Fermanagh - Your Life in Your Hands

This project intends to build on the success in equipping individuals with mental health problems, who are obese, with the skills necessary to make healthier lifestyle choices.Particpants will work as a group and support each other. A range of sessions were held on health issues of importance to clients (stress, exercise, mental health) through information workshops, training, pharmacy clinics, cooking etc. For the participants involved in the project their confidence has grown and they are able to share their learning with others at the centre. The clients are aware of other services and how to access them. The pharmacist role played a visit to the doctors to help clients get the best out of their appointment. The mental health of those involved has also imporved and has spurred them on to make changes in their overall lifestyle.

Long-term transcutaneous monitoring of oxygen tension and carbon dioxide at 42 degrees C in critically ill neonates: improved performance of the tcpo2 monitor with topical metabolic inhibition.

Whereas during the last few years handling of the transcutaneous PO2 (tcPO2) and PCO2 (tcPCO2) sensor has been simplified, the high electrode temperature and the short application time remain major drawbacks. In order to determine whether the application of a topical metabolic inhibitor allows reliable measurement at a sensor temperature of 42 degrees C for a period of up to 12 h, we performed a prospective, open, nonrandomized study in a sequential sample of 20 critically ill neonates. A total of 120 comparisons (six repeated measurements per patient) between arterial and transcutaneous values were obtained. Transcutaneous values were measured with a control sensor at 44 degrees C (conventional contact medium, average application time 3 h) and a test sensor at 42 degrees C (Eugenol solution, average application time 8 h). Comparison of tcPO2 and PaO2 at 42 degrees C (Eugenol solution) showed a mean difference of +0.16 kPa (range +1.60 to -2.00 kPa), limits of agreement +1.88 and -1.56 kPa. Comparison of tcPO2 and PaO2 at 44 degrees C (control sensor) revealed a mean difference of +0.02 kPa (range +2.60 to -1.90 kPa), limits of agreement +2.12 and -2.08 kPa. Comparison of tcPCO2 and PaCO2 at 42 degrees C (Eugenol solution) showed a mean difference of +0.91 (range +2.30 to +0.10 kPa), limits of agreement +2.24 and -0.42 kPa. Comparison of tcPCO2 and PaCO2 at 44 degrees C (control sensor) revealed a mean difference of +0.63 kPa (range 1.50 to -0.30 kPa), limits of agreement +1.73 and -0.47 kPa. CONCLUSION: Our results show that the use of an Eugenol solution allows reliable measurement of tcPO2 at a heating temperature of 42 degrees C; the application time can be prolongued up to a maximum of 12 h without aggravating the skin lesions. The performance of the tcPCO2 monitor was slightly worse at 42 degrees C than at 44 degrees C suggesting that for the Eugenol solution the metabolic offset should be corrected.

Therapeutic drug monitoring of imatinib: Bayesian and alternative methods to predict trough levels

Background: The imatinib trough plasma concentration (C(min)) correlates with clinical response in cancer patients. Therapeutic drug monitoring (TDM) of plasma C(min) is therefore suggested. In practice, however, blood sampling for TDM is often not performed at trough. The corresponding measurement is thus only remotely informative about C(min) exposure. Objectives: The objectives of this study were to improve the interpretation of randomly measured concentrations by using a Bayesian approach for the prediction of C(min), incorporating correlation between pharmacokinetic parameters, and to compare the predictive performance of this method with alternative approaches, by comparing predictions with actual measured trough levels, and with predictions obtained by a reference method, respectively. Methods: A Bayesian maximum a posteriori (MAP) estimation method accounting for correlation (MAP-ρ) between pharmacokinetic parameters was developed on the basis of a population pharmacokinetic model, which was validated on external data. Thirty-one paired random and trough levels, observed in gastrointestinal stromal tumour patients, were then used for the evaluation of the Bayesian MAP-ρ method: individual C(min) predictions, derived from single random observations, were compared with actual measured trough levels for assessment of predictive performance (accuracy and precision). The method was also compared with alternative approaches: classical Bayesian MAP estimation assuming uncorrelated pharmacokinetic parameters, linear extrapolation along the typical elimination constant of imatinib, and non-linear mixed-effects modelling (NONMEM) first-order conditional estimation (FOCE) with interaction. Predictions of all methods were finally compared with 'best-possible' predictions obtained by a reference method (NONMEM FOCE, using both random and trough observations for individual C(min) prediction). Results: The developed Bayesian MAP-ρ method accounting for correlation between pharmacokinetic parameters allowed non-biased prediction of imatinib C(min) with a precision of ±30.7%. This predictive performance was similar for the alternative methods that were applied. The range of relative prediction errors was, however, smallest for the Bayesian MAP-ρ method and largest for the linear extrapolation method. When compared with the reference method, predictive performance was comparable for all methods. The time interval between random and trough sampling did not influence the precision of Bayesian MAP-ρ predictions. Conclusion: Clinical interpretation of randomly measured imatinib plasma concentrations can be assisted by Bayesian TDM. Classical Bayesian MAP estimation can be applied even without consideration of the correlation between pharmacokinetic parameters. Individual C(min) predictions are expected to vary less through Bayesian TDM than linear extrapolation. Bayesian TDM could be developed in the future for other targeted anticancer drugs and for the prediction of other pharmacokinetic parameters that have been correlated with clinical outcomes.

Ballina Eat Wise Project

The Mayo North East Ballina Eat Wise project will proactively engage with disadvantaged communities, including migrant and Traveller groups, in Ballina to encourage and support people to make informed decisions regarding their diet and that of their families. The project aims to empower people with the resources, skills and knowledge to improve their physical and mental wellbeing through affordable healthy eating. A steering group comprising local stakeholders will be established to co-ordinate and inform the CFI’s work and to ensure it is fully addressing the needs of the target group. The CFI will begin by developing a training module to equip a group of peer researchers to carry out a needs analysis. The information gathered will inform the practical aspects of the project ensuring participation and a sense of ownership from the local community. Young people will be targeted through local schools and youth organisations. Training will be provided for both adults and young people in vegetable/fruit growing, nutrition, cooking, preventing food wastage, smart shopping and budgeting. Practical cookery demonstrations coupled with advice on healthy eating will take place in the target areas. The project will also engage with local supermarkets and takeaways to encourage the provision of healthy affordable options. Other options to increase the availability of healthy food in the target areas will be explored. Part of theCFI Programme 2013-2015 Initiative Type Nutrition Education and Training Programmes Location Mayo Target Groups Children (13-18 years) Families Partner Agencies safefood

Multiple nodules of the scrotum: histopathological findings and surgical procedure. A study of five cases.

BACKGROUND: Multiple nodules of the scrotum are uncommonly reported. Their origin is controversial. Treatment is always surgical but the best procedure is still to be determined. MATERIALS AND METHODS: Five new cases are reported with description of the histopathological findings and surgical procedure. RESULTS: Nodules of the scrotum were more frequent in patients with dark skin suggesting an ethnic susceptibility. No other predisposing factors were noted. Screening for disturbances of phosphate or calcium balance was negative. The following histopathological findings were observed: non-calcified epidermoid cysts (3 patients), calcified epidermoid cysts (1 patient) and nodular calcifications without epithelial or glandular structures (1 patient). Subtotal excisions of the scrotum wall using tumescent anaesthesia were performed in all patients without any significant complications. Cosmetic results were excellent. No new lesions were observed during the 1-year follow-up period. CONCLUSIONS: Most cases of multiple nodules of the scrotum are due to non-calcified epidermoid cysts. The term scrotal calcinosis is therefore probably abusively used by many authors. Some cases of nodular calcifications may be due to dystrophic calcification of epidermoid cysts, but calcifications may also occur without any visible epithelial or glandular structure. Subtotal excision of the scrotum wall is a safe and effective surgical procedure to treat multiple nodules of the scrotum. Cosmetic results are excellent and recurrences are rare.

Can health beliefs help in explaining attendance to follow-up care? The Swiss childhood cancer survivor study.

Objective: Improved treatment has increased the survival of childhood cancer patients in recent decades, but follow-up care is recommended to detect and treat late effects. We investigated relationships between health beliefs and follow-up attendance in adult childhood cancer survivors.Methods: Childhood cancer survivors aged younger than 16 years when diagnosed between 1976 and 2003, who had survived for more than 5 years and were currently aged 20+ years, received a postal questionnaire. We asked survivors whether they attended follow-up in the past year. Concepts from the Health Belief Model (perceived susceptibility and severity of future late effects, potential benefits and barriers to follow-up, general health value and cues to action) were assessed. Medical information was extracted from the Swiss Childhood Cancer Registry.Results: Of 1075 survivors (response rate 72.3%), 250 (23.3%) still attended regular follow-up care. In unadjusted analyses, all health belief concepts were significantly associated with follow-up (p < 0.05). Adjusting for other health beliefs, demographic, and medical variables, only barriers (OR = 0.59; 95% CI: 0.43-0.82) remained significant. Younger survivors, those with lower educational background, diagnosed at an older age, treated with chemotherapy, radiotherapy, or bone marrow transplantation and with a relapse were more likely to attend follow-up care.Conclusions: Our study showed that more survivors at high risk of cancer-and treatment-related late effects attend follow-up care in Switzerland. Patient-perceived barriers hinder attendance even after accounting for medical variables. Information about the potential effectiveness and value of follow-up needs to be available to increase the attendance among childhood cancer survivors. Copyright (C) 2010 John Wiley & Sons, Ltd.

Leukemic cluster growth in culture is an independent risk factor for acute myeloid leukemia and short survival in patients with myelodysplastic syndrome.

In patients with myelodysplastic syndrome (MDS) precursor cell cultures (colony-forming unit cells, CFU-C) can provide an insight into the growth potential of malignant myeloid cells. In a retrospective single-center study of 73 untreated MDS patients we assessed whether CFU-C growth patterns were of prognostic value in addition to established criteria. Abnormalities were classified as qualitative (i.e. leukemic cluster growth) or quantitative (i.e. strongly reduced/absent growth). Thirty-nine patients (53%) showed leukemic growth, 26 patients (36%) had strongly reduced/absent colony growth, and 12 patients showed both. In a univariate analysis the presence of leukemic growth was associated with strongly reduced survival (at 10 years 4 vs. 34%, p = 0.004), and a high incidence of transformation to AML (76 vs. 32%, p = 0.01). Multivariate analysis identified leukemic growth as a strong and independent predictor of early death (relative risk 2.12, p = 0.03) and transformation to AML (relative risk 2.63, p = 0.04). Quantitative abnormalities had no significant impact on the disease course. CFU-C assays have a significant predictive value in addition to established prognostic factors in MDS. Leukemic growth identifies a subpopulation of MDS patients with poor prognosis.

Effect of a pilot gait and balance training program: The importance of fear of falling.

Purpose: To determine the evolution of fear of falling, and its relationship with gait performance after a 10-week gait and balance training program. Population and methods: Participants (N=50) were community-dwelling elderly persons enrolled voluntarily in a 10-week, low intensity, gait and balance training program. At baseline, fear of falling was assessed using a previously validated version of Tinetti's Fall Efficacy Scale (FES, range 0-120, higher score indicating higher confidence), that assesses one's confidence in performing 12 activities of daily life without falling. Gait parameters were measured over a 20m walk at preferred gait speed, using the Physilog system (Aminian K, et al., J Biomechanics, 2002). This system uses 4 kinematics sensors attached to the lower limbs and a data logger carried by the subject. Follow-up data on fear of falling and gait were collected one week after completion of the program. Results: Overall, 43 (86%) of the participants completed the program. Mean age was 78.1 years, 79% were women. At baseline, mean FES score was 98.8 (range 58-120) and mean gait speed was 0.92 m/sec (range 0.43-1.47). At follow-up, participants modestly improved their FES score (98.8±17.0 vs 103.2±16.0, P=.04) and gait speed (0.92±0.27 vs 0.99±0.26 m/sec, P<.01). In secondary analyses stratified by subject's baseline FES, those with lower than average confidence (N=21) improved significantly both FES score (84.4±11.8 vs 94.5±17.9, P<.01) and gait speed (0.79±0.26 vs 0.90±0.28 m/sec, P<.01), while no similar improvement was observed in subjects (N=22) with higher baseline confidence (112.5±6.6 vs 111.5±7.5, P=.56 and 1.03±0.22 vs 1.07±0.21 m/sec, P=.41). After adjustment for age, gender and baseline gait speed, subjects with lower baseline confidence had higher odds than the others to improve their confidence (AdjOR=10.8, 95%CI 1.8- 64.8 P=.01) and gait speed (AdjOR=3.3, 95%CI 0.6-19.7, P=.19) at follow-up. Conclusions: This pilot program of low intensity exercise modestly improved participants' fear of falling and gait speed. Interestingly, subjects with higher baseline fear of falling seemed more likely to benefit. Despite methodological limitations (pre-post comparisons, small sample), these results suggest that measuring fear of falling might be useful to better target subjects most likely to benefit from similar programs.

Réduction de volume pulmonaire dans l'emphysème sévère: importance d'une prise en charge multidisciplinaire [Lung volume reduction (LVR) in severe emphysema: a multidisciplinary approach].

Most cases of emphysema are managed conservatively. However, in severe symptomatic emphysema associated with hyperinflation, lung volume reduction (LVR) may be proposed to improve dyspnea, exercice capacity, pulmonary functions, walk distance and to decrease long-term mortality. LVR may be achieved either surgically (LVRS) or endoscopically (EVLR by valves or coils) according to specific clinical criteria. Currently, the optimal approach is discussed in a multidisciplinary setting. The latter permits a personalized evaluation the patient's clinical status and allows the best possible therapeutic intervention to be proposed to the patient.

Viability study of a multiplex diagnostic platform for Chagas disease

A new multiplex assay platform was evaluated to detect Trypanosoma cruzi infection using the recombinant antigens CRA, FRA, CRAFRA fusion and parasite lysate. The antigens presented different sensitivity and specificity in a singleplex test when compared to a serial dilution of two pools comprising 10 positive serum samples and one pool of 10 negative samples. The recombinant protein CRA presented lower sensitivity (55%) in contrast to the 100% specificity and sensitivity of FRA, CRAFRA and T. cruzi lysate. These antigens also showed good results in a duplex test and the duplex test with CRAFRA/T. cruzi lysate showed better performance with 100% specificity and sensitivity, as well as a lower cut-off value in comparison to the other duplex test, FRA/T. cruzi lysate. Hence, when the antigens were used in duplex format, both tests showed decreased cut-off values and no interference between different bead sets, resulting in increasing sensitivity and specificity. The results of these multiplex tests show that they could be an alternative to singleplex detection for Chagas disease, and also indicate the necessity of using multiplex diagnostic tools to increase the sensitivity and specificity for diagnostic tests. Emerging data from the T. cruzi genome and from its ORFeome project will also allow the identification of new antigens for this disease detection application.

Role of comorbidities in outcome prediction after status epilepticus.

Status epilepticus (SE) is associated with significant mortality and morbidity. A reliable prognosis may help better manage medical resources and treatment strategies. We examined the role of preexisting comorbidities on the outcome of patients with SE, an aspect that has received little attention to date. We prospectively studied incident SE episodes in 280 adults occurring over 55 months in our tertiary care hospital, excluding patients with postanoxic encephalopathy. Different models predicting mortality and return to clinical baseline at hospital discharge were compared, which included demographics, SE etiology, a validated clinical Status Epilepticus Severity Score (STESS), and comorbidities (assessed with the Charlson Comorbidity Index) as independent variables. The overall short-term mortality was 14%, and only half of patients returned to their clinical baseline. On bivariate analyses, age, STESS, potentially fatal etiologies, and number of preexisting comorbidities were all significant predictors of both mortality and return to clinical baseline. As compared with the simplest predictive model (including demographics and deadly etiology), adding SE severity and comorbidities resulted in an improved predictive performance (C statistics 0.84 vs. 0.77 for mortality, and 0.86 vs. 0.82. for return to clinical baseline); comorbidities, however, were not independently related to outcome. Considering comorbidities and clinical presentation, in addition to age and etiology, slightly improves the prediction of SE outcome with respect to both survival and functional status. This analysis also emphasizes the robust predictive role of etiology and age.

Lésions cérébrales du prématuré et techniques d'imagerie à visée pronostique du développement neurocognitif [Cerebral brain injury in preterm infants and the role of neuroimaging in predicting neurodevelopmental outcomes].

Due to advances in neonatal intensive care over the last decades, the pattern of brain injury seen in very preterm infants has evolved in more subtle lesions that are still essential to diagnose in regard to neurodevelopmental outcome. While cranial ultrasound is still used at the bedside, magnetic resonance imaging (MRI) is becoming increasingly used in this population for the assessment of brain maturation and white and grey matter lesions. Therefore, MRI provides a better prognostic value for the neurodevelopmental outcome of these preterms. Furthermore, the development of new MRI techniques, such as diffusion tensor imaging, resting state functional connectivity and magnetic resonance spectroscopy, may further increase the prognostic value, helping to counsel parents and allocate early intervention services.

Genetic analysis of c-Myc in mouse bone marrow and liver

1. Summary The transcription factor and proto-oncogene c-myc plays an important role in integrating many mitogenic signals within the cell. The consequences are both broad and varied and include the regulation of apoptosis, cellular differentiation, cellular growth and cell cycle progression. It is found to be mis-regulated in over 70% of all cancers, however, our knowledge about c-Myc remains limited and very little is known about its physiological role in mammalian development and in adulthood. We have addressed the physiological role of c-Myc in both the bone marrow and the liver of mice by generating adult c-myc flox/flox mice that lacked c-myc in either the bone marrow or the liver after conversion of the c-myc flox alleles into null alleles by the inducible Mx¬Cre transgene with polyI-polyC. In investigating the role of c-Myc in the haematopoietic system, we concentrated on the aspects of cellular proliferation, cellular differentiation and apoptosis. Mice lacking c-Myc develop anaemia between 3-8 weeks and all more differentiated cell types are severely depleted leading to death. However in addition to its role in driving proliferation in transient amplifying cells, we unexpectedly discovered a new role for c-Myc in controlling haematopoietic stem cell (HSC) differentiation. c-Myc deficient HSCs are able to proliferate normally in vivo. In addition, their differentiation into more committed progenitors is blocked. These cells expressed increased adhesion molecules, which possibly prevent HSCs from being released from the special stem cell supporting stromal niche cells with which they closely associate. Secondly we used the liver as a model system to address the role of c-Myc in cellular growth, meaning the increase in cell size, and also cellular proliferation. Our results revealed c-Myc to play no role in metabolic cellular growth following a period of fasting. Following treatment with the xenobiotic TCPOBOP, c-Myc deficient hepatocytes increased in cell size as control hepatocytes and could surprisingly proliferate albeit at a reduced rate demonstrating a c-Myc independent proliferation pathway to exist in parenchymal cells. However, following partial hepatectomy, in which two-thirds of the liver was removed, mutant livers were severely restricted in their regeneration capacity compared to control livers demonstrating that c-Myc is essential for liver regeneration. Résumé Le facteur de transcription et proto-oncogène c-myc joue un rôle important dans l'intégration de nombreux signaux mitogéniques dans la cellule. Les conséquences de son activation sont étendues et variées et incluent la régulation de l'apoptose, de la différenciation, de la croissance et de la progression du cycle cellulaire. Même si plus de 20% des cancers montrent une dérégulation de c-myc, les connaissances sur ce facteur de transcription restent limitées et ses rôles physiologiques au cours du développement et chez l'adulte sont très peu connus. Nous avons étudié le rôle physiologique de c-Myc dans la molle osseuse et le foie murin en générant des souris adultes c-myc flox/flox. Dans ces souris, les allèles c-myc flox sont convertis en allèles nuls par le transgène Mx-Cre après induction avec du Poly-I.C. Pour notre étude du rôle de c-Myc dans le système hématopoiétique, nous nous sommes concentrés sur les aspects de la prolifération et de la différenciation cellulaire, ainsi que sur l'apoptose. Les souris déficientes pour c-Myc développent une anémie 3 à 8 semaines après la délétion du gène; tous les différents types cellulaires matures sont progressivement épuisés ce qui entraîne la mort des animaux. Néanmoins, outre sa capacité à induire la prolifération des cellules transitoires de la molle osseuse, nous avons inopinément découvert un nouveau rôle pour c-Myc dans le contrôle de la différenciation des cellules souches hématopoiétiques (HSC). Les HSC déficientes pour c-Myc prolifèrent normalement in vivo mais leur différenciation en progéniteurs plus engagés dans une voie de différenciation est bloquée. Ces cellules surexpriment certaines molécules d'adhésion ce qui empêcherait les HSC d'être relachées du stroma spécialisé, ou niche, auquel elles sont étroitement associées. D'autre part, nous avons utilisé le foie comme système modèle pour étudier le rôle de c-Myc dans la prolifération et dans la croissance cellulaire, c'est à dire l'augmentation de taille des cellules. Nos résultats ont révélé que c-Myc ne joue pas de rôle dans le métabolisme cellulaire qui suit une période de jeûne. L'augmentation de la taille cellulaire des hépatocytes déficients pour c-Myc suite au traitement avec l'agent xénobiotique TCPOBOP est identique à celle observée pour les cellules de contrôle. Le taux de prolifération des hépatocytes mutants est par contre réduit, indiquant qu'une voie de différenciation indépendante de c-Myc existe dans les cellules parenchymales. Néanmoins, après hépatectomie partielle, où deux-tiers du foie sont éliminés chirurgicalement, les foies mutants sont sévèrement limités dans leur capacité de régénération par rapport aux foies de contrôle, montrant ainsi que c-Myc est essentiel pour la régénération hépatique.

Analysis of c-Myc function in mouse epidermis

Abstract The c-myc gene is one of the most frequently mutated oncogenes found in human tumors. c-Myc has been implicated in the regulation of various biological processes including cell cycle progression, cellular growth, differentiation, angiogenesis, immortalization and apoptosis. To assess the normal role of c-Myc in epithelial cell types in vitro and in vivo we have deleted the c-myc gene in keratinocytes and in the adult skin epidermis by conditional Cre/loxP mediated recombination. Similar to what we have previously shown in mouse embryonic fibroblasts acute elimination of c-Myc activity in cultured keratinocytes causes cells to cease proliferation and adapt a flat cell morphology. Mutant cells accumulate in a diploid Ki67neg stage, indicative of a quiescent Go stage. This demonstrates that c-Myc activity is essential to maintain keratinocytes in a productive cell cycle. In addition, mutant keratinocytes showed a defect in Ca2+ induced induction of the differentiation marker Keratin 1 suggesting a role for c-Myc during differentiation. To assess the in vivo role of c-Myc we used a tamoxifen inducible K5::CreERT transgene to delete the c-myc gene in the adult skin epidermis. Unexpectedly, despite strong c-Myc expression in the basal compartment it is not required for maintenance of the skin epidermis in the adult mouse. The epidermis appeared normal with respect to both proliferation and differentiation. In addition, no selection against c-Myc deficient epidermal cells occurred over many months, further confirming that c-Myc is dispensable for normal skin homeostasis. Even more surprising, TPA induced hyperproliferation also occurred in a c-Myc independent manner. Treatment of the skin with the mutagen DMBA prior to TPA is a classical way to induce papillomas by selecting for mutations that lead to dominant activation of the oncogene Ha-Ras. Most interestingly tumor formation was severely inhibited suggesting that tumor progression requires endogenous c-Myc. Further studies are required to address whether the role of c-Myc in the activation of telomerase or the Werner protein, or its role to induce angiogenesis is required for skin tumor progression, In conclusion, this work shows that while c-Myc is not required for maintenance or hyperplasia of mouse epidermis, it is essential for skin tumor progression in collaboration with Ras. Résumé Le gène c-myc est un des oncogènes les plus fréquemment mutés dans les tumeurs humaines. c-Myc est impliqué dans la régulation de processus biologiques variés, comme la progression du cycle cellulaire, la croissance cellulaire, la différenciation, l'angiogenèse, l'immortalisation et l'apoptose. Pour caractériser le rôle physiologique de c-Myc dans les cellules de type épithélial in vitro et in vivo, le gène c-myc a été délété dans des kératinocytes primaires et dans l'épiderme de peau de souris adultes par des recombinaisons conditionnelles (système Cre/loxP). De la même façon que dans les fibroblastes d'embryon de souris, l'élimination aiguë de l'activité de c-Myc dans les kératinocytes en culture primaire provoque l'arrêt de la prolifération des cellules et leur applatissement morphologique. Les cellules mutantes restent dans un stade diploïde Ki67neg, indiquant un stade quiescent Go. Cela démontre que l'activité de c-Myc est essentielle pour maintenir les kératinocytes dans le cycle cellulaire. De plus, les kératinocytes mutants montrent une déficience pour le marqueur de différenciation Kératine 1 au cours de la différenciation induite par le calcium, suggérant un rôle de c-Myc dans la différenciation cellulaire. Pour comprendre le rôle de c-Myc in vivo, le transgène K5::CreERT inductible par le tamoxifen a été utilisé pour déléter le gène c-inyc dans l'épiderme de souris adultes. Etonnemment, malgré une forte expression de c-Myc dans le compartiment basal de l'épiderme, ce gène n'est pas nécessaire pour la maintenance de l'épiderme de la peau chez la souris adulte. L'épiderme apparait normal avec une prolifération et une différenciation physiologique des cellules. De plus, il n'y a pas de sélection contre les cellules épidennales c-Myc déficientes après plusieurs mois, ce qui confirme que c-Myc n'est pas nécessaire pour l'homéostasie normale de la peau. Encore plus surprenant, une hyperprolifération est également induite par du TPA chez les souris mutantes, impliquant une voie de prolifération indépendante de c-Myc. Le traitement de la peau par le mutagène DMBA avant le traitement au TPA est une voie classique d'induction de papillomes, par sélection de mutations conduisant à l'activation de l'oncogène Ha-Ras. La formation des tumeurs est fortement inhibée chez les souris mutantes, suggérant que la progression des tumeurs nécessite la présence endogène de c-Myc. De nouvelles études sont nécessaires pour savoir si c-Myc a un rôle dans l'activation de la télomérase ou de la protéine de Werner, ou encore dans l'angiogénèse, qui sont nécessaires pour la progression tumorale. En conclusion, ce travail montre que même si c-Myc n'est pas nécessaire pour la maintenance ou l'hyperplasie de la peau de souris, il est essentiel pour la progression des tumeurs de la peau en collaboration avec Ras.

Irinotecan loaded in eluting beads: preclinical assessment in a rabbit VX2 liver tumor model.

PURPOSE: The purpose of this study was to study the pharmacokinetics of irinotecan injected intravenously, intra-arterially, or loaded onto a delivery platform. MATERIAL AND METHODS: Fifty-four New Zealand White rabbits with VX2 liver tumor, divided in 3 groups of 17 rabbits, each received irinotecan either by intravenous (IV) route, intra-arterial hepatic (IA) route, or loaded on drug-eluting beads (DEBIRI). Animals were killed at 1, 6, and 24 h. Irinotecan and SN-38 concentrations were measured at different time points in serum, tumor, and normal liver. RESULTS: Twelve milligrams of irinotecan were injected IV and IA, whereas 6-16.5 mg were injected loaded onto DEBIRI. Normalized serum irinotecan reached a peak of 333 ng/ml (range 198.8-502.5) for IV, 327.1 ng/ml (range 277.1-495.6) for IA, and 189.7 ng/ml (range 111.1-261.9) for DEBIRI (P < 0.001) delivery. The area-under-the-curve value from 10 to 60 min of serum irinotecan concentration was significantly lower for DEBIRI (P = 0.0009). Tumor irinotecan levels for IV, IA, and DEBIRI (in ng/200 mg of tissue followed by ranges in parentheses) were, respectively, 23.6 (0.3-24.9), 36.5 (7.7-1914.1), and 20.2 (2.9-319) at 1 h; 4.2 (1-27.9), 99.3 (46.6-159.5), and 42.1 (11.3-189) at 6 h; and 2.7 (2.5-6.9), 18.3 (1.5-369.1), and 174.4 (3.4-5147.3) at 24 h (P = 0.02). At 24 h, tumor necrosis was 25% (10-30), 60% (40-91.25), and 95% (76.25-95) for IV, IA, and DEBIRI, respectively (P = 0.03). CONCLUSION: Compared with IV or IA, DEBIRI induces lower early serum levels of irinotecan, a high and prolonged intratumoral level of irinotecan, and a greater rate of tumor necrosis at 24 h. Further evaluation of the clinical benefit of DEBIRI is warranted.