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PubMed2003

New approach to generalized two-dimensional correlation spectroscopy. IV: eigenvalue manipulation transformation (EMT) for partial attenuation of dominant factors.

This paper extends our previous work on the potential of eigenvalue manipulating transformation (EMT) of a data matrix for spectral selectivity enhancement in two-dimensional (2D) correlation analysis. EMT operation by uniformly lowering the power of a set of eigenvalues associated with the original data exaggerates the information content of minor principal components and reduces that of major principal components. Thus, much more subtle differences of spectral behavior for each component are now highlighted. Similarly, the selective truncation of dominant principal component (PC) factors to bring up the subtle contributions of minor factors is also considered. The EMT-reconstructed data matrix where power parameter m is negative greatly reduces the contribution of the first PC. Hybrid models for the attenuation of the contribution of the first PC are discussed. Synchronous 2D correlation spectra from PC1-attenuated data matrix A** obtained by varying the value of the attenuation parameter k show a much more profound effect than asynchronous 2D correlation spectra. As the value of k is increased, features of 2D correlation spectra start looking very much like those from the principle component analysis (PCA)-reconstructed data with only the second and third PCs and from the EMT-reconstructed data matrix where the power parameter m is negative.

Artifacts↗
PubMed2005

Colorectal cancer progression: integrin alphavbeta6 and the epithelial-mesenchymal transition (EMT).

Carcinomas, those tumors that arise from epithelial tissues, represent the most prevalent form of human malignancies. Moreover, it is the metastatic spread of these cancers, rather than the development of primary neoplasms that predominantly accounts for patient mortality. Thus, understanding the mechanisms that contribute to the process of cancer progression is of fundamental importance lo designing better therapeutic strategies for treating this disease. The epithelial-mesenchymal transition (EMT), which facilitates the process by which epithelial tumors become invasive and progress towards malignant disease, provides a superb paradigm for studying such mechanisms. Using a colon carcinoma model of EMT, it was discovered that increased expression of the integrin alphavbeta6 is elicited as a consequence of the transition. Importantly, the consequences of the elevated alphavbeta6 expression are directly linked to both tumor cell function and to the mechanism of the EMT itself. Most significantly increased alphavbeta6 expression in human tumors is a prognostic variable and one that is predictive of outcome for early-stage disease. These findings reinforce the importance of the EMT event in late stage tumorigenesis, and define alphavbeta6 as a novel therapeutic candidate for aggressive colorectal cancer.

Antigens, Neoplasm↗
PubMed1996

Interaction of interleukin-11 with cytotoxic therapies in vitro against CEM cells and in vivo against EMT-6 murine mammary carcinoma.

Interleukin-11(rhIL-11) is a cytokine that has been shown to enhance the recovery of bone marrow and intestinal crypt cells after cytotoxic insult with radiation or anticancer drugs. The current study examined the effects of rhIL-11 on the response of CEM human lymphoblastic leukemia cells and on the EMT-6 murine mammary carcinoma in vivo to cytotoxic anticancer therapies. Exposure of CEM cells to rhIL-11 for 24 hr did not alter the cytotoxicity of melphalan or radiation, increased the cytotoxicity of CDDP (100 muM) and 4-hydroperoxycyclophosphamide (50 betaM) and decreased the cytotoxicity of 5-fluorouracil and ara-C toward the cells. Treatment of mice bearing the EMT-6 tumor with rhIL-11 twice daily for 4 days prior to and the day of cytotoxic therapy resulted in no significant change in the tumor cell killing or bone marrow CFU-GM killing by melphalan, cyclophosphamide, thiotepa, CDDP, radiation, 5-fluorouracil or ara-C. Administration of rhIL-11 twice per day on days 7-18 to EMT-6 tumor bearing animals receiving high dose chemotherapy (melphalan, thiotepa or cyclophosphamide) as a single dose on day 7 followed by mobilized peripheral blood cells on day 8 and rhG-CSF on days 8-20, tended to prolong the tumor growth delay produced by the drugs. This rhIL-11 treatment also resulted in a more rapid recovery of white blood cells and granulocytes in the animals. Furthermore, animals treated with rhIL-11 had improved survival rates compared with animals receiving all other normal tissue support without rhIL-11.

Animals↗
PubMed1997

Photodynamic activities and biodistribution of fluorinated zinc phthalocyanine derivatives in the murine EMT-6 tumour model.

The photodynamic properties and biodistribution pattern of zinc dodecafluoro-4-sulphophthalocyanine (ZnPcF12S1), zinc hexadecafluorophthalocyanine (ZnPcF16) and zinc phthalocyanine (ZnPc) were evaluated in the murine EMT-6 tumour model. All 3 dyes were formulated as a Cremophor oil-water emulsion after initial solubilization in methanol, acetone and pyridine, respectively. Comparison of their phototoxicity after in vitro incubation with EMT-6 cells and exposure to various fluences of red light showed that ZnPcF12S1 is about 50 times more active than ZnPcF16, reflecting better cell-penetrating properties. Solubilisation of ZnPc in 1-methyl-2-pyrrolidinone prior to formulation resulted in loss of photoactivity upon dilution in serum due to precipitation of the dye in the aqueous environment. In contrast, initial solubilisation in pyridine likely forms a ZnPc-pyridinium salt, and this preparation was 6 times more phototoxic than ZnPcF12S1. In vivo comparison of monosulphonated ZnPcF12S1 with perfluorinated ZnPcF16 showed improved pharmacokinetics in mice, including lower liver and spleen retentions and higher tumour-to-non-target tissue ratios. However, photodynamic therapy (PDT) of the EMT-6 tumour in BALB/c mice with red light, 24 or 48 hr post-injection of 1 micromol x kg(-1) of ZnPcF12S1 induced mortality. Lowering the drug and/or light dose or extending the time interval between drug administration and irradiation to 72 hr avoided adverse effects but also resulted in poor tumour response. The best tumour control (25% of animals) was obtained at 0.1 micromol x kg(-1) and a fluence of 400 J x cm(-2) at 24 hr post-injection. In contrast, ZnPcF16 required a 20-fold higher drug dose to induce a similar tumour response. The systemic shock following PDT with the amphiphilic ZnPcF12S1 likely results from extensive cellular effects.

Animals↗
PubMed2007

Fibrosis and cancer: do myofibroblasts come also from epithelial cells via EMT?

Myofibroblasts produce and modify the extracellular matrix (ECM), secrete angiogenic and pro-inflammatory factors, and stimulate epithelial cell proliferation and invasion. Myofibroblasts are normally induced transiently during wound healing, but inappropriate induction of myofibroblasts causes organ fibrosis, which greatly enhances the risk of subsequent cancer development. As myofibroblasts are also found in the reactive tumor stroma, the processes involved in their development and activation are an area of active investigation. Emerging evidence suggests that a major source of fibrosis- and tumor-associated myofibroblasts is through transdifferentiation from non-malignant epithelial or epithelial-derived carcinoma cells through epithelial-mesenchymal transition (EMT). This review will focus on the role of EMT in fibrosis, considered in the context of recent studies showing that exposure of epithelial cells to matrix metalloproteinases (MMPs) can lead to increased levels of cellular reactive oxygen species (ROS) that stimulate transdifferentiation to myofibroblast-like cells. As deregulated MMP expression and increased cellular ROS are characteristic of both fibrosis and malignancy, these studies suggest that increased MMP expression may stimulate fibrosis, tumorigenesis, and tumor progression by inducing a specialized EMT in which epithelial cells transdifferentiate into activated myofibroblasts. This connection provides a new perspective on the development of the fibrosis and tumor microenvironments.

Animals↗
PubMed1995

Potentiation of cytotoxic therapies by TNP-470 and minocycline in mice bearing EMT-6 mammary carcinoma.

The ability of the antiangiogenic agents TNP-470 and minocycline, singly or in combination, to potentiate the antitumor effects of several cytotoxic therapies was assessed in the murine EMT-6 mammary carcinoma as well as in two drug resistant sublines of that tumor designated EMT-6/CTX and EMT-6/CDDP. The antiangiogenic agents alone or in combination did not alter the growth of the tumors. However, their administration along with cyclophosphamide, CDDP, or thiotepa substantially increased the tumor growth delay produced by these cytotoxic therapies in tumors responsive to the drugs--the increase was about 2-fold for TNP-470 and minocycline together. In drug resistant tumors, treatment with the antiangiogenic agents did not reverse drug resistance but did increase the effect of the cytotoxic drugs. Treatment with TNP-470/minocycline also increased the oxygenation of each of the three tumors. Thus, TNP-470/minocycline administration increased the efficacy of fractionated radiation therapy, especially when used along with a perflubron emulsion oxygen delivery agent/carbogen. These results indicate that treatment regimens including therapies directed toward the proliferating normal cells within a tumor mass as well as therapies directed toward the malignant cells can produce improved outcomes.

Animals↗
PubMed1980

Marker segregation without chromosome loss at the emt locus in Chinese hamster cell hybrids.

Segregation, defined as the reexpression of the recessive phenotype, has been examined in Chinese hamster cell hybrids heterozygous at the recessive emtr locus. Segregants were selected in emetine, and the role of chromosome loss in the segregation process was evaluated by detailed karyotype comparison of segregants with their hybrid parent. In emtr CHO x emt+ CHO hybrids (CHO is thought to be hemizygous at the emt locus), segregants were obtained at high frequency, and no consistent chromosome loss was found in the segregants. In hybrids made with Emtr CHO and wild-type lines other than CHO (CHW,CHL,V-79), where two wild-type alleles are thought to be present in the hybrid, segregants were obtained at much lower frequency, consistent with a two-step segregation process. These segregants revealed consistent loss of one chromosome 2 or deletion of a part of the long arm of a chromosome 2. Thus, one step in segregation seems to be chromosome loss while the other step must have a different mechanism, possibly the same mechanism that operates in the CHO x CHO hybrids. Two major conclusions can be drawn: (1) the emt gene maps to a hemizygous region of the long arm of a chromosome 2 in Chinese hamster, and (2) a segregation mechanism other than chromosome loss appears to operate with high efficiency in intraspecific hybrids.

Aneuploidy↗
PubMed2003

Genetic variability of the extraneuronal monoamine transporter EMT (SLC22A3).

The extraneuronal monoamine transporter EMT (HGNC Nomenclature SLC22A3) is the molecular correlate of the classical uptake(2) system responsible for the non-neuronal inactivation of circulating and centrally released catecholamines. Because of its functional profile and expression pattern, EMT is regarded as a candidate gene for diseases related to the sympathetic nervous system and neuropsychiatric disorders. We describe the first investigation of the genetic variability of the EMT gene in human. Six single-nucleotide substitutions and one deletion were detected within the assumed core promoter, the exonic and flanking intronic sequences and the 3'-untranslated region in 100 Caucasian individuals. No amino acid changes were found and Tajima's D was positive (D=2.91; P<0.01). However, the synonymous nucleotide substitution 1233G-->A might serve as a cryptic splice acceptor site. Analysis of linkage disequilibrium between polymorphisms yielded 12 possible haplotypes accounting for more than 90% of all haplotypes. Knowledge of the sequence variation and frequency of the underlying polymorphisms in this member of the amphiphilic solute facilitator family of transporters provides the basis for subsequent association studies and candidate gene approaches.

Genetic Variation↗
PubMed1995

Five-chlorodeoxycytidine and biomodulators of its metabolism result in fifty to eighty percent cures of advanced EMT-6 tumors when used with fractionated radiation.

PURPOSE: To extend our findings in previous radiation and biochemical studies with five rodent tumors, in which we used one and occasionally two or three irradiations. The extent of control of the EMT-6 mammary adenocarcinoma was determined using fractionated radiation (12 irradiations) over a 3-week period using the radiosensitizer 5-chloro-2'-deoxycytidine (CldC) and biomodulators of its metabolism: N-(Phosphonacetyl)-L-aspartate (PALA), tetrahydrouridine and 5-fluoro-2'-deoxycytidine (FdC). METHODS AND MATERIALS: Mammary adenocarcinoma EMT-6 tumors implanted 1 week prior to therapy in BALB/c mice were subjected to single daily doses of focused radiation, not exceeding a total of 60 Gy, on days 2-5 of each week. N-(Phosphonacetyl)-L-aspartate (PALA) was administered on the first day of therapy. Five-fluoro-2'-deoxycytidine and CldC were administered in the morning and afternoon, respectively, of the next 2 days, and CldC was administered on the fourth day. Tetrahydrouridine was always coadministered with FdC or CldC. Drug and radiation treatments overlapped for 3 weeks. RESULTS: Fifty to 80% cures (usually 70%) were obtained with no apparent morbidity and the same moderate weight loss that occurs with radiation alone. Neither tumor regrowth delay nor cures were obtained with drugs or radiation alone. An apparent threefold dose increase effect was obtained with the end point: "days to reach 4 times initial tumor volume." Increasing the radiation dose threefold (without drugs) resulted in four out of five deaths; increasing the dose twofold (without drugs) resulted in extensive weight loss and hair loss in the entire ventral area and no cures. Increasing the dose of drugs or radiation 1.5-fold, in the complete protocol, did not result in increased morbidity. Comparative studies with Iododeoxyuridine demonstrate the heightened efficacy of CldC. CONCLUSIONS: One cannot achieve the same results obtained with CldC and the modulators by merely increasing the dose of radiation. There is a significant window of safety in this approach. The evidence we have obtained with EMT-6, the fifth rodent tumor we have studied with CldC, as well as the demonstrated and proposed reasons for its superior efficacy over 5-Iododeoxyuridine (and 5-Bromodeoxyuridine), drugs in current use, indicate that CldC will allow more aggressive treatment of human tumors with radiation than is now feasible.

Adenocarcinoma↗
PubMed2006

Found in translation: A new player in EMT.

Epithelial mesenchymal transition (EMT) is a complex process that involves changes in gene expression, cytoskeleton organization, cell adhesion, and extracellular matrix composition. Screening for genes mediating EMT and cancer metastasis, Waerner, Alacakaptan, and colleagues identified ILEI, a cytokine-like protein that plays an essential role in EMT, tumor growth, and late steps of metastasis.

Animals↗
PubMed2004

Norepinephrine transporter (NET), serotonin transporter (SERT), vesicular monoamine transporter (VMAT2) and organic cation transporters (OCT1, 2 and EMT) in human placenta from pre-eclamptic and normotensive pregnancies.

Pre-eclampsia is one of the most common causes of perinatal and maternal morbidity and mortality. High blood pressure and proteinuria are important clinical signs of pre-eclampsia. Sympathetic overactivity and elevated level of circulating vaso active substances, such as monoamines has been shown. Extracellular concentrations of monoamines are normally kept low by specific transporter proteins of which many are expressed in the placenta. In this study we used in situ hybridization and real-time PCR to study the gene expression of monoamine transporters, such as NET, SERT, VMAT2, EMT and OCT1/2, in normal as well as in pre-eclamptic placentae. We demonstrated high expression of NET mRNA in the trophoblast cells of the anchoring villi and a lower expression intensity in the chorionic villi. SERT mRNA was mainly detected in chorionic villi. VMAT2 mRNA was not detected in the central part of the placenta but was present in the spiral arteries of placenta bed biopsies, in cytokeratin positive cells. EMT mRNA was mainly detected in the intra lobular septa and together with OCT1 and OCT2 mRNAs also expressed in scattered cells of placental vessel adventitias. Moreover, quantitative analysis showed a significant lower expression of NET and EMT mRNAs in pre-eclamptic placentae as compared to the control group. A defective gene expression or function of these monoamines transporters might explain the elevated concentrations of monoamines in pre-eclamptic patients. Monoamine transporters may serve as a protective mechanism preventing vasoconstriction in the placental vascular bed and thereby securing a stable blood flow to the fetus.

Adult↗
PubMed1981

Morphology and histochemistry of the thalamus in the course of intoxication by ethyl-mercury-p-toluenesulphanilide (EMTS).

Organic Mercury compounds are known for their neurotoxicity. From our previous studies it appeared that a variable degree of damage is brought about in the individual structures of the CNS by ingestion of organic mercurials. A detailed study was undertaken on the histotopography of pathological changes occurring in the thalamus - the major integrator of various cerebral functions - following intragastric administration of EMTS, a fungicide widely applied in agriculture. Rats served as the experimental animals. They were treated intragastrically with a daily dose of 15 mg of EMTS over a period of 10 days ( the per os DL50 for rats is 100 mg/kg of body weight). The results of our study have revealed that chronic ingestion of large doses of EMTS brings about a considerable inhibition of the activities of AChE, BuTJ, acP and ATPase in many thalamic nuclei with a concomitant elevation of TPPase and NsE activities. There was considerable variation as to the degree of histoenzymatic changes in the individual thalamic nuclei. The accompanying glial reaction was evaluated aw well. An interpretation of the findings made in this study has been undertaken.

Acetylcholinesterase↗
PubMed1982

A time efficient EMT-A course for first year medical students.

The purpose of the study was to design an EMT-A course for freshman medical students that maximized practical work and minimized lecture hours. A 48-hour required course was given up to 101 members of the first-year class at The Medical College of Pennsylvania. Ten hours of lecture-demonstration time were included. Test scores were comparable to scores of regular EMT-A candidates and medical students who had a full lecture series included in their course. Means of further decreasing the number of hours of the course are discussed. By decreasing the number of curricular hours, it is hoped that medical schools not having EMT-A certification programs in their preclinical years will be encouraged to do so.

Allied Health Personnel↗
PubMed1985

Comparison of EMT blood pressure measurements with an automated blood pressure monitor: on scene, during transport, and in the emergency department.

Auscultation or palpation of blood pressure in critically ill patients by emergency medical technicians (EMTs) can be difficult, if not impossible, because of ambient noise, motion artifact, limited access to patients, or weak pulses. Automated blood pressure monitors (ABPMs) have been designed to overcome these problems during field emergencies and patient transport. Our study compared blood pressure measurements taken by EMTs with measurements provided by a Lifestat ABPM. Measurements in emergency patients on scene, during transport, in the emergency department (ED), and in a controlled environment were compared. Measurements in the various sites were obtained from 57 patients, and provision was made for two measurements at each site. Comparison of on-scene systolic blood pressures yielded a mean absolute systolic difference of 10.46 +/- 1.42 mm Hg and a mean absolute diastolic difference of 9.33 +/- 1.32 mm Hg. During transport systolic pressures showed a mean absolute difference of 11.50 +/- 1.72 mm Hg, and diastolic pressures showed a mean absolute difference of 7.59 +/- 1.16 mm Hg. Mean absolute differences in the ED were 11.23 +/- 1.49 mm Hg systolic and 8.37 +/- 1.25 mm Hg diastolic. Ninety comparison measurements in a controlled environment yielded a mean absolute systolic difference of 8.74 +/- 0.87 mm Hg and a mean absolute diastolic difference of 7.97 +/- 0.72 mm Hg. Comparison of mean diastolic pressure differences between EMT and ABPM measurements in various settings revealed some small, but statistically significant, discrepancies that were not considered clinically relevant.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Pressure↗
PubMed2003

Lipid a radiosensitizes hypoxic EMT-6 tumor cells: role of the NF-kappaB signaling pathway.

PURPOSE: Lipid A has shown promising immunostimulatory effects in both experimental tumor models and advanced stage cancer patients. This study examines whether lipid A may directly modulate the radioresponse of tumor cells by activating inducible nitric oxide synthase (iNOS) or cyclooxygenase-2 (COX-2) through nuclear factor-kappaB (NF-kappaB) signaling. METHODS AND MATERIALS: Hypoxic EMT-6 tumor cells were exposed to lipid A and analyzed for the level of COX-2 and iNOS by Western blotting and enzymatic assays. The hypoxic radioresponse of EMT-6 cells was estimated by clonogenic survival. The activation of NF-kappaB was examined by immunostaining of its p65 subunit and by luciferase reporter gene assay. RESULTS: Lipid A dose-dependently increased the expression and activity of iNOS with a maximal effect at plasma achievable concentrations of 3-30 micro g/mL. The COX-2 mediated production of prostaglandin E2 was constitutively high and further upregulated by lipid A. The radiosensitivity of hypoxic EMT-6 cells was increased up to 2.5 times and counteracted by the iNOS inhibitor aminoguanidine but not by the COX-2 inhibitor NS-398. The mechanism of radiosensitization was linked to NF-kappaB signaling, because its inhibition by phenylarsine oxide impaired both iNOS activation and radioresponse. CONCLUSION: Lipid A is an efficient hypoxic cell radiosensitizer at plasma relevant concentrations, which provides a rationale to combine lipid A with radiotherapy in further studies.

Cell Hypoxia↗
PubMed1986

Refibrillation managed by EMT-Ds: incidence and outcome without paramedic back-up.

Some patients converted from ventricular fibrillation to organized rhythms by defibrillation-trained ambulance technicians (EMT-Ds) will refibrillate before hospital arrival. The authors analyzed 271 cases of ventricular fibrillation managed by EMT-Ds working without paramedic back-up. Of 111 patients initially converted to organized rhythms, 19 (17%) refibrillated, 11 (58%) of whom were reconverted to perfusing rhythms, including nine of 11 (82%) who had spontaneous pulses prior to refibrillation. Among patients initially converted to organized rhythms, hospital admission rates were lower for patients who refibrillated than for patients who did not (53% versus 76%, P = NS), although discharge rates were virtually identical (37% and 35%, respectively). Scene-to-hospital transport times were not predictively associated with either the frequency of refibrillation or patient outcome. Defibrillation-trained EMTs can effectively manage refibrillation with additional shocks and are not at a significant disadvantage when paramedic back-up is not available.

Allied Health Personnel↗
PubMed1997

Photograph documentation of motor vehicle damage by EMTs at the scene: a prospective multicenter study in the United States.

The purpose of this study was to determine if emergency medical service (EMS) personnel could take instant photographs of motor vehicle damage at crash scenes depicting the area and severity of damage of the crash under adverse weather conditions, in different lighting, and quickly enough so as not to interfere with patient care. This prospective multicenter trial involved 35 ambulances responding to motor vehicle crash scenes in rural, suburban, and urban areas in five centers in four states. Emergency medical technicians (EMTs) reported their experience implementing a protocol for use of an instant camera to photograph vehicle damage at crash scenes. Time reported by EMTs to take the photographs was 1 minute or less in 204 of 288 (70.9%) of motor vehicle crashes and 2 minutes or longer in 12 of 288 (4.2%) of motor vehicle crashes. From one EMS agency in the study, 48 scene times during which photographs were taken were, on average, 1.5 minutes shorter than 48 scene times immediately before implementation of on-scene crash photography. Photographs were taken in different weather and lighting conditions. EMTs reported they were able to determine both area and severity of damage in 260 of 290 (92.5%) crash photographs, but they were unable to determine area and severity of damage in only 2 of 290 (0.7%) crash photographs.

Accidents, Traffic↗
PubMed1978

Immunodiagnostics of malignant disease. VI. Electrophoretic mobility test (EMT) in malignant melanoma.

The electrophoretic mobility test (EMT) is an in vitro assay for demonstrating cellular immunity. In the presence of tumor antigens lymphocytes of tumor patients liberate lymphokines, which reduce the charge of indicator particles resulting in a measurable reduction of their eletrophoretic mobility. Lymphocytes of 174 patients were tested by EMT. The antigens used were a basic myelin protein termed encephalitogenic factor (EF) and a 3M KCl extract from melanoma tissue. In 91% of the cancer patients there was a positive lymphocyte response. In contrast to this the controls and non-malignant diseases showed a positive result in only 8.7% of the cases. Using the 3M KCl extract from melanoma tissue as tissue as antigen 1 of the benign controls, 3 patients with nonmalignant diseases and none of the 49 patients with malignant diseases reacted positively, whereas in the melanoma group 86% showed a positive lymphocyte response. The results show the possibility of demonstrating tumor specific immune reaction in the EMT.

Antigens↗