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N Zimmermann

Publications and source records attributed to N Zimmermann.

At least 37 records · Page 2Linked to original sources
PubMed1999

The R576 IL-4 receptor alpha allele correlates with asthma severity.

BACKGROUND: Atopic disorders, including asthma, are very prevalent, affecting up to 40% of populations, and their incidence is on the rise. Although environmental factors are important in the development of atopy, there is a strong genetic predisposition. Several genes and chromosomal regions have been linked to atopy and asthma, supporting the polygenic nature of these disorders. IL-4 and IL-13 are T(H)2 cytokines with numerous activities that contribute to allergic inflammation and asthma. Both IL-4 and IL-13 use the IL-4 receptor alpha chain (IL-4Ralpha) as a component of their respective receptor systems. Allelic variants of IL-4Ralpha have been reported, and the R576IL-4Ralpha allele was recently shown to be a risk factor for atopy. OBJECTIVE: We sought to determine whether the R576 allele was associated with the prevalence or clinical severity of asthma. METHODS: We developed a rapid, reliable, PCR-based assay to screen individuals for the R576IL-4Ralpha allele and used this assay to genotype prospectively recruited individuals with asthma (n = 149) and control subjects (n = 57). RESULTS: There was a strong association of R576IL-4Ralpha with the prevalence and clinical severity of asthma. In a prospective cohort, homozygosity for R576 was significantly increased in individuals with asthma (n = 149, P =.03; relative risk 8.2) compared with controls (n = 57). Furthermore, 1 or 2 copies R576IL-4Ralpha correlated with asthma severity establishing a genotype-phenotype relationship and suggesting a gene dosage effect. CONCLUSIONS: Thus R576IL-4Ralpha acts as an allergic asthma susceptibility and disease-modifying gene and may serve as a clinically useful marker of asthma severity.

Adult↗
PubMed1999

Chemokines and chemokine receptors: their role in allergic airway disease.

One of the hallmarks of allergic pulmonary disorders is the accumulation of an abnormally large number of leukocytes including eosinophils, neutrophils, lymphocytes, basophils, and macrophages in the lung. There is now substantial evidence that eosinophils, under the control of T lymphocytes, are major effector cells in the pathogenesis of asthma. Therefore, understanding the mechanisms by which eosinophils accumulate and are activated in tissues is a fundamental question very relevant to allergic diseases. Another characteristic of allergic inflammation is the activation of leukocytes resulting in the release of biologically active mediators, such as histamine from mast cells and basophils. It is now apparent that chemokines are potent leukocyte chemoattractants, cellular activating factors, histamine releasing factors, and regulators of homeostatic immunity, making them particularly important in the pathogenesis of airway inflammation in asthma. In this regard, chemokines are attractive new therapeutic targets for the treatment of allergic disease. This article focuses on recently emerging data on the importance of chemokines and their receptors in allergic airway inflammation.

Animals↗
PubMed1999

Post-perfusion syndrome and disturbed microcirculation after cardiac surgery: the role of angiotensin-converting-enzyme inhibitors.

BACKGROUND: The sympathoadrenal and the renin-angiotensin system (RAS) are involved in blood pressure regulation. They are known to be activated during cardiac surgery. We investigated the influence of preoperative RAS-blockade using angiotensin-converting-enzyme inhibitors (ACEI) on hemodynamic variables and on the perioperative need for exogenous catecholamines. METHODS: 240 patients undergoing coronary artery bypass grafting (CABG) or valve surgery were divided into three matched groups (group A: pre- and postoperative ACEI; group B: ACEI only pre-, not postoperatively; group C: no ACEI). In these three groups we analyzed hemodynamic variables, the need for catecholamines and the incidence of a "post-perfusion syndrome" or systemic inflammatory response syndrome (SIRS) with impaired microcirculation. RESULTS: There were significant differences in the intra- and postoperative need for catecholamines in groups A and B compared to C (intraop. A: 35%, B: 35%, C: 15%; postop. A: 21.2%, B: 16.2%, C: 10%) (p < 0.05). In the ACEI groups (A and B) there were 9 patients with a postoperative SIRS, only 2 cases in group C. Furthermore 4 patients of group B suffered from disturbances of the intestinal microcirculation postoperatively. CONCLUSIONS: Long-term ACEI treatment before cardiac surgery raises the perioperative need for catecholamines. Patients with preoperative long-term use of ACEI who do not receive ACEI postoperatively face an increased risk of impaired microcirculation. The inhibition of angiotensin-II (AT II) generation causes the vasodilatatory effects of ACEI, and could be one reason for a post-perfusion syndrome or a SIRS.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1999

Pharmacological characterization of protein phosphatase activities in preparations from failing human hearts.

beta-Adrenoceptor stimulation acts in the heart in part by increasing the phosphorylation state of phospholamban and phospholemman. There is evidence that the beta-adrenoceptor-mediated increase in phospholamban phosphorylation is in part due to inhibition of type 1 phosphatases. The aim of the present study was to elucidate which phosphatases dephosphorylate phospholamban and phospholemman in the human heart. In the past, cardiac serine/threonine phosphatases have been studied using phosphorylase a as substrate. Here, type 1 and type 2A phosphatase activities were studied in preparations from failing human hearts using phosphorylated phospholamban and phospholemman as substrates. Phospholamban and phospholemman phosphatase activity was detectable in human cardiac homogenates. Moreover, using a heparin-Sepharose column, the catalytic subunits of type 1 and type 2A phosphatases could be separated from human ventricles. Okadaic acid and cantharidin inhibited phosphatase activities dephosphorylating phospholamban, phospholemman, and phosphorylase a in homogenates in a concentration-dependent manner. However, okadaic acid was more potent. Cantharidin inhibited type 2A and type 1 activities against all substrates studied with IC50 values <15 nM and >290 nM, respectively. Okadaic acid inhibited type 1 and type 2A phosphatase activities as effectively but 10-30 times more potently than cantharidin. This work provides evidence that in the human heart, type 1 and 2A phosphatases are involved in the dephosphorylation of phospholamban and phospholemman and could play a role in the effects of beta-adrenergic stimulation in the heart.

Animals↗
PubMed1999

Inotropic effects of diadenosine tetraphosphate (AP4A) in human and animal cardiac preparations.

Diadenosine tetraphosphate (AP4A) is an endogenous compound and exerts diverse physiological effects in animal systems. However, the effects of AP4A on inotropy in ventricular cardiac preparations have not yet been studied. The effects of AP4A on force of contraction (FOC) were studied in isolated electrically driven guinea pig and human cardiac preparations. Furthermore, the effects of AP4A on L-type calcium current and [Ca]i were studied in isolated guinea pig ventricular myocytes. In guinea pig left atria, AP4A (0.1-100 microM) reduced FOC maximally by 36.5 +/- 4.3%. In guinea pig papillary muscles, AP4A (100 microM) alone was ineffective, but reduced isoproterenol-stimulated FOC maximally by 29.3 +/- 3.4%. The negative inotropic effects of AP4A in atria and papillary muscles were abolished by the A1-adenosine receptor antagonist 1, 3-dipropyl-cyclopentylxanthine. In guinea pig ventricular myocytes, AP4A (100 microM) attenuated isoproterenol-stimulated L-type calcium current and [Ca]i. In human atrial and ventricular preparations, AP4A (100 microM) alone increased FOC to 158.3 +/- 12.4% and 167.5 +/- 25.1%, respectively. These positive inotropic effects were abolished by the P2-purinoceptor antagonist suramin. On the other hand, AP4A (100 microM) reduced FOC by 27.2 +/- 7.4% in isoproterenol-stimulated human ventricular trabeculae. The latter effect was abolished by 1,3-dipropyl-cyclopentylxanthine. In summary, after beta adrenergic stimulation AP4A exerts negative inotropic effects in animal and human ventricular preparations via stimulation of A1-adenosine receptors. In contrast, AP4A alone can exert positive inotropic effects via P2-purinoceptors in human ventricular myocardium. Thus, P2-purinoceptor stimulation might be a new positive inotropic principle in the human myocardium.

Animals↗
PubMed1998

Polymorphisms in the human CC chemokine receptor-3 gene.

CC chemokine receptor (CCR)-3 is a seven-transmembrane-spanning G-protein-coupled receptor (GPCR) that is involved in the recruitment of inflammatory cells in allergic responses and acts as a co-receptor for entry of HIV into cells. Selected polymorphisms in GPCRs have been shown to have dramatic effects on the manifestation and/or susceptibility to a variety of diseases. In this report, we tested whether the human CCR-3 gene locus is genetically polymorphic. Using single-stranded conformational polymorphism analysis of genomic DNA, the CCR-3 gene is shown to contain four nucleotide polymorphisms with allele frequencies ranging from 0.005 to 0.13. Two polymorphisms encode for an amino acid change. One of these polymorphisms encodes for a non-conservative change of arginine to glutamine at position 275 of the third extracellular loop. Stratification of the DNA samples into a population with asthma suggested no change in this allele's frequency. Another polymorphism encodes for a leucine to proline substitution in the intracellular cytoplasmic tail of CCR-3. The most frequent polymorphism, T51C, occurs in 26% of individuals and encodes for a silent substitution. Thus, CCR-3 contains several genetic variations which may have consequences in disease processes that involve this receptor.

Adolescent↗
PubMed1998

Eotaxin is required for the baseline level of tissue eosinophils.

Eotaxin is an eosinophil-selective chemokine that is constitutively expressed in a variety of organs such as the intestine. Previous studies have demonstrated that the recruitment of eosinophils during inflammation is partially dependent on eotaxin, but the function of constitutive eotaxin during homeostasis has not been examined. To elucidate the biological role of this molecule, we now examine tissue levels of eosinophils in healthy states in wild-type and eotaxin-deficient mice. The lamina propria of the jejunum of wild-type mice is demonstrated to express eotaxin mRNA, but not mRNA for the related monocyte chemoattractant proteins. Wild-type mice contained readily detectable eosinophils in the lamina propria of the jejunum. In contrast, mice genetically deficient in eotaxin had a large selective reduction in the number of eosinophils residing in the jejunum. The reduction of tissue eosinophils was not limited to the jejunum, because a loss of thymic eosinophils was also observed in eotaxin-deficient mice. These studies demonstrate that eotaxin is a fundamental regulator of the physiological trafficking of eosinophils during healthy states. Because a variety of chemokines are constitutively expressed, their involvement in the baseline trafficking of leukocytes into nonhematopoietic tissue should now be considered.

Animals↗
PubMed1998

Increased preoperative C-reactive protein (CRP)-values without signs of an infection and complicated course after cardiopulmonary bypass (CPB)-operations.

OBJECTIVE: C-Reactive protein (CRP) is known to be a sensitive indicator of infection. Since it is also involved in the acute phase reaction, it is of great interest, whether an isolated preoperative increase of CRP without further signs of infection is of any prognostic value for postoperative outcome after cardiac surgery with cardiopulmonary bypass (CPB), which itself is possibly causing a systemic inflammatory response syndrome (SIRS). METHODS: Fifty patients with an isolated CRP-elevation (>5 mg/l) (from 6.2 to 93.3 mg/l) were operated using CPB (group A). A control group (group B) consisted of 50 cardiac surgery patients, matched in the patterns of age, gender and kind of disease. No preoperative CRP-elevation (from 0 to 4.8 mg/l) occurred in this group. RESULTS: The postoperative course of both groups showed significant differences. Septic complications were seen more often in group A (20%) than in the controls (2%) (P < 0.01). Microbiology (blood culture, cultures from nose, tracheal aspirate and urine) was positive only in 10% of these patients. Catecholamine support (epinephrine, norepinephrine and/or doses of dopamine or dobutamine of more than 3 microg/kg per min) was needed in 26% of group A cases, whereas it was only needed in 10% of group B (P < 0.05). A significantly longer respiratory support was also necessary in patients with elevated CRP (25.2 +/- 6.4 h vs. 6.6 +/- 0.8 h) (P < 0.01). Furthermore there was a significant difference in the duration of intensive care (4.6 +/- 0.8 days vs. 2.6 +/- 0.3 days) (P < 0.05). CONCLUSIONS: These data show that patients without apparent infection or inflammation, who had elevated CRP-values preoperatively, face an increased risk of septic complications after extracorporeal circulation. As microbiology tests are negative in most cases, it may be speculated that the majority of septic complications are due to a SIRS.

C-Reactive Protein↗
PubMed1998

Calcium sensitization as new principle of inotropic therapy in end-stage heart failure?

OBJECTIVE: Due to shortage of donor hearts and increasing waiting-lists of patients with end-stage heart disease, new pharmacological principles for bridging therapies are necessary. The positive inotropic effects of cAMP-increasing drugs (e.g. catecholamines, phosphodiesterase-inhibitors) are diminished in the failing myocardium. Hence, we investigated the usefulness and mechanism of the two calcium sensitizers, levosimendan and CGP 48506 in preparations from end-stage failing human hearts since the exact mechanism of the positive inotropic effects is not yet clearly understood. METHODS: Failing human hearts which required orthotopic heart transplantation due to idiopathic dilated cardiomyopathy were investigated. Contraction experiments were performed using muscle strips of ventricles. Calcium sensitization was investigated in skinned fibers and phosphodiesterase activity was measured in ventricular homogenate. In addition, cAMP levels were quantified in myocytes from guinea-pig hearts. RESULTS: In muscle stripes from failing human hearts levosimendan (10 micromol/l) increased the force of contraction only to 112.8 +/- 6.7% of predrug values. In contrast, CGP 48506 increased the force of contraction to 311 +/- 59% of predrug values at 100 micromol/l. The time to peak tension and time of relaxation were increased to 175 +/- 4% and 205 +/- 15% of control levels at 100 micromol/l. Skinned fibers from failing human hearts were sensitized to calcium with an EC50 of 10 micromol/l. Other mechanisms of action were excluded since CGP 48506 affected neither the activity of phosphodiesterase isoenzymes I-IV in failing human hearts, nor cAMP levels in guinea-pig cardiomyocytes. On the other hand, levosimendan (1 micromol/l) increased cAMP content from 6.3 +/- 0.3 to 8.1 +/- 0.3 pmol/mg protein. CONCLUSION: CGP 48506 is an inotropic agent with calcium-sensitizing properties in the human heart, that is devoid of inhibitory activity on human cardiac phosphodiesterase isoenzymes. It offers, therefore, a new form of positive inotropic therapy that can be useful for the bridging treatment of heart failure before transplantation. On the other hand, levosimendan is a calcium sensitizer showing less-effective inotropic effects accompanied by increased cAMP levels.

Azocines↗
PubMed1997

The three-dimensional solution structure of the lantibiotic murein-biosynthesis-inhibitor actagardine determined by NMR.

The three-dimensional solution structure of the lantibiotic actagardine was determined at high resolution by homonuclear and heteronuclear two-dimensional and three-dimensional NMR spectroscopy in [2H3]acetonitrile/H2O (7:3). 133 non-trivial distance and 22 torsional-angle constraints were derived from the NMR data. An ensemble of 15 low-energy structures was calculated by distance geometry followed by an iterative relaxation-matrix-refinement procedure. The rmsd of the backbone coordinates with respect to the average structure was 17 pm. The two distinct thioether ring systems 1-6 and 7-19 were even better defined, with backbone rmsd of 10 pm and 14 pm, respectively. Actagardine shows a rigid compact globular shape based on the constraining bridging pattern, which is composed of an N-terminal lanthionine ring from residues 1-6 and three intertwined C-terminal methyllanthionine rings comprising residues 7-12, 9-17 and 14-19. In addition, this C-terminal ring system is stabilised by a short antiparallel beta sheet. A feature of the actagardine structure is the presence of two putative binding pockets. A pocket is generated by the covalent constraints of the C-terminal thioether ring system. The rim of this pocket is built up by a loop structure comprising residues 12-19, whose backbone amide protons are all directed to the centre of the pocket. The second pocket is formed by an L-shaped orientation of the N-terminal and C-terminal thioether ring systems. The only two hydrophilic amino acid residues of actagardine, Glu11 and Ser2, are directed to this pocket. A region of high sequence similarity with the related lantibiotic mersacidin is located exactly at the position of the second pocket (residues 3-12). This suggests that the second pocket is responsible for the antibiotic mode of action of actagardine and mersacidin as inhibitors of the murein biosynthesis of gram-positive bacteria.

Amino Acid Sequence↗
PubMed1997

Increased expression of cardiac phosphatases in patients with end-stage heart failure.

Type 1 phosphatase activity was increased in membrane vesicles from failing human ventricles compared with non-failing controls. Likewise, expression of the mRNA encoding for type 1 phosphatase was enhanced by 37%. The present study provides evidence that alterations of phosphatase activity coincide with end-stage heart failure. Thus, enhanced activity of phosphatases may be causally related to heart failure and/or may aggravate the well known decreased cardiac responsiveness to positive inotropic agents in end-stage heart failure.

Adenylyl Cyclases↗
PubMed1997

Quantitation of diltiazem in human cardiac tissue using high-performance liquid chromatography.

A new high-performance liquid chromatographic method has been developed for the determination of diltiazem in human cardiac tissue. Tissue samples are homogenized and digested with trypsin solution. Diltiazem and the internal standard are extracted with acetone. The extract is evaporated to dryness and reconstituted in potassium phosphate buffer. Samples are then cleaned up with solid-phase extraction columns. Diltiazem and the internal standard show recoveries of 59% +/- 16 and 52% +/- 13. The linearity range is 0.12-2.25 ng/mg wet weight. The limit of quantitation is 0.12 ng/mg (w/w). The percentage coefficient of variation of intra-assay varies between 3.57 and 11.2, and that of interassay varies between 5.42 and 11.7. As an application of the assay, a diltiazem cardiac tissue level in a patient on oral therapy for supraventricular tachycardia is reported.

Calcium Channel Blockers↗
PubMed1997

Mechanisms of the contractile effects of levosimendan in the mammalian heart.

In spontaneously beating guinea pig right atria, levosimendan (LS, or R-[[-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)- phenyl]-hydrazono]propanedinitrile) exerted a positive chronotropic effect starting at 0.1 microM. In electrically driven guinea pig left atria, LS (0.1-10 microM) increased force of contraction without changing time parameters of contraction. In electrically driven right papillary muscles, LS (0.1-10 microM) enhanced force of contraction without affecting time parameters of contraction. The maximal effect on force of contraction at 10 microM amounted to 130 +/- 8.6% of predrug value. The positive inotropic effect of LS in papillary muscles was greatly diminished by additionally applied carbachol. In [32P]-labeled guinea pig ventricular cardiomyocytes, LS increased the phosphorylation state of phospholamban, the inhibitory subunit of troponin and C-protein. The maximal effect at 1 microM amounted to 134 +/- 8.6%, 124 +/- 4.2% and 121 +/- 8% of control for phospholamben, the inhibitory subunit of troponin and C-protein, respectively. LS (1 microM) increased cAMP content from 6.3 +/- 0.3 to 8.1 +/- 0.3 pmol/mg protein in guinea pig ventricular cardiomyocytes. Furthermore, whole-cell patch-clamp studies were performed in guinea pig ventricular cardiomyocytes. In this setup, 10 microM LS increased the amplitude of L-type Ca++ current to 402 +/- 86% of predrug value.

Animals↗
PubMed1996

Determination of sotalol in human cardiac tissue by high-performance liquid chromatography.

A sensitive and quantitative reversed-phase HPLC method for the analysis of D,L-sotalol in human atria, ventricles, blood and plasma was developed. Sotalol was determined in about 100 mg of human right atria, left ventricles, and in 500 microliters of blood and plasma samples of patients undergoing coronary bypass surgery or heart transplantation. Patients were taking 80-160 mg of sotalol as an antiarrhythmic agent. Atenolol was used as an internal standard certifying high precision of measurement. Sotalol blood and plasma concentrations correlated linearly to the obtained signals from 26.5 ng/ml to 2.12 micrograms/ml. Sotalol tissue concentrations showed linearity between 0.27 ng/mg and 10.6 ng/mg wet weight. The limit of quantitation was 0.27 ng/mg at a signal-to-noise ratio of 10. Sotalol was extracted from homogenized tissue with a buffer solution (pH9) and the remaining pellet was extracted with methanol. The methanol extract was evaporated under nitrogen and reconstituted in buffer (pH3). The whole extract was cleaned by solid-phase column extraction, eluted with methanol, evaporated again, reconstituted in the mobile phase (acetonitrile-15 mM potassium phosphate buffer pH3, 17:83, v/v) and injected onto the HPLC column (Spherisorb C6 column, 5 microns, 150 x 4.6 mm I.D.). For the detection of sotalol, the UV wavelength was set to 230 nm. Recoveries of sotalol and atenolol in atria and ventricles were 65.6 and 75.0%, respectively. Intra- and inter-assay coefficients of variation for tissue concentrations were 3.38 and 6.14%, respectively. Intra- and inter-assay accuracy for determined tissue sotalol concentrations were 94.9 +/- 6.3 and 99.6 +/- 4.1%.

Adrenergic beta-Antagonists↗
PubMed1996

PACAP induces bradycardia in guinea-pig heart by stimulation of atrial cholinergic neurones.

Based on previous studies which indicated that pituitary adenylate cyclase activating peptide (PACAP) acts as a positive inotropic and chronotropic substance in different species via the cAMP signal transduction pathway, the objective of the present work was to investigate cAMP-regulated myocardial key proteins in response to PACAP in isolated ventricular cells of the guinea pig. Surprisingly, the two molecular forms of PACAP, PACAP(1-27) and PACAP(1-38), showed no effect on intracellular cAMP-levels, L-type Ca2+ channel current or phosphorylation of troponin inhibitor (TnI) and phospholamban (PLB). Additionally, inotropy of isolated guinea-pig ventricular strips was not affected by the neuropeptide. However, in isolated spontaneously beating guinea-pig atria, PACAP(1-27) and PACAP(1-38), but not VIP induced severe bradycardia in a dose-dependent manner. This effect could be prevented by preincubation with the PACAP receptor antagonist PACAP(6-38), by atropine and by omega-conotoxin, a blocker of neuronal N-type Ca2+ channels. PACAP stimulates release of [3H]-labelled acetylcholine. Only preparations showing an increase in [3H]acetylcholine release developed bradycardia, indicating a causal relationship between both phenomena. It was concluded that PACAP exerts no influence on guinea-pig ventricular tissue, but induces negative chronotropic effects in isolated guinea-pig atria by stimulation of acetylcholine release from parasympathetic neurons via PACAP type 1 receptors.

Acetylcholine↗
PubMed1996

Mechanisms of the contractile effects of 2,3-butanedione-monoxime in the mammalian heart.

We studied the mechanisms of action of a negative inotropic compound, 2,3-butanedione-monoxime (BDM), which has been suggested to be a cardioprotective agent. In guinea-pig papillary muscles the negative inotropic effect of BDM start at 100 mumol/l amounting to 18.32 +/- 2.09% of predrug value at 10 mmol/l without any effects on time parameters (n = 12, each). 30 mmol/l BDM totally abolished force of contraction; this effect was reversible after washout. In the presence of the phosphatase-inhibitor cantharidin (30 mumol/l) the concentration response curve on force of contraction was shifted to higher concentrations of BDM. 100 mmol/l BDM decreased the phosphorylation state of the inhibitory subunit of troponin (TnI) and phospholamban (PLB) in [32P]-labeled guinea-pig ventricular myocytes to 76.5 +/- 4.7% and 49.7 +/- 4.2%, respectively (n = 7). Furthermore, BDM enhanced the activity of phosphorylase phosphatases in guinea-pig ventricular homogenates amounting to a stimulation to 203.5 +/- 10.4% at 100 mmol/l whereas type 1 phosphorylase phosphatase activity increased only by 24.5% (n = 5). PLB phosphatase activity was enhanced to 155.9 +/- 11.7% by 100 mmol/l BDM (n = 5). It is concluded that the effects of BDM on contractile parameters are accompanied by decreased phosphorylation of the cardiac regulatory proteins TnI and PLB which could in part be due to activation of type 1 or 2A phosphatase activity. Hence, it is suggested that BDM affects the phosphorylation state of TnI and PLB not directly, but via activation of their phosphatases.

Animals↗
PubMed1996

Absence of retinoblastoma gene product in human primary oral cavity carcinomas.

Oral cavity cancer is a major health concern worldwide. Despite advances in surgery, radiotherapy and chemotherapy over the past 35 years, there has been no significant enhancement in the survival of oral cavity cancer patients. Improved survival will require identification of reliable prognostic markers that provide a rational basis for assessment of risk for progression. The altered retinoblastoma (RB) gene has been linked to the hereditary retinoblastoma. This gene is defective in several types of human malignancies. The intent of this study was to evaluate the role of the RB gene in oral cavity tumorigenesis and to explore whether or not there is a relationship between the loss of RB protein and each of several clinicopathological parameters in oral cavity carcinomas. We have analysed the expression of the RB gene in four cell lines (J82, ML1, SaOS2 and WERI-RB-1), 182 oral cavity carcinomas (75 T1 and 107 T3 and T4 lesions) and 55 normal tissues adjacent to cancer by means of an immunohistochemical method and Western immunoblotting. The expression of RB protein was then correlated with clinical outcome in the patients with primary tumours. The significantly higher rate of altered RB expression was found in advanced oral cavity tumours (40 of 107; 37%) in comparison with low grade tumours (9 of 75; 7%). In T3 and T4 tumours, RB gene expression did not correlate with presence or absence of lymph node metastasis, degree of differentiation and patient survival. However, in the T1 cohort, poorer survival rate was seen for those patients who had a tumour with loss of RB protein. This study suggests that tumours in which the RB protein was altered were more aggressive than tumours in which the RB protein was present and that loss of RB protein in oral cavity cancer may be a prognostic variable of tumour progression.

Biomarkers, Tumor↗