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Dans le developpement des cancers, la tumorigenese est une etape essentielle ou un processus a l’origine moleculaire et cellulaire devient tissulaire et surtout clinique. Cette etape est rendue possible par la mise en place et le developpement d’interactions entres les cellules epitheliales transformees et leur microenvironnement stromal tissulaire. Les cellules stromales recrutees et activees sont les myofibroblastes, les macrophages, les cellules precurseurs medullaires et cellules inflammatoires. Le stroma, via ces cellules activees devient un partenaire actif du developpement tumoral. Les consequences de ces interactions entre tumeurs et microenvironnement sont

Acute bacterial meningitis (ABM) is a potentially life-threatening neurological emergency. An agreed protocol for early, evidence-based and effective management of community-acquired ABM is essential for best possible outcome. A literature search of peer-reviewed articles on ABM was used to collect data on the management of ABM in older children and adults. Based on the strength of published evidence, a consensus guideline was developed for initial management, investigations, antibiotics and supportive therapy of community-acquired ABM. Patients with ABM should be rapidly hospitalized and assessed for consideration of lumbar puncture (LP) if clinically safe. Ideally, patients should have fast-track brain imaging before LP, but initiation of antibiotic therapy should not be delayed beyond 3 h after first contact of patient with health service. In every case, blood sample must be sent for culture before initiating antibiotic therapy. Laboratory examination of cerebrospinal fluid is the most definitive investigation for ABM and whenever possible, the choice of antibiotics, and the duration of therapy, should be guided by the microbiological diagnosis. Parenteral therapy with a third-generation cephalosporin is the initial antibiotics of choice in the absence of penicillin allergy and bacterial resistance; amoxicillin should be used in addition if meningitis because of Listeria monocytogenes is suspected. Vancomycin is the preferred antibiotic for penicillin-resistant pneumococcal meningitis. Dexamethasone should be administered both in adults and in children with or shortly before the first dose of antibiotic in suspected cases of Streptococcus pneumoniae and H. Influenzae meningitis. In patients presenting with rapidly evolving petechial skin rash, antibiotic therapy must be initiated immediately on suspicion of Neisseria meningitidis infection with parenteral benzyl penicillin in the absence of known history of penicillin allergy.

Resume La glande prostatique est androgenodependante. L’implication des androgenes dans le developpement, la fonction et la pathologie de la glande prostatique (hypertrophie benigne ou HBP, cancer), peut etre examinee de deux manieres : Soit au travers de donnees directes, issues des modeles experimentaux (in vitro–in vivo) ou de l’analyse biologique des tissus prostatiques humains normaux et pathologiques qui permettent de decrire les mecanismes moleculaires, cellulaires et tissulaires mis en jeu ; soit au travers de donnees indirectes issues des etudes epidemiologiques et cliniques, de suppression, ou supplementation androgenique decrivant l’impact sur la glande prostatique. Sur le plan experimental, il est generalement admis que la croissance de la prostate est regulee par les androgenes (testosterone et ses metabolites actifs). Un niveau approprie de testosterone circulante est necessaire pour maintenir la croissance, le developpement, la differenciation et la fonction de la glande prostatique. L’orchidectomie bilaterale induit la mort cellulaire programmee (apoptose) et l’involution de la glande ; l’administration de testosterone exogene est alors capable d’induire la croissance prostatique jusqu’au niveau normal. Il en va de meme lorsqu’on traite un animal impubere. La reponse de la prostate a la testosterone exogene ne produit donc pas une croissance au-dela du volume normal qui est maintenu par l’equilibre entre proliferation et mort cellulaire en presence de niveaux physiologiques d’androgenes. L’etude des mecanismes de regulation de la croissance prostatique donne une justification fondamentale aux traitements medicamenteux et hormonaux utilises par les urologues dans le traitement de l’HBP du cancer de prostate. Dans le cadre du deficit androgenique lie a l’âge (DALA), il persiste un doute sur une action potentiellement nefaste du traitement androgenique substitutif sur la prostate.

Various studies suggested that cytotoxicity induced by 5-fluorouracil (5-FU) is an apoptotic mechanism possibly mediated by the Fas/FasL system. In this preliminary work, we studied retrospectively the role the Fas/FasL expression as a predictive response factor with fluoropyrimidine-based chemotherapies. We developed a real-time PCR method for measuring Fas and FasL expression in various biopsies from patients treated with a FUFOL-like protocol. No correlation was found between Fas or FasL expression and overall survival or partial response. However, the PCR assay was simple and convenient to use for quantitation of Fas/FasL in tumor biopsies.

The quantized states of a 60 nm wide potential well in a large tilted magnetic field are investigated using scaled field resonant tunnelling spectroscopy. In contrast to previous experiments on this type of system, the tunnelling characteristics are measured by changing both the magnetic field strength B and the applied bias voltage V such that V/B2 is approximately constant. This ensures that the classical phase space for electrons in the potential well has the same mixed stable-chaotic character for all fields. As a consequence of this scaling, each closed orbit in the potential well produces many periodic resonant peaks in plots of d2I/dB2 versus B. This type of scaled field experiment can be used to probe quantum states corresponding to dynamical regimes which are inaccessible to fixed field resonant tunnelling studies. We also consider analogies between the electron orbits and light rays in gradient refractive index lenses.

Since the few data exploring a possible association between Epstein–Barr virus (EBV) and breast cancer are conflicting, we investigated this association together with the influences of geographical areas. 509 breast cancers were sampled from areas with varying risks of nasopharynx carcinoma (NPC) such as North Africa (Algeria and Tunisia, high-risk area); southern France (Marseille, intermediate-risk area); and northern Europe (northern France, the Netherlands and Denmark; low-risk areas). Polymerase chain reaction (PCR) of a subregion of EBV BamHIC encoding the EBERs demonstrated that 31.8% of the tumours contained the viral genome. No significant differences were observed among the geographical areas. However, positive samples showed higher loads of the EBV genome in the NPC high- and intermediate-risk areas than in the low-risk areas. EBV type 1 was the dominant strain. In situ hybridization studies using a35S-labelled riboprobe for EBER1 and a laser capture microdissection, combined with quantitative PCR, showed that EBV localization was restricted to some tumour epithelial cell clusters. EBV could not be detected in the stroma. Considering the whole population covered, the presence of the EBV genome was not correlated with age, menopausal status, tumour, size, nodal status or histological grade. © 2001 Cancer Research Campaign http://www. bjcancer.com

Resume Objectifs – Les traitements hormonaux substitutifs (THS) sont utilises de plus en plus frequemment par les femmes menopausees. Bien que ces traitements n'augmentent que moderement le risque de cancer, de plus en plus de cas de cancers du sein sont ainsi diagnostiques au cours d'un THS. Le but de cette etude est l'evaluation des effets des THS sur les facteurs pronostiques et l'evolution des cancers du sein diagnostiques au cours de tels traitements. Patientes et methodes – Les donnees concernant 1 223 patientes menopausees traitees par une seule equipe entre janvier 1990 et decembre 1998 ont ete systematiquement et prospectivement saisies dans une banque informatique. Les caracteristiques cliniques, biologiques et les probabilites de survie de 245 patientes sous THS lors du diagnostic de cancer ont ete comparees a celles de 245 patientes appariees n'ayant jamais recues de THS. Resultats – Les patientes sous THS ont plus de cancers de faibles dimensions, moins de tumeurs evoluees, moins d'envahissements ganglionnaires axillaires, et des tumeurs mieux differenciees (differences significatives). La receptivite hormonale aux œstrogenes est quantitativement plus faible pour les patientes sous THS. Les probabilites de survie sans metastases sont significativement plus elevees pour les patientes sous THS. Conclusion – Dans notre serie, les THS n'aggravent pas le pronostic des cancers du sein. Le depistage radiologique et la surveillance medicale reguliere permettent le diagnostic de lesions de petites dimensions. Le nombre eleve de cancers bien differencies et les caracteristiques de la receptivite hormonale pourraient refleter l'existence d'interactions entre les hormones exogenes et les tissus neoplasiques.

Capacitance spectroscopy is used to study electronic properties of self-assembled InAs quantum dots. The capacitance-voltage, C(V), measurements in combination with the magneto-capacitance, C(B), results make it possible to investigate the electrostatic profile of a series of single-barrier n-i-n GaAs/AlAs/GaAs heterostructures incorporating a layer of self-assembled InAs quantum dots in the AlAs barrier. We find that the negative charge associated with electron filling of the dots is closely compensated by a positive charge in the AlAs barrier, which we ascribe to ionised defects or impurities, possibly in association with the quantum dots. It is shown the compensation degree considerably depends on the growth conditions. Ємнiсна спектроскопiя використується для дослiдження електронних властивостей само-органiзованих InAs квантових точок. Вимiрювання вольт-фарадних характеристик, C(V), одночасно з даними по магнето-емностi, C(B), дозволяють дослiджувати електростатичний профiль однобар.єрних p-i-n GaAs/AlAs/GaAs гетероструктур, якi мiстять в AlAs бар.єрі шар само-органiзованих InAs квантових точок. Ми визначили, що негативний заряд, пов.язаний з заповненням квантових точок електронами, майже повнiстю компенсується позитивним зарядом в AlAs бар.єрi, що, на нашу думку, пов.язано з iонiзованими дефектами чи домiшками, якi обумовлені квантовими точками. Показано, що мiра компенсацiї суттєво залежить вiд ростових умов. Емкостная спектроскопия используется для исследования электронных свойств само-организованных InAs квантовых точек. Измерение вольт-фарадных характеристик, C(V), совместно с данными по магнето-емкости, C(B), позволяют исследовать электростатический профиль однобарьерных p-i-n GaAs/AlAs/GaAs гетероструктур, содержащих в AlAs барьере слой само-организованных InAs квантовых точек. Мы установили, что отрицательный заряд, связанный с заполнением квантовых точек электронами, почти полностью компенсируется положительным зарядом в AlAs барьере, который, по нашему мнению, связан с ионизованными дефектами или примесями, обусловленными квантовыми точками. Показано, что степень компенсации существенно зависит от ростовых условий.

We use tunnel current spectroscopy to investigate the quantum states of two GaAs quantum wells coupled by a low (100 meV) (AlGa)As tunnel barrier. A high tilted magnetic field is used to generate strongly chaotic electron motion in the two wells which act as coupled chaotic `stadia'. The effect of the tunnel barrier on the dynamics of the system depends on the magnitude of the applied bias voltage V. For V≳375 mV, the central potential barrier acts as a perturbation which modifies the trajectories of selected periodic orbits in the quantum well. Scattering off the central barrier also generates new periodic orbits involving multiple collisions on all three barriers. These orbits `scar' distinct sets of eigenstates which generate periodic resonant peaks in the current–voltage characteristics of the device. When the device is biased such that the injected electrons just surmount the central barrier, our calculations reveal novel hybrid scarred states with both stable and chaotic characteristics.

Results of conservative treatment with surgery and radiation therapy of 132 non-palpable ductal carcinomas in situ of the breast. Purpose. — Retrsopective analysis of results of treatment of 132 subclinical ductal carcinomas in situ, non-palpable. Material and methods. — Patients were treated with limited surgery and 70 Gy radiation therapy (70 Gy). Results. — With a median follow-up of 7 years, the total recurrence rate was 6%, and the actuarial rate at 5 years 4% and at 10 years 13% at. These have no influence on recurrence on the specific actuarial survival rate which was 100% at 10 years. In spite of five infiltrating recurrences of seven, no metastasis appeared 48 months after the salvage surgery. The global rate of breast preservation was 92% at 7 years. Discussion and conclusion. — Therapeutic indications were developed taking into account the present analysis and a literature review (2,338 in situ ductal carcinomas, palpable or not, treated with conservative surgery, with or without adjuvant radio-therapy).

An automated system for determinations of transport current–voltage (I–V) characteristics as a function of temperature (25–125 K), magnetic field (0–1.6 T), and magnetic field orientation (−125 to +145°) is described. Currents of up to 100 A are applied either as a continuous ramp or as pulses of 2–100 ms duration. A closed‐cycle helium refrigerator provides a rapid (∼45 min), convenient, cost effective, cooldown from 300 to 25 K. Control of current, temperature, magnetic field, and field orientation is fully automated and requires no user interaction. The characterization of performance of a ceramic superconductor typically involves several temperatures, fields, and orientations and requires 8–30 h to complete.

Si l’exposition au rayonnement solaire est connue depuis 1924 comme facteur de prevention du rachitisme, la vitamine D et sa structure n’ont ete isolees qu’en 1971. Depuis les annees 1980, on classe la vitamine D dans la superfamille des hormones steroidiennes alors que le terme hormone sous-entend la secretion par une glande endocrine, ce qui n’est pas le cas de la vitamine D. Cependant, la vitamine D est un derive du metabolisme du cholesterol comme les hormones steroidiennes et son action necessite un recepteur nucleaire proche des recepteurs steroidiens et retinoiques.

Seebeck, electrical, and thermal conductivity data are reported on CoSb3, and doped and undoped alloys of Co1−x Ir x Sb3−y As y from 20 to 700 K. n‐type semiconductors were obtained by doping with Ni, Te, or Pd, and the hole concentration in p‐type samples was increased by substitution of Fe, Ru, Os, and Ge. An estimated maximum value for ZT of 0.6 (Z is the figure of merit) was found for a Te‐doped (n‐type) alloy at 700 K. For p‐type alloys, the maximum value of ZT was found to be 0.3 at 550 K. Electrical and thermal transport data also are reported for CoAs3, RhSb3, and IrSb3. Most of the samples investigated were polycrystalline, but a few measurements on CoSb3 single crystals also are discussed.

Objective To ascertain the influence of hormone replacement therapy on clinical and biologic prognostic factors of breast cancer. Methods Between 1976–1992, we treated 1081 postmenopausal women for breast cancer at our institution. Of these, 68 were undergoing postmenopausal hormone replacement therapy at the time of diagnosis. These patients were compared with a matched control group of 272 breast cancer patients who had not undergone prior hormone replacement therapy. Results Patients who developed breast cancer during hormone replacement therapy had fewer locally advanced cancers (large tumors and extensive lymph node involvement) and more well-differentiated cancers (infiltrating lobular cancers and grade 1 cancer). The number of patients with estradiol or progesterone receptors was lower in the hormone-treated group. Metastasis-free survival curves showed a tendency ( P = .05) for better prognosis in hormone-treated patients both overall and in stage T2. Conclusions Hormone replacement therapy per se does not affect the prognosis of breast cancer. Regular surveillance during hormone replacement therapy reduces the number of locally advanced cancers and thus improves the survival rate. The higher number of well-differentiated cancers and the distribution of hormone receptivity may reflect interaction between neoplastic tissue and exogenous hormones.

Currently, the benefit of chemotherapy (CT) in node-negative breast carcinoma (NNBC) is discussed. The evaluation of classical clinical and histological factors is limited to assess individual outcome. A statistical model was developed to improve the prognostic accuracy of NNBC.A total of 305 node-negative breast carcinomas who underwent surgery (+/- radiotherapy) but no adjuvant treatment were selected. Putative prognosis factors including age, tumour size, oestrogen receptor (ER), progesterone receptor (PgR), Scarff-Bloom-Richardon (SBR) grading, urokinase plasminogen activator (uPA), plasminogen activator inhibitor 1 (PAI-1) and thymidine kinase (TK) were evaluated. The developed model was internally validated using Harrell's concordance index. A prognosis index (PI) was proposed and compared with Adjuvant! Online program.Age (p0.001), pathological tumour size (pT) (p0.001), PgR (p = 0.02), and PAI-1 (p ≤ 0.001) were included in the Cox regression model predicting Breast cancer specific survival (BCSS) at 5-years. Internal validation revealed a concordance index of 0.71. A PI score was derived from our nomogram. The PI score was significantly associated with BCSS (hazard ratio (HR): 4.1 for intermediate, p=0.02, HR: 8.8, p0.001 for high group) as compared to Adjuvant! Online score (HR: 1.4, p=0.14).A nomogram can be used to predict probability survival curves for individual breast cancer patients.

Repondre a la question de l’evolution des tumeurs necessite un rappel des faits anatomocliniques et le developpement progressif de nos connaissances fondamentales sur les causes de la carcinogenese et sur les hypotheses explicatives du developpement tumoral.

The electrical and optical properties of an n-oped triple barrier resonant tunneling diode are investigated. A thin central AlAs barrier provides strong coupling between the two GaAs quantum wells which have equal widths. Photoluminescence (PL) arises from both spatially direct and spatially indirect transitions in the quantum wells. The intense spatially indirect transition shows a pronounced red shift with increasing bias. A strong intrinsic bistability effect is observed in one of the three resonant peaks in the current-voltage curve. This effect is also seen in the photon energy and intensity of the PL from the wells. Photoluminescence excitation spectroscopy is used to identify the optical transitions and the strength of the tunneling interaction.

The electroluminescence spectrum and current-voltage characteristics of a forward biased triple-barrier p-i-n diode are investigated. The thin AlAs central barrier provides strong coupling between the two GaAs quantum wells. EL arises from the GaAs contact layers and both spatially direct and indirect recombination in the quantum wells. The latter line is much the stronger and shows a marked red shift with increasing bias. Two electron and two hole resonant peaks are observed in I(V) and in the intensity-bias plots of the EL emission lines. A pronounced intrinsic bistability is observed in both I(V) and the EL spectra. The effect of magnetic field on the EL spectra is investigated.

Meningioma benign tumors possess significant levels of 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) activity. Two different 17 beta-HSDs have been cloned and characterized. The cytosolic 17 beta-HSD I which exclusively catalyzes the interconversion of 17 beta-estradiol (E2) and estrone (E1) preferentially uses NADP+ and NADPH as cofactors. In contrast, the mitochondrial-microsomal 17 beta-HSD II catalyzes both the estrogenic as well as the androgenic substrates of the 17 beta-HSD and uses NAD+ and NADH as cofactors. We demonstrated here that the 17 beta-HSD activity in meningioma tissue homogenate is both estrogenic and androgenic with Km values of 2.4, 0.4, 14.7, and 2.0 microM for E2, E1, testosterone (T), and delta 4-androstenedione (delta 4), respectively. NAD(+)-NADH is almost exclusively used as cofactor in this tissue. Moreover, fractionation of meningioma tissue revealed that most of the 17 beta-HSD activity is present in the mitochondrial-microsomal fraction. Although Northern blot analysis on meningiomas with a specific probe for human 17 beta-HSD I showed no band, the specific cDNA probe of human 17 beta-HSD II hybridized at the expected size of 1.5 kb, which was also present in placenta. On four different meningioma tumors, we were able to correlate 17 beta-HSD II mRNA expression to high levels of 17 beta-HSD activity. Taken together, the present data suggest that the meningioma 17 beta-HSD could be the 17 beta-HSD II.

Sphere-sphere, rod-rod and rod-plane air gaps, each 5-cm long, were tested with lightning surges of eight voltage waves of both polarities. The critical breakdown voltage levels of the tested air gaps attained a minimum plateau within a specific range of wavefronts of the lightning surges. Long time delays of breakdown for the fast-front and short time delays for the slow-front waves were observed. These phenomena would significantly affect the insulation coordination of the power apparatus and systems. >

Biobanks in general, and specifically tumour banks, are considered as essential tools for the development of translational and clinical research in biology and oncology. Biobank tasks include the collection and preservation of biological samples, and their association with information that will be essential for further scientific use ("annotations" that allow for the "qualification" of biological samples in biological resource). A collection is made of a series of biological resource that are representative of a homogeneous group of individuals or patients that are defined on the basis of clinical or biological information. Collections are used by scientists that are aware of their existence. In the absence of a published catalogue, this awareness is most often limited to research teams that are geographically close, or to investigators who already established collaborative projects with medical teams within the hospital that operates the tumour bank. Publications of catalogues, especially digitalized and online catalogues, should foster the development of high-level, large-scale and multicentric scientific projects. In addition, tumour banks will formalize rules that allow publication of collections, and upstream, rules that are used to qualify biological samples in biological resource: this should translate in an improved overall quality of samples and annotations. Tumour bank catalogues remain relatively few; however, some recent achievements established the "proof of concept" and already raise questions regarding rules for publication. It will be important to demonstrate that these high expectations translate into measurable benefits.

The electroluminescence and current-voltage characteristics of a p-i-n double-barrier structure based on GaAs/AlAs are investigated. Electroluminescence lines due to carrier recombination in the GaAs contact layers and in the quantum well are observed. The bias dependence of the intensity of these lines exhibits the pronounced peaks that are also seen in the I(V) characteristics, which are due to electron and hole resonant tunneling. The quantum-well emission lines correspond to recombination of holes in the two lowest-energy valence subbands (LH1 and HH1)

Capacitance measurements are used to investigate a series of single-barrier n-i-n GaAs/AlAs/GaAs heterostructures incorporating a layer of self-assembled InAs quantum dots into the AlAs barrier. They reveal a low-density, excess positive charge in the AlAs barrier which we attribute to defects associated with quantum dot formation. The quantity of positive charge is proportional to the amount of AlAs deposited on top of the dots.

Myelination was a major step in the evolution of the nervous system. Appearing first in jaw fish, myelination allows the fast and secure propagation of action potentials at a low energetic cost, and without exaggerated increase in axonal diameter. In the peripheral nervous system of mammals, myelination results from the tight interactions between Schwann cells and axons, leading to the formation of highly differentiated domains along the axon. The molecular determinants of these interactions are starting to be well identified. Their understanding provides a precise framework to interpret the defects, which occur in pathological circumstances. This review summarizes the present state of knowledge concerning axoglial interactions in peripheral nerves.

Acute bacterial meningitis (ABM) is a potentially life-threatening neurological emergency. An agreed protocol for early, evidence-based and effective management of community-acquired ABM is essential for best possible outcome. A literature search of peer-reviewed articles on ABM was used to collect data on the management of ABM in older children and adults. Based on the strength of published evidence, a consensus guideline was developed for initial management, investigations, antibiotics and supportive therapy of community-acquired ABM. Patients with ABM should be rapidly hospitalized and assessed for consideration of lumbar puncture (LP) if clinically safe. Ideally, patients should have fast-track brain imaging before LP, but initiation of antibiotic therapy should not be delayed beyond 3 h after first contact of patient with health service. In every case, blood sample must be sent for culture before initiating antibiotic therapy. Laboratory examination of cerebrospinal fluid is the most definitive investigation for ABM and whenever possible, the choice of antibiotics, and the duration of therapy, should be guided by the microbiological diagnosis. Parenteral therapy with a third-generation cephalosporin is the initial antibiotics of choice in the absence of penicillin allergy and bacterial resistance; amoxicillin should be used in addition if meningitis because of Listeria monocytogenes is suspected. Vancomycin is the preferred antibiotic for penicillin-resistant pneumococcal meningitis. Dexamethasone should be administered both in adults and in children with or shortly before the first dose of antibiotic in suspected cases of Streptococcus pneumoniae and H. Influenzae meningitis. In patients presenting with rapidly evolving petechial skin rash, antibiotic therapy must be initiated immediately on suspicion of Neisseria meningitidis infection with parenteral benzyl penicillin in the absence of known history of penicillin allergy.

L’analyse faite pour les facteurs UPA PA1 est exemplaire et doit faire partie d’un travail plus general de classification et d’evaluation standardisee de tous les facteurs biologiques proposes a ce jour. Ceci permettant de passer d’etudes retrospectives, qui ont un interet essentiel dans la connaissance et les publications de travaux, a une utilisation clinique prospective dans des essais cliniques randomises dont le marqueur biologique serait l’objectif principal. Cette demarche permettra de repondre aux questions cliniques de pronostic, de ciblage et de reponse therapeutique. Enfin, tout nouveau marqueur propose devra etre evalue de facon prospective par rapport a l’ensemble des parametres classes en LOE I et UC+++ pour evaluer la complementarite, la redondance ou la facilite d’utilisation.

La pratique clinique fait appel a: — un marqueur prevalent: le carbohydrate 15-3 ou CA 15-3; — un marqueur secondaire: l’antigene carcinoembryonnaire ou ACE. D’autres marqueurs peu frequemment etudies et utilises sont: — un antigene tissulaire polypeptidique (TPA); — un mucine like carcinoma associated antigen (MCA); — des carbohydrates 549 et/27-29. Un nouveau marqueur evalue et valide doit faire l’objet d’une recommandation — ECD, HER2 en 2007.

Neuroendocrine (NE) differentiation in prostate cancer (CaP) has been reported to be an early marker associated with the development of androgen independence. The mechanisms by which CaP acquires NE properties are poorly understood. In this study, a putative role of adrenomedullin (AM) in the NE differentiation was investigated. The expression of AM and AM receptors (calcitonin receptor-like receptor (CRLR)/receptor activity modifying protein-2 and -3 (RAMP2 and RAMP3) was evaluated after experimental manipulation of androgen status. Levels of AM mRNA and immunoreactive AM (ir-AM) increased four- to sevenfold in androgen-sensitive LNCaP cells after androgen withdrawal in vitro and in LNCaP xenografts in animals after castration. Treatment of LNCaP cells with androgen analogue (dihydrotestosterone; 10(-9) M) prevented the increase in AM mRNA and ir-AM levels. Interestingly, the expression of CRLR, RAMP2 and RAMP3 is not regulated by androgen status. We demonstrate that in the presence of serum, AM is able to induce an NE phenotype in LNCaP cells via CRLR/RAMP2 and RAMP3, which includes extension of neuritic processes and expression of the neuron-specific enolase (NSE), producing cGMP in a dose-dependent manner, which is mediated by a pertussis toxin-sensitive GTP-binding protein. 8-Bromo-cGMP mimicked the effects of AM on cell differentiation. We demonstrate that AM induces a G-kinase Ialpha translocation to the nucleus. The protein kinase G inhibitor KT-5823 inhibited the neurite outgrowth induced by both AM and 8-bromo-cGMP. In noncastrated animals, administration of AM enhanced expression of NSE and chromogranin A in LNCaP xenografts with a significant increase of NSE levels in serum and no changes in tumor growth. In castrated animals, intraperitoneal injection of AM resulted in a 240+/-18% (P

SummaryIt has previously been reported that EGF enhances uPA but not tPA in the A431 squamous carcinoma cell line. To determine whether the absence of tPA modulation by EGF reflected steady levels or the action of an anti-activator, we assayed tPA, PAI-1 and tPA/PAI-1 complexes by zymography and immunological assays. Under conditions in which EGF had no effect on tPA activity, tPA antigen paradoxically increased with a concomitant rise of tPA/PAI-1 complexes. This indicated that tPA was rapidly inactivated through the formation of a complex, immunologically and electrophoretically related to tPA/PAI-1. tPA antigen and tPA/PAI-1 complexes were modulated by EGF in a time and concentration dependent manner. PAI-1 antigen was secreted into A431 medium (CM) after a lag phase of 16 h in both control andEGF-treated cultures. Evidence is presented here that two forms ofPAI-1 are present in A431 CM: an inactive form and an active form which neutralizes the tPA secreted, masking its enhancement by EGF infunctional assays.

The recurrence and progression of treated intracranial meningiomas highlights the problem of the type of follow-up that should be used and whether early complementary treatment is indicated. The aim of this study was to evaluate different biochemical markers involved in cell proliferation and transformation to identify new prognostic factors in intracranial meningiomas. Between 1989 and 2003, 120 intracranial meningiomas were studied biochemically. The levels of estrogen receptors (RE), progesterone receptors (RP), cathepsin B (CB), cathepsin L (CL), stefin A (ATA), stefin B (STB), cystatin C (CYSC), urokinase (u-PA), type 1 plasminogen activator inhibitors (PAI-1), cathepsin D (CD) and thymidine kinase activity (TK) were measured in tumor extracts using biochemical assays.Out of 120 meningiomas, 73 were grade I, 39 grade II and eight grade III according to the WHO classification. Of these patients, 17 showed recurrence. The mean follow-up was 47 months. Monofactorial analysis showed that expression of progesterone receptors (RP) had an inverse correlation with recurrence (p=0.0025 %) and that thymidine kinase activity (TK), cathepsin L (CL), the WHO grade and the degree of tumor resection correlated with recurrence (p0.05). Principal component analysis and linear discriminant analysis confirmed these results. The results of this study confirm the importance of biological parameters (PR, CL, TK) as prognostic factors for the risk of recurrence in intracranial meningiomas.

Dans l’evolution potentielle a partir de tests LOEI « gold standards » actuels vers des tests pluriparametriques, soit proteomiques, soit de biologie moleculaire, il est important de rappeler que toutes les etapes d’evaluation et validation que nous vous avons exposees en debut de cette revue generale sont, en fait, a franchir en ce qui concerne la validation de ces nouvelles approches analytiques.

Transforming growth factor-beta (TGFbeta)1 is thought to be implicated in breast cancer progression. However, data about the influence of TGFbeta1 on breast cancer development are conflicting. To clarify the clinical relevance of TGFbeta1, TGFbeta1 protein level has been measured by enzyme-immunoassay in 193 breast tumour samples. We found that 94.3% of patients expressed TGFbeta1 with a range of 0-684 pg mg(-1) protein. In the overall population, an increase of tumoral TGFbeta1 was observed in premenopausal patients when compared to postmenopausal subgroup (P=0.0006). When patients were subdivided according to nodal status, TGFbeta1 was correlated to type-1 plasminogen activator inhibitor in the node-negative subgroup (P=0.040). Multivariate analysis revealed that, after lymph node status (P=0.0002) and urokinase-type plasminogen activator (P=0.004), TGFbeta1 was an independent prognostic marker for DFS (P=0.005) in the overall population. In the node-negative population, TGFbeta1 was the prominent prognostic factor (P=0.010). In the same population, Kaplan-Meier curves demonstrated that high TGFbeta1 level was correlated with a shorter disease-free survival (P=0.020). These data suggest that the measurement of tumoral TGFbeta1 protein level, especially for node-negative patients, might help to identify a high-risk population early in tumour progression.

International audience; Background & Aims: Cytochrome P450 1A1 catalyzes the degradation of endobiotics (estradiol, fatty acids, and so on) and the bioactivation of numerous environmental procarcinogens, such as arylamines and polycyclic aromatic hydrocarbons, that are found in food. Several peroxisome proliferators and arachidonic acid derivatives enhance cytochrome P450 1A1 activity, but the mechanisms involved remain unknown. The aim of this work was to study the role of peroxisome proliferator—activated receptors in cytochrome P450 1A1 gene induction.Methods: The role of peroxisome proliferator—activated receptor transcription factors in cytochrome P450 1A1 induction was assessed by means of enzymatic activities, quantitative real-time polymerase chain reaction, gene reporter assays, mutagenesis, and electrophoretic mobility shift assay.Results: We show that peroxisome proliferator—activated receptor-α agonists (WY-14643, bezafibrate, clofibrate, and phthalate) induce human cytochrome P450 1A1 gene expression, whereas 2,4-thiazolidinedione, a specific peroxisome proliferator—activated receptor-γ agonist, represses it. The induction of cytochrome P450 1A1 transcripts by WY-14643 was associated with a marked increase of ethoxyresorufin O-deethylase activity (10-fold at 200 μmol/L). Transfection of peroxisome proliferator—activated receptor-α complementary DNA enhanced cytochrome P450 1A1 messenger RNA induction by WY-14643, although WY-14643 failed to activate xenobiotic responsive element sequences. Two peroxisome proliferator response element sites were located at positions −931/−919 and −531/−519 of the cytochrome P450 1A1 promoter. Their inactivation by directed mutagenesis suppressed the inductive effect of WY-14643 on cytochrome P450 1A1 promoter activation. Electrophoretic mobility shift assay and chromatin immunoprecipitation assay experiments showed that the 2 cytochrome P450 1A1 peroxisome proliferator response element sites bind the peroxisome proliferator—activated receptor-α/retinoid X receptor-α heterodimer.Conclusions: We describe here a new cytochrome P450 1A1 induction pathway involving peroxisome proliferator—activated receptor-α and 2 peroxisome proliferator response element sites, indicating that peroxisome proliferator—activated receptor-α ligands, which are common environmental compounds, may be involved in carcinogenesis.

Various studies suggested that cytotoxicity induced by 5-fluorouracil (5-FU) is an apoptotic mechanism possibly mediated by the Fas/FasL system. In this preliminary work, we studied retrospectively the role the Fas/FasL expression as a predictive response factor with fluoropyrimidine-based chemotherapies. We developed a real-time PCR method for measuring Fas and FasL expression in various biopsies from patients treated with a FUFOL-like protocol. No correlation was found between Fas or FasL expression and overall survival or partial response. However, the PCR assay was simple and convenient to use for quantitation of Fas/FasL in tumor biopsies.