, is fused to the CHOP gene in the t(12;16) (q13;p11) that characterizes myxoid liposarcomas (MLS) and to the ERG gene in acute myeloid leukemia (AML) with t(16;21) (p11;q22). In the present study we have mapped the breakpoints within FUS in 13 MLS with t(12;16) and in one AML with t(16;21). This region of FUS is about 3.9 kb and contains four exons. The breakpoints clustered to two zones (1 and 2). A strong association was found between the two known types of FUS/CHOP transcripts and the genomic localization of the breakpoints. In all cases expressing only type I or both type I and II FUS/CHOP transcript the genomic breakpoints mapped to zone 1. In all cases expressing only the type II transcript the breakpoints occurred in zone 2. The breakpoint in the AML case was in zone 1, suggesting that in-frame fusion transcripts are selected by similar mechanisms in both MLS and AML.

Base Sequence↗

PubMed1995

Mouse chromosomal location of the CCAAT/enhancer binding proteins C/EBP beta (Cebpb), C/EBP delta (Cebpd), and CRP1 (Cebpe).

There are four known members of the C/EBP family of basic region-leucine zipper transcription factors: Cebpa, Cebpb, Cebpd, and Cebpe. Cebpa has previously been mapped to mouse chromosome 7. Here, we show that Cebpb maps to mouse chromosome 2, Cebpd to chromosome 16, and Cebpe to chromosome 14. The assignment of Cebpd to chromosome 16 identifies a new region of homology between mouse chromosome 16 and human chromosome 8.

Animals↗

PubMed1986

The 89,000-Mr murine cytomegalovirus immediate-early protein activates gene transcription.

To study trans-activation of gene expression by murine cytomegalovirus (MCMV) immediate-early (IE) proteins, the IE coding region 1 (ie1), which encodes the 89,000-Mr IE phosphoprotein (pp89), was stably introduced into L cells. A cell line was selected and characterized that efficiently expressed the authentic viral protein. The pp89 that was constitutively expressed in L cells stimulated the expression of transfected recombinant constructs containing the bacterial chloramphenicol acetyltransferase (CAT) gene under the control of viral promoters. The regulatory function of the ie1 product was confirmed by transient expression assays in which MCMV IE genes were cotransfected into L cells together with recombinant constructs of the CAT gene. For CAT activation by the ie1 product, a promoter region was required, but there was no preferential activation of a herpes simplex virus type 1 delayed-early promoter. All plasmid constructs that contained the intact coding sequences for pp89 induced gene expression in trans. The MCMV enhancer region was not essential for the expression of a functional IE gene product, and testing of the cis-regulatory activity of the MCMV enhancer revealed a low activity in L cells. Another region transcribed at IE times of infection, IE coding region 2, was unable to induce CAT expression and also did not augment the functional activity of ie1 after cotransfection.

Animals↗

PubMed1990

Effects of the DNA topoisomerase II inhibitor, VM26, on transcriptional initiation in vitro.

Inhibitors of DNA topoisomerase II have been shown to influence the expression of specific genes in vivo, leading investigators to suggest that the topological state of certain genes may affect their expression. In the present study, we have examined the effects of the topoisomerase II inhibitor, VM26, on transcriptional initiation in vitro. VM26 inhibited transcriptional initiation from the rat prolactin and adenovirus major late promoters in an in vitro transcription assay using rat pituitary tumor GH3 cell nuclear extracts. Transcriptional initiation from both supercoiled and linear DNA templates was equally inhibited by VM26 in a dose dependent manner. In order to identify sequences around the prolactin promoter recognized by topoisomerase II, we have mapped topoisomerase II cleavage sites using GH3 cell nuclear extracts as a source for the endogenous enzyme. Using a 910 bp genomic DNA fragment containing 423 bp of 5'-flanking sequences from the prolactin gene, we observed five VM26-enhanced topoisomerase II cleavage sites. Some of these sites map to positions near or within previously described regulatory DNA elements, and thus, may provide the structural basis for the sensitivity of prolactin gene expression to topoisomerase II inhibitors in vivo. These data suggest that inhibition of transcriptional initiation was a consequence of VM26 induced cleavage in the promoter region.

Animals↗

PubMed1996

The timSL mutant of the Drosophila rhythm gene timeless manifests allele-specific interactions with period gene mutants.

To identify new components of the Drosophila circadian clock, we screened chemically mutagenized flies for suppressors or enhancers of the long periods characteristic of the period (per) mutant allele perL. We isolated a novel mutant that maps to the rhythm gene timeless (tim). This novel allele, timSL, alters the temporal pattern of perL protein nuclear localization and restores temperature compensation to perL flies. timSL more generally manifests specific interactions with different per alleles. The identification of this first period-altering tim allele provides further evidence that TIM is a major component of the clock, and the allele-specific interactions with PER provide evidence that the PER/TIM heterodimer is a unit of circadian function. Although timSL fails to restore PER-L/TIM temperature insensitivity in yeast, it alters the TIM phosphorylation pattern during the late night. The effects on phosphorylation suggest that timSL functions as a partial bypass suppressor of perL and provide evidence that the TIM phosphorylation program contributes to the circadian timekeeping mechanism.

Alleles↗

PubMed1995

Mapping of gene loci in the Q13-Q15 region of chromosome 12.

The gene loci CDK4, GLI, CHOP and MDM2 have been mapped to the q13-q15 region of chromosome 12. Using fluorescence in situ hybridization onto simultaneously DAPI-banded metaphase chromosomes and interphase nuclei, we have more precisely mapped and ordered these loci, together with a number of Genethon microsatellite markers. GLI and CHOP localize to 12q13.3-14.1, CDK4 to 12q14 and MDM2 to 12q14.3-q15, and the gene order is cen-GLI/CHOP-CDK4-MDM2. The Genethon microsatellites D12S80 and D12S83 flank MDM2.

CCAAT-Enhancer-Binding Proteins↗

PubMed2002

Estrogen receptor-mediated effects of tamoxifen on human endometrial cancer cells.

Tamoxifen is an estrogen receptor (ER)-antagonist that is widely used for the treatment of breast cancer, although it increases the risk of endometrial cancer. The mechanism mediating the stimulatory effect of tamoxifen on endometrial cancer is presently unknown. In this study we examined the effects of tamoxifen on Ishikawa 3H-12 endometrial cancer cells and MCF-7 breast cancer cells. Ishikawa cell growth was stimulated by 4-hydroxytamoxifen and accompanied by increased transcriptional activity of the endogenous ER. These stimulatory effects did not occur in MCF-7 cells. The relative transcriptional activity of the activation function (AF) 1 domain of ERalpha compared with that of the AF2 domain was 4-fold higher in Ishikawa cells than in MCF-7 cells. Mitogen-activated protein (MAP) kinase, which stimulates the transcriptional activity of AF1, was constitutively activated in Ishikawa cells, but not in MCF-7 cells. These observations suggest that the constitutively activated MAP kinase-signaling pathway in Ishikawa cells enhances the transcriptional activity of ERalpha via the AF1 domain. This ERalpha activation pathway may be involved in the stimulatory effect of tamoxifen on the development and/or progression of endometrial cancer.

Adenocarcinoma↗

PubMed2002

A neural-network-based approach to the double traveling salesman problem.

The double traveling salesman problem is a variation of the basic traveling salesman problem where targets can be reached by two salespersons operating in parallel. The real problem addressed by this work concerns the optimization of the harvest sequence for the two independent arms of a fruit-harvesting robot. This application poses further constraints, like a collision-avoidance function. The proposed solution is based on a self-organizing map structure, initialized with as many artificial neurons as the number of targets to be reached. One of the key components of the process is the combination of competitive relaxation with a mechanism for deleting and creating artificial neurons. Moreover, in the competitive relaxation process, information about the trajectory connecting the neurons is combined with the distance of neurons from the target. This strategy prevents tangles in the trajectory and collisions between the two tours. Results of tests indicate that the proposed approach is efficient and reliable for harvest sequence planning. Moreover, the enhancements added to the pure self-organizing map concept are of wider importance, as proved by a traveling salesman problem version of the program, simplified from the double version for comparison.

Journal Article↗

PubMed1999

Beneficial effects of combined terlipressin and tetramethylpyrazine administration on portal hypertensive rats.

The purpose of this study was to investigate the therapeutic effects of terlipressin (TP) alone or in combination with tetramethylpyrazine (TMP) on anesthetized portal hypertensive rats. Portal hypertension was induced by either partial portal vein ligation (PVL, without cirrhosis) or bile duct ligation (BDL, with cirrhosis) in Sprague-Dawley rats. Each PVL or BDL rat received only one of the two regimens: vehicle for 3 min followed by TP (0.017 mg x kg(-1) x min(-1) for 3 min) or TMP (10 mg x kg(-1) x min(-1) for 3 min) followed by TP. In PVL rats, infusion of vehicle followed by TP induced significant reduction of portal venous pressure (PVP, -15.0+/-1.0%) and prominent elevation of mean arterial pressure (MAP, 57.3+/-8.1%) as well as total peripheral resistance (TPR, 113+/-11%) from baseline, and there was a cardiodepressant response (cardiac index, CI, -26.3+/-1.1%). Infusion of TMP followed by TP induced significant reduction of PVP (-20.3+/-0.4%) and CI (-9.9+/-1.2%) and significant elevation of MAP (31.3+/-2.5%) and TPR (46.0+/-4.1%) from baseline. In BDL rats, infusion of vehicle followed by TP also induced significant reduction of PVP (-13.8+/-1.7%) but an increase in MAP (57.1+/-2.2%) and TPR (101+/-6%) from baseline, and there also was a cardiodepressant response (CI, -21.4+/-2.3%). Infusion of TMP followed by TP induced significant reduction of PVP (-18.9+/-1.4%) and CI (-11.9+/-2.1%), but an increase in MAP (36.2+/-2.5%) and TPR (55.0+/-5.2%). Compared with vehicle followed by TP, TMP not only significantly enhanced portal hypotensive (PVP reduction) effects of TP but also attenuated the systemic pressor (MAP and TPR elevation) and cardiodepressant (CI reduction) effects of TP in both PVL and BDL rats. Our results suggest that TP, alone or in combination with TMP, induced portal hypotensive effects in two models of portal hypertensive rats. Combination of TP and TMP was beneficial in enhancing portal hypotensive effects of TP and ameliorating the systemic pressor and cardiodepressant effects of TP.

Animals↗

PubMed2001

Lithium induces NF-kappa B activation and interleukin-8 production in human intestinal epithelial cells.

Lithium has been documented to regulate apoptosis and apoptotic gene expression via NF-kappa B and mitogen-activated protein (MAP) kinase-dependent mechanisms. Since both NF-kappa B and MAP kinases are also important mediators of inflammatory gene expression, we investigated the effect of lithium on NF-kappa B- and MAP kinase-mediated inflammatory gene expression. Incubation of human intestinal epithelial cells with lithium induced both enhanced NF-kappa B DNA binding and NF-kappa B-dependent transcriptional activity. In addition, lithium stimulated activation of both the p38 and p42/44 MAP kinases. This lithium-induced up-regulation of NF-kappa B and MAP kinase activation was associated with an enhancement of interleukin-8 mRNA accumulation as well as an increase in interleukin-8 protein release. These proinflammatory effects of lithium were, in large part, mediated by activation of Na(+)/H(+) exchangers, because selective blockade of Na(+)/H(+) exchangers prevented the lithium-induced intestinal cell inflammatory response. These results demonstrate that lithium stimulates inflammatory gene expression via NF-kappa B and MAP kinase activation.

Adrenergic alpha-Agonists↗

PubMed2026

Assessment of differentially culturable tubercle bacteria assays for the detection of tuberculosis infection in asymptomatic household contacts and the implications for intra-household transmission: a longitudinal cohort study.

BACKGROUND: Conventional culture methods for tuberculosis diagnosis miss differentially culturable tubercle bacteria (DCTB), which grow only in liquid assays supplemented with growth-enhancing factors. This limitation, combined with inadequate contact tracing and screening, often fails to identify asymptomatic individuals, with live bacilli detectable by enhanced culture methods. This shortfall results in undiagnosed reservoirs of bacteria, potentially fuelling ongoing transmission. In this study, we aimed to investigate whether DCTB assays provide greater sensitivity by detecting more Mycobacterium tuberculosis infections than conventional culture and whether this enhanced detection improves the resolution of intrahousehold transmission mapping. In addition, we sought to evaluate whether DCTB populations can progress to conventional culture positivity, thereby highlighting their clinical and epidemiological relevance. METHODS: In this prospective observational longitudinal cohort study, drug-susceptible or rifampicin-resistant tuberculosis index participants aged 12 years or older, were recruited from primary healthcare clinics from two South African districts. Inclusion criteria were informed consent, Xpert MTB/RIF Ultra-positive results, tuberculosis symptoms (>2 weeks), provision of baseline samples, at least one consenting household contact, and documented HIV status. Household contacts of the index patients and control households were also recruited. Sputum specimens were collected at baseline and 2, 4, 8, 12, and 16 months from the index participants and household contacts. Samples were analysed by conventional mycobacterial growth indicator tube (MGIT) culture, and colony-forming unit assays to identify viable bacteria. Enhanced culture to detect DCTB involved serial dilution of sputum in liquid culture, supplemented with M tuberculosis culture filtrate as a source of growth stimulatory factors. Whole-genome sequencing (WGS) of cultured isolates was performed to trace household transmission. FINDINGS: Between June 1, 2020, and Feb 6, 2024, 293 index participants (183 [62%] male), 701 household contacts (453 [65%] female), and 122 control participants (67 [55%] female) were enrolled. At baseline, 249 (85%) of 293 index participants and 110 (16%) of 701 household contact sputum samples were positive for M tuberculosis by MGIT conventional culture. For baseline MGIT-negative specimens, DCTB assays detected M tuberculosis in an additional 21 (7%) of 293 index participants and 26 (4%) of 701 household contacts. Over 16 months of follow-up, DCTB assays identified 61 (8·7%) of 701 additional tuberculosis-positive household contacts not detected by conventional culture. WGS-guided transmission mapping using conventional culture identified transmission in 16 (15%) of 104 households, whereas DCTB assays detected an additional 19 (18%) of 104 transmission events. No evidence of intrahousehold transmission was found in the remaining 69 (66%) of 104 tuberculosis-positive households. Over the 16-month follow-up period, conventional culture identified 233 positive household contacts, of which 195 (84%) were asymptomatic. DCTB assays detected an additional 94 cases of M tuberculosis positivity in household contacts, of which 79 (84%) were asymptomatic. In control households, tuberculosis prevalence at baseline was two (2%) of 122, with an additional three (3%) of 122 identified during follow-up. INTERPRETATION: DCTB assays provide substantial value by detecting asymptomatic individuals missed by conventional culture, revealing a potentially important reservoir of subclinical infection, which could sustain transmission. In addition, DCTB detection uncovers transmission linkages missed by conventional culture, providing a more comprehensive understanding of M tuberculosis transmission dynamics and highlighting the need to incorporate enhanced culture methods into diagnostic and surveillance strategies, to strengthen early case identification and tuberculosis control efforts. FUNDING: National Institutes of Health.

Humans↗

PubMed1991

Genetic analysis of microtubule motor proteins in Drosophila: a mutation at the ncd locus is a dominant enhancer of nod.

The nod (no distributive disjunction) and the ncd (non-claret disjunctional) mutations are both female-specific, recessive meiotic mutations in Drosophila melanogaster. Mutations at either locus show high frequencies of nondisjunction at meiosis I and both have been shown to encode kinesin-like proteins. Unlike the ncd mutation, which affects all chromosome pairs, the nod mutation affects only the disjunction of nonexchange chromosomes. Although both the nod and ncd mutations are fully recessive, females doubly heterozygous for nod and ncd mutations show levels of X and fourth chromosome nondisjunction that are 6- to 35-fold above those observed in control females. Exchange between chromosomes can suppress this effect; thus, only nonexchange chromosomes segregating via the distributive system are sensitive in double heterozygotes. Since the phenotype of double heterozygotes mimics that of the nod mutation, we infer that ncd is a dominant enhancer of nod. Failure of ncd to fully complement nod reveals the chromosome segregation machinery to be dosage sensitive. The probability that the distributive system will fail is enhanced in females simultaneously haploinsufficient at the nod and ncd loci.

Animals↗

PubMed1999

Orientation and positional mapping of the subunits of the multicomponent transcription factors RFX and X2BP to the major histocompatibility complex class II transcriptional enhancer.

Major histocompatibility complex class II genes contain a common complex enhancer that allows for their coordinate regulation. The X box element of the enhancer cooperatively binds the multisubunit transcription factors RFX and X2BP. RFX is an essential class II transcription factor and contains three distinct proteins: RFX5, RFX-B/Ank and RFXAP. X2BP, a CREB/ATF family transcription factor, most likely binds as a homodimer. A site-specific protein-DNA photocrosslinking assay was used to investigate the interactions of the subunits of RFX and X2BP with X box DNA. Two of the RFX subunits, RFX5 and RFX-B/Ank, were found to bind defined sites within the X1 half of the X box. The third RFX subunit, RFXAP, made extensive X1 box contacts. The subunits of X2BP made contacts with the edges of the X2 half of the X box in a manner consistent with other bZIP transcription factor contact patterns. The resulting map provides specific base pair contacts and subunit orientation with respect to the DNA sequence of the RFX-X2BP-X box complex. Our results suggest possible stoichiometry of the RFX subunits and potential interaction between RFX-B/Ank and RFXAP with one of the subunits of X2BP.

Base Sequence↗

PubMed1999

Mitogen-activated protein (MAP) kinases are involved in interleukin-1 (IL-1)-induced IL-6 synthesis in osteoblasts: modulation not of p38 MAP kinase, but of p42/p44 MAP kinase by IL-1-activated protein kinase C.

We previously reported that interleukin-1alpha (IL-1alpha)-induced activation of protein kinase C (PKC) via phosphatidylcholine-specific phospholipase C (PC-PLC) limits IL-6 synthesis induced by IL-1alpha itself in osteoblast-like MC3T3-E1 cells. In the present study, we further investigated the mechanism behind IL-1alpha-induced IL-6 synthesis in MC3T3-E1 cells. IL-1alpha time-dependently stimulated the phosphorylation of both p42/p44 mitogen-activated protein (MAP) kinase and p38 MAP kinase. PD98059, a specific inhibitor of the upstream kinase that activates p42/p44 MAP kinase, inhibited the IL-1alpha-induced IL-6 synthesis as well as the phosphorylation of p42/p44 MAP kinase induced by IL-1alpha. SB203580, a specific inhibitor of p38 MAP kinase, also reduced both the phosphorylation of p38 MAP kinase and the IL-6 synthesis. 1-Oleoyl-2-acetylglycerol, an activator of PKC, suppressed the IL-1alpha-induced IL-6 synthesis. Calphostin C, a specific inhibitor of PKC, or D-609, a specific inhibitor of PC-PLC, significantly enhanced the IL-1alpha-induced phosphorylation of p42/p44 MAP kinase without affecting the phosphorylation of p38 MAP kinase. The phosphorylation of p42/p44 MAP kinase by IL-1alpha was markedly increased in PKC-down-regulated MC3T3-E1 cells. Neither 12-O-tetradecanoylphorbol-13-acetate, known to be an activator of PKC, nor 1-oleoyl-2-acetylglycerol affected the phosphorylation of p38 MAP kinase induced by IL-1alpha. These results strongly suggest that IL-1alpha-induced IL-6 synthesis is mediated via activations of both p42/p44 MAP kinase and p38 MAP kinase in osteoblasts, and that PKC activated by IL-1alpha itself negatively regulates IL-6 synthesis at a point upstream from p42/p44 MAP kinase.

Animals↗

PubMed2006

Paclitaxel and ceramide synergistically induce cell death with transient activation of EGFR and ERK pathway in pancreatic cancer cells.

The molecular and cellular mechanism of the development of pancreatic cancer is under constant and intensive study, and yet the cure is still out of reach. While surgical treatment is optional, conventional chemotherapy or chemo-radiotherapy remains the best choice. Among others, paclitaxel is proven to be a popular and, to a certain extent, effective chemotherapy agent. We proposed that the combination of paclitaxel and membrane permeable ceramide would enhance the fatality of cancer cells, and reported that the combination increased cell death of both head and neck and leukemic cancer cells. In this study, we treated pancreatic cancer cells (L3.6 cells) with paclitaxel and ceramide at the concentrations of clinical relevance, and treatment was then followed up with an investigation of the molecular mechanism of the synergism of paclitaxel and ceramide. The results of Western blot analysis indicated that the combo synergistically induced ERK and JNK phosphorylation, but not p38 and Akt phosphorylation. We also found that the combination (combo) induced EGFR phosphorylation in a synergistic manner. Furthermore, we observed that paclitaxel, ceramide, or combo-induced EGFR phosphorylation was inhibited by EGFR inhibitor, PD153035, while paclitaxel, ceramide, or combo-induced JNK and ERK phosphorylation was blocked by EGFR inhibitor, PD153035 and ERK inhibitor, U126. Taken together, our results demonstrated that the combination of paclitaxel and ceramide synergistically induced pancreatic cancer cell death through differential activation of EGFR-mediated MAP kinases. EGFR and ERK inhibitors may further enhance the paclitaxel and ceramide effect.

Antineoplastic Combined Chemotherapy Protocols↗