Loss of epithelial p53 and αv integrin cooperate through Akt to induce squamous cell carcinoma yet prevent remodeling of the tumor microenvironment.

Most of the squamous cell carcinomas (SCCs) of the skin and head and neck contain p53 mutations. The presence of p53 mutations in premalignant lesions suggests that they represent early events during tumor progression and additional alterations may be required for SCC development. Here we show that codeletion of the p53 and αv integrin genes in mouse stratified epithelia induced SCCs in 100% of the mice, more frequently and with much shorter latency than deletion of either gene alone. The SCCs that lacked p53 and αv in the epithelial tumor cells exhibited high Akt activity, lacked multiple types of infiltrating immune cells, contained a defective vasculature and grew slower than tumors that expressed p53 or αv. These results reveal that loss of αv in epithelial cells that lack p53 promotes SCC development, but also prevents remodeling of the tumor microenvironment and delays tumor growth. We observed that Akt inactivation in SCC cells that lack p53 and αv promoted anoikis. Thus, tumors may arise in these mice as a result of the increased cell survival induced by Akt activation triggered by loss of αv and p53, and by the defective recruitment of immune cells to these tumors, which may allow immune evasion. However, the defective vasculature and lack of a supportive stroma create a restrictive microenvironment in these SCCs that slows their growth. These mechanisms may underlie the rapid onset and slow growth of SCCs that lack p53 and αv.

Myc, Aurora Kinase A, and mutant p53(R172H) co-operate in a mouse model of metastatic skin carcinoma.

Clinical observations, as well as data obtained from the analysis of genetically engineered mouse models, firmly established the gain-of-function (GOF) properties of certain p53 mutations. However, little is known about the underlying mechanisms. We have used two independent microarray platforms to perform a comprehensive and global analysis of tumors arising in a model of metastatic skin cancer progression, which compares the consequences of a GOF p53(R172H) mutant vs p53 deficiency. DNA profiling revealed a higher level of genomic instability in GOF vs loss-of-function (LOF) p53 squamous cell carcinomas (SCCs). Moreover, GOF p53 SCCs showed preferential amplification of Myc with a corresponding increase in its expression and deregulation of Aurora Kinase A. Fluorescent in situ hybridization confirmed amplification of Myc in primary GOF p53 SCCs and its retention in metastatic tumors. We also identified by RNA profiling distinct gene expression profiles in GOF p53 tumors, which included enriched integrin and Rho signaling, independent of tumor stage. Thus, the progression of GOF p53 papillomas to carcinoma was marked by the acquisition of epithelial-to-mesenchymal transition and metastatic signatures. In contrast, LOF p53 tumors showed enrichment of genes associated with cancer proliferation and chromosomal instability. Collectively, these observations suggest that genomic instability has a prominent role in the early stages of GOF p53 tumor progression (that is, papillomas), whereas it is implicated at a later stage in LOF p53 tumors (that is, SCCs). This model will allow us to identify specific targets in mutant p53 SCCs, which may lead to the development of new therapeutic agents for the treatment of metastatic SCCs.

[History of the evaluation of medicines aiming for marketing authorization]. / Historique de l'évaluation des médicaments en vue d'une autorisation de mise sur le marché.

The European Directive on Medicines Evaluation and Marketing Authorization were issued in 1975. For more than 30 years, Marketing Authorization criteria have been defined as pharmaceutical and biological quality, therapeutic efficacy, and safety. The application comes from the pharmaceutical company and must include the full data on drug development. French procedures have always included practical assessment of the drug by health practitioners: clinicians, pharmacists, biologists, and specialists in biostatistics.

[Age, an independent risk factor for thrombosis. Epidemiologic data]. / L'âge, un facteur indépendant de risque de thrombose. Données épidémiologiques.

The incidence of thrombosis--arterial and venous--increases with age. This is the case for atheromatous diseases, atrial fibrillation and even venous thromboembolic disease. Ischemic heart disease is the most common cause of death in the elderly. Atrial fibrillation, an independent risk factor for cerebral vascular accidents, affects around 10% of persons older than 80 years. The incidence of venous thromboembolic disease increases with age, reaching 12.5 per 1000 people older than 75 years, compared with 5 per 1000 aged 60-75 and 2.5 per 1000 aged 40-59. Elderly persons often have two or more cardiovascular or venous thromboembolic risk factors and thus a still higher risk of thrombotic events. Their risk of thrombosis justifies the systematic search for acquired risk factors to assess the level of risk and take appropriate prevention measures.

[What explains the increased rate of thromboses among the elderly? Pathophysiological data]. / Comment expliquer l'augmentation des thromboses chez le sujet âgé?

The incidence of both arterial and venous thrombosis increases with age. The explanation is probably multifactorial, since elderly patients often have several risk factors. Aging per se appears to be an independent risk factor for thrombosis: age-related modifications of the vascular apparatus and blood components contribute to the development of a procoagulant state. Arterial and venous thromboses involve varying degrees of coagulation and platelet activation.

Lack of effect of a low-molecular-weight heparin (nadroparin) on mortality in bedridden medical in-patients: a prospective randomised double-blind study.

BACKGROUND: Hospitalised medical patients are at significant risk of venous thromboembolic disease through fatal pulmonary embolism; low-molecular-weight heparins have been proved efficient in preventing deep venous thrombosis in surgical and medical patients, but their effect on mortality in bedridden medical patients remains unknown. METHODS: In a multi-centre, randomised, double-blind, placebo-controlled study, 2,474 consecutive patients aged over 40 years admitted to internal medicine departments in the last 24 h and unable to move alone were randomised to receive 0.3 ml nadroparin (7,500 anti-Xa units) or placebo for up to 21 days. The primary end-point was overall mortality at day 21. RESULTS: There were no significant differences between the patients' characteristics. Overall mortality between the two groups was not statistically different [10.08% (124 of 1,230) versus 10.29% (128 of 1,244), respectively, in the nadroparin and in the placebo groups; relative risk reduction 0.02, CI (-0.27, +0.25), P=0.89]. An autopsy was performed in 123 of the 252 patients who died (49%). Pulmonary embolism was discovered at autopsy in 10 of 63 patients in the nadroparin group and in 17 of 60 in the placebo group [relative risk reduction 0.38, CI (-0.27, +0.70), P=0.13]. CONCLUSION: Nadroparin does not have a significant effect on mortality in bedridden medical patients, based on the study results. The study provides no data suggesting that low-molecular-weight heparins might reduce the incidence of thromboembolic in-patients hospitalised for an acute medical disease.

Paracetamol: a haemorrhagic risk factor in patients on warfarin.

AIM: To quantify the effect of paracetamol on the anticoagulant effect of warfarin under normal clinical conditions. PATIENTS AND METHODS: In a prospective double-blind, cross-over, placebo-controlled study, 11 patients on stable warfarin therapy received in random order two 14-day regimens of paracetamol 4 g day(-1) or placebo, with a 14-day or more wash-out period in between, time necessary to fulfil the inclusion criteria. RESULTS: In patients on paracetamol, the mean maximum increase in the International Normalized Ratio (INR) observed was 1.04 +/- 0.55 vs. 0.20 +/- 0.32 in those on placebo (P = 0.003). The mean maximum INR observed was significantly higher with paracetamol than with placebo (3.47 vs. 2.61, P = 0.01). In patients receiving paracetamol, the mean observed INR was significantly increased after 4 days (+ 0.6 +/- 0.6, P < 0.001). CONCLUSION: Paracetamol at 4 g day(-1) induces a significant increase in INR in patients receiving a stable regimen of warfarin, increasing the risk of bleeding associated with warfarin.

[Which antithrombotic treatment should be used in the treatment of an elderly patient with chronic atrial fibrillation?]. / Quel traitement antithrombotique chez un patient âgé en fibrillation auriculaire chronique?

UNLABELLED: FREQUENCY AND CONSEQUENCES: The incidence of atrial fibrillation (AF) increases regularly with age and affects nearly 10% of persons aged over 80. The risk of thromboembolism (notably stroke) associated is enhanced the older the patient and the more cardiovascular risk factors she/he exhibits. ADVANTAGES AND RISKS OF ANTICOAGULANTS: Treatment with anticoagulants is the only treatment that has demonstrated its efficacy in reducing the risks of thromboembolism, however there is a risk of haemorrhage. IN PRACTICE: A patient with AF exhibits both a risk of thromboembolism and a risk of haemorrhage. When confronted with such patients, the practitioner must choose an antithrombotic (anticoagulant or anti-arrhythmic agent) after careful objective and individual assessment of all the risks present in a given patient.

D-dimer: a characteristic of the coagulation state of each patient with chronic atrial fibrillation.

BACKGROUND AND OBJECTIVE: It is accepted that patients with atrial fibrillation (AF) are characterised by increased levels of plasmatic D-dimers, with a wide inter-individual variability depending on the patients and therapeutic characteristics, but it has not been established if this level was predictive of the risk of arterial thromboembolic event. In order to answer such a question, it has to be established if the D-dimer level in a given patient is characteristic of such a patient (stable over time) if also fluctuating with time (and useless to characterise the patient). METHODS AND RESULTS: One hundred thirty clinically stable patients with chronic AF were recruited (anticoagulant: group 1, antiaggregant aspirin: group 2, no antithrombotic: group 3). During the follow-up of patients without clinical events (n=63), it is notable that in patients with D-dimer levels <500 ng/ml, these remained <1000 ng/ml, in patients with levels between 500 and 1000 ng/ml, these did not reach 1590 ng/ml, and in those with D-dimers >1000 ng/ml, the levels remained relatively stable. Mean age and D-dimer levels were lower in group 1 (74.4 years and 509.1 ng/ml, respectively) than in group 2 (82.4 years, p=0.0003 and 1015.7 ng/ml, p<0.0001, respectively) and in group 3 (79.3 years and 1289.3 ng/ml, p<0.0001, respectively). The effect of the antithrombotic therapy was independent of the age of patients (p=0.017). CONCLUSION: D-dimer levels in patients with chronic AF remain in the same range over time. They are lower on anticoagulant therapy than on antiaggregant or no antithrombotic therapy, irrespective of age. Thus, D-dimers appear to be a useful parameter for assessing the degree of hypercoagulability of patients whatever their age.

[Fatal fulminant acute amebic colitis in metropolitan France]. / Colite amibienne aiguë fulminante mortelle chez un métropolitain.

BACKGROUND: Emergency care is required for patients presenting dysentery and fever. CASE REPORT: A 65-year old patient living in metropolitan France was hospitalized for watery diarrhea that had progressively worsened over the last month. Rectal bleeding was also noted. Serology tests at admission, together with parasitology examination of the fecal matter and colonoscopy led to the diagnosis of intestinal amebiasis a few hours before the patient's rapid death. Serology was positive for amebas and the diagnosis was confirmed by pathology examination of the colonoscopy biopsies. DISCUSSION: The diagnosis of amebiasis should be entertained even in Europe when there is no history of travel to endemic areas in patients who develop suggestive manifestations. Identification of amebas in the fecal matter and serology tests provide certain diagnosis. Clinicians should recall that rapidly fatal outcome is not uncommon in severe forms. Emergency care is mandatory.

Endoscopic evaluation of the gastrotolerance of short-term antalgic treatment with low dose k-diclofenac: a comparison of ibuprofen and aspirin.

In a short-term gastro-duodenal endoscopic study in 12 healthy volunteers, the gastrotoxicity was not different after intake of diclofenac-K 12.5 mg (0.33) or ibuprofen 200 mg (0.42, P=0.66) but significantly higher after aspirin 500 mg (2.67, P=0.002).

Increased oral ganciclovir bioavailability in HIV-infected patients with chronic diarrhoea and wasting syndrome--a population pharmacokinetic study.

AIMS: Despite a lack of data, the antiviral agent ganciclovir is not indicated in AIDS patients with diarrhoea because of its presumed poor oral bioavailability. To assess the effect of diarrhoea on ganciclovir intestinal absorption, we conducted a pharmacokinetic study in 42 HIV-infected patients categorized into three groups: A, HIV stage A and B (n = 15); B, AIDS stage C (n = 13); C, AIDS with chronic diarrhoea and wasting syndrome (n = 14). METHODS: Each patient was evaluated for nutritional (body mass index, albumin, transferrin serum levels), inflammatory (haptoglobin, orosomucoid), immunological (CD4 count, plasma viral load) and intestinal (D-xylose test, faecal fat and nitrogen output, intestinal permeability) status. Ganciclovir (1 g) was administered orally to fasted patients. Six blood samples were collected over 24 h. Serum was analysed for ganciclovir by h.p.l.c. Population pharmacokinetic analysis was performed using a nonlinear mixed effects modelling program, MP2. RESULTS: Mean intestinal permeability (lactulose/mannitol urinary ratio) was increased in group C (0.2) compared with group A (0.05) and B (0.1) patients. Drug concentration-time profiles were best described by a two-compartment model. Apparent oral clearance (CL/F) and central volume of distribution (V1/F) were influenced by clinical status (group). For groups A and B combined, final parameter estimates of CL/F and V1/F were 256 +/- 98 l h(-1) and 1320 +/- 470 l, respectively. Final parameter estimates for group C were 118 +/- 108 l h(-1) and 652 +/- 573 l for CL/F and V1/F, respectively. The 95% confidence intervals on differences between A and B combined and C were statistically significant ([ + 70, + 206] for CL/F, and [+ 314, + 1022] for V1/F). Compared with groups A and B, ganciclovir CL/F was significantly decreased in group C patients. CONCLUSIONS: AIDS patients with diarrhoea and severe disease may benefit from ganciclovir therapy, but a dose adjustment may be required according to their digestive and immunological status.

Interaction between aspirin and ACE inhibitors in patients with heart failure.

Both aspirin (acetylsalicylic acid) and ACE inhibitors are often used concomitantly, especially in patients with both heart failure and ischaemic heart disease, which is the most common underlying cause of heart failure. The safety of the association has been questioned because both drugs affect a related prostaglandin-mediated pathway. Thanks to their vasodilating properties, prostaglandins play an important role in heart failure where peripheral vasoconstriction occurs. Some of the beneficial effects of ACE inhibitors might be related to reduced degradation of bradykinin that enhances the synthesis of prostaglandins, while aspirin, through inhibiting the enzyme cyclo-oxygenase, inhibits the production of prostaglandins. To date no prospective study has been conducted to investigate the effect of long term aspirin treatment in the postinfarction period allowing the possible impact of the interaction between aspirin and ACE inhibitors upon survival to be confirmed or negated. However, the practitioner needs to know how to optimise the treatment of his or her patients. In order to stimulate arguments for and against the use of aspirin in patients with heart failure receiving ACE inhibitors, we searched MEDLINE from 1960 to 2000 using the key words heart failure, aspirin, and ACE inhibitors for English language articles and conducted a review of the available data. We report on the potential mechanisms of the interaction and the results of experimental studies on haemodynamic parameters. Results of retrospective clinical studies, subgroup analysis that were undertaken to evaluate the overall action upon haemodynamic parameters and survival of the association are summarised. Conflicting conclusions have been reported in the literature. Many explanations can be advanced to try to understand these conflicting conclusions: differences in study design (results of retrospective trials have to be interpreted with caution); differences in the choice of the evaluation parameter (problem of the clinical relevance of haemodynamic parameters); differences in the characteristics of the patient (different underlying cardiopathy, e.g. heart failure, hypertension or ischaemic cardiopathy); and differences in the type and the dosage of each treatment (especially ACE inhibitors and aspirin since an interaction might occur more often with dosage of aspirin greater than 250mg).

[Self-medication: Is regulation needed...from whom?]. / Automédication: faut-il une politique? Laquelle? Table Ronde no 3 de Giens. XV.

The participants attending the 1999 French Clinical Pharmacological meeting in Giens eventually reached a consensus about the necessity to set up a clear policy regarding self-medication products in France. Despite a wish by French people to take more responsibility for their own health care, self-medication products' use and development in France have been held back for many years for the reasons reported below. However, self-medication could be developed while respecting or even improving public health care by applying the following key principles: (1) the acknowledgement of a consensual definition. 'A self-medication drug is a drug (the guarantees for which are provided by marketing authorization approval and dispensation and advice of a pharmacist) specifically suitable for use without any physician's prescription'; (2) the advertising of self-medication products to the general public is authorized; (3) the safe use of self-medication products is linked to the selected indications and the relevance of the information provided to the general public; (4) the self-medication drug approval procedure could be simplified, managed by a specific AFSSAPS unit; (5) the role of the pharmacist involved, as well as suitable pharmacovigilance, is mentioned; (6) more than 1000 previously marketed drugs without any clear status, the so called 'grey zone drugs', should be taken into consideration. According to the participants at the meeting, it is possible to set up a new clear and dynamic policy for self-medication products in France in conformity with EU requirements.

Oral ganciclovir systemic exposure is enhanced in HIV-infected patients with diarrhea and weight loss.

OBJECTIVE: To determine whether diarrhea and intestinal malabsorption during HIV infection alter oral ganciclovir systemic exposure. METHODS: We studied the oral disposition of ganciclovir in 42 HIV-infected patients stratified into three groups: A (n = 15), HIV (stage A and B); B (n = 13), AIDS (stage C); and C (n = 14), AIDS with chronic diarrhea and wasting syndrome (10% or more weight loss). Each patient was evaluated for nutritional (body mass index, serum albumin and transferrin), immunologic (CD4 count, plasma viral load) and intestinal status (D-xylose test, fecal fat and nitrogen excretion, and intestinal permeability). Following an overnight fast, 1 g oral ganciclovir was given to patients. Six blood samples were collected over 24 hours. Serum was analyzed for ganciclovir by high performance liquid chromatography. Drug disposition was characterized using a population pharmacokinetic approach. RESULTS: Mean intestinal permeability increased as HIV disease progressed (0. 05, 0.1, and 0.2 for groups A, B, and C, respectively). Average weight-adjusted maximum concentration (Cmax) in group C was twofold more than that in group A and B patients (12.5 versus 6 and 6.4 ng/ml/kg), and average area under the curve (AUC0-infinity) was threefold greater in group C patients (193 versus 59 and 65 ng. hour/ml/kg in groups A and B, respectively). Mean oral clearance was threefold lower in group C (96 versus 258 and 212 L/hour in groups A and B, respectively). CONCLUSION: Because systemic exposure of oral ganciclovir is enhanced in AIDS patients with diarrhea and wasting syndrome, oral ganciclovir therapy may benefit these patients.

Keratin-dependent, epithelial resistance to tumor necrosis factor-induced apoptosis.

Tumor necrosis factor (TNF) is a cytokine produced by macrophages and T lymphocytes that acts through two distinct receptors, TNFR1 (60 kD, CD120a) and TNFR2 (80 kD, CD120b), to affect cellular proliferation, differentiation, survival, and cell death. In addition to its proinflammatory actions in mucosal tissue, TNF is important for liver regeneration. Keratin 8 (K8) and keratin 18 (K18) form intermediate filaments characteristic of liver and other single cell layered, internal epithelia and their derivative cancers. K8-deficient (K8(-)) mice, which escape embryonic lethality, develop inflammatory colorectal hyperplasia, mild liver abnormalities, and tolerate hepatectomy poorly. We show that normal and malignant epithelial cells deficient in K8 and K18 are approximately 100 times more sensitive to TNF-induced death. K8 and K18 both bind the cytoplasmic domain of TNFR2 and moderate TNF-induced, Jun NH(2)-terminal kinase (JNK) intracellular signaling and NFkappaB activation. Furthermore, K8(-) and K18(-) mice are much more sensitive to TNF dependent, apoptotic liver damage induced by the injection of concanavalin A. This moderation of the effects of TNF may be the fundamental function of K8 and K18 common to liver regeneration, inflammatory bowel disease, hepatotoxin sensitivity, and the diagnostic, persistent expression of these keratins in many carcinomas.

[Survey of the negativation of bacteriologic tests in patients with active pulmonary tuberculosis: how long should the isolation be?]. / Etude de la négativation des examens bactériologiques chez les patients présentant une tuberculose pulmonaire bacillifère: quelle doit être la durée de l'isolement?

The risk of contamination by contact with patients with tuberculosis is reduced by isolation of patients until negativation of direct sputum analysis for the research of tuberculosis bacilli. To evaluate the efficacy of this isolation, we compared, in 32 patients with active tuberculosis, the results of direct examination and culture of the sputum and the clinical outcome. Thirty-two successive patients hospitalized in the same internal medicine unit, received antituberculosis drugs and had 3 sputum examinations per week with direct analysis and culture until negativation of the 3 direct examinations. Then, isolation ended. At the time of direct-negativation, 14 of the 32 patients kept positive cultures. In the 18 remaining subjects, the cultures became negative, about seven days before direct-negativation. Patients with negative cultures had more frequently weight increase (83% versus 71%), were more rapidly without fever (11 days versus 19 days), had less cough and had less severe radiologic disease (50% versus 75%) compared to patients with positive cultures but these differences were not statistically significant due to the small sample size. In tuberculosis patients, 3 successive negative direct sputum examinations do not eliminate the risk of tuberculosis transmission, specially to hospitalized or immunocompromised patients. The risk of contamination in these cases, although unknown, may be weak. Terminating isolation should not be based on sputum examination alone, but also on other factors such as the clinical course (resolution of cough and fever, weight), the initial number of bacilli, and the severity of the radiological lesions.

Interaction between angiotensin-converting enzyme inhibitors and aspirin: a review.

Aspirin and angiotensin-converting enzyme inhibitors (ACEIs) are often associated for the treatment of coronary disease and/or chronic heart failure, but conclusions of some prospective and retrospective studies show a possible negative interaction between aspirin and ACEIs. ACEIs inhibit the conversion of angiotensin I to angiotensin II and also the catabolism of bradykinin, which results in increased synthesis of vasodilatory agents [prostaglandins and nitric oxide (NO)], whereas aspirin inhibits prostaglandin synthesis. Thus, a potential interaction from the opposing effects of aspirin and ACEIs could affect the metabolism of bradykinin. We conducted an extensive Medline search, as well as a manual search, of published literature including pharmacodynamic studies and clinical trials concerning the impact of aspirin on the effect of ACEIs in hypertension, coronary disease and chronic heart failure. A review of this literature shows five studies in hypertension (all prospective and using blood pressure as the main criterion of assessment), five in coronary disease (three retrospective and two prospective trials, four of which use mortality as the criterion of assessment) and 13 in chronic heart failure (eight using haemodynamic measurements of which seven are prospective--one prospective study using pulmonary tests, four using clinical events including mortality as criterion of assessment of which two are prospective). The counteraction of ACEI efficacy by aspirin is demonstrated in one out of five studies in hypertension, one out of four of studies in coronary disease and nine out of thirteen in chronic heart failure. This counteraction is more often observed with high dosages of aspirin (greater than 250 mg/day, four out of six studies) and less often with lower dosages (less than or equal to 250 mg/day, three out of 11 studies). These studies are retrospective analyses or use haemodynamic end-points, so there is as yet no methodological argument strong enough to contraindicate the aspirin-ACEI association or to prove the clinical relevance of this interaction. In conclusion, prospective studies using mortality as a criterion of assessment are needed to offer the practitioner the answer to the question of ACEI-aspirin association.