A positive FGFR3/FOXN1 feedback loop underlies benign skin keratosis versus squamous cell carcinoma formation in humans.

Seborrheic keratoses (SKs) are common, benign epithelial tumors of the skin that do not, or very rarely, progress into malignancy, for reasons that are not understood. We investigated this by gene expression profiling of human SKs and cutaneous squamous cell carcinomas (SCCs) and found that several genes previously connected with keratinocyte tumor development were similarly modulated in SKs and SCCs, whereas the expression of others differed by only a few fold. In contrast, the tyrosine kinase receptor FGF receptor-3 (FGFR3) and the transcription factor forkhead box N1 (FOXN1) were highly expressed in SKs, and close to undetectable in SCCs. We also showed that increased FGFR3 activity was sufficient to induce FOXN1 expression, counteract the inhibitory effect of EGFR signaling on FOXN1 expression and differentiation, and induce differentiation in a FOXN1-dependent manner. Knockdown of FOXN1 expression in primary human keratinocytes cooperated with oncogenic RAS in the induction of SCC-like tumors, whereas increased FOXN1 expression triggered the SCC cells to shift to a benign SK-like tumor phenotype, which included increased FGFR3 expression. Thus,we have uncovered a positive regulatory loop between FGFR3 and FOXN1 that underlies a benign versus malignant skin tumor phenotype.

A combination of ascorbic acid and α-tocopherol to test the effectiveness and safety in the fragile X syndrome: study protocol for a phase II, randomized, placebo-controlled trial.

BACKGROUND Fragile X syndrome (FXS) is an inherited neurodevelopmental condition characterised by behavioural, learning disabilities, physical and neurological symptoms. In addition, an important degree of comorbidity with autism is also present. Considered a rare disorder affecting both genders, it first becomes apparent during childhood with displays of language delay and behavioural symptoms.Main aim: To show whether the combination of 10 mg/kg/day of ascorbic acid (vitamin C) and 10 mg/kg/day of α-tocopherol (vitamin E) reduces FXS symptoms among male patients ages 6 to 18 years compared to placebo treatment, as measured on the standardized rating scales at baseline, and after 12 and 24 weeks of treatment.Secondary aims: To assess the safety of the treatment. To describe behavioural and cognitive changes revealed by the Developmental Behaviour Checklist Short Form (DBC-P24) and the Wechsler Intelligence Scale for Children-Revised. To describe metabolic changes revealed by blood analysis. To measure treatment impact at home and in an academic environment. METHODS/DESIGN A phase II randomized, double-blind pilot clinical trial. SCOPE male children and adolescents diagnosed with FXS, in accordance with a standardized molecular biology test, who met all the inclusion criteria and none of the exclusion criteria. INSTRUMENTATION clinical data, blood analysis, Wechsler Intelligence Scale for Children-Revised, Conners parent and teacher rating scale scores and the DBC-P24 results will be obtained at the baseline (t0). Follow up examinations will take place at 12 weeks (t1) and 24 weeks (t2) of treatment. DISCUSSION A limited number of clinical trials have been carried out on children with FXS, but more are necessary as current treatment possibilities are insufficient and often provoke side effects. In the present study, we sought to overcome possible methodological problems by conducting a phase II pilot study in order to calculate the relevant statistical parameters and determine the safety of the proposed treatment. The results will provide evidence to improve hyperactivity control and reduce behavioural and learning problems using ascorbic acid (vitamin C) and α-tocopherol (vitamin E). The study protocol was approved by the Regional Government Committee for Clinical Trials in Andalusia and the Spanish agency for drugs and health products. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT01329770 (29 March 2011).

Overcoming the rare species modelling paradox: test of a novel hierarchical framework with an Iberian endemic plant

Rare species have restricted geographic ranges, habitat specialization, and/or small population sizes. Datasets on rare species distribution usually have few observations, limited spatial accuracy and lack of valid absences; conversely they provide comprehensive views of species distributions allowing to realistically capture most of their realized environmental niche. Rare species are the most in need of predictive distribution modelling but also the most difficult to model. We refer to this contrast as the "rare species modelling paradox" and propose as a solution developing modelling approaches that deal with a sufficiently large set of predictors, ensuring that statistical models aren't overfitted. Our novel approach fulfils this condition by fitting a large number of bivariate models and averaging them with a weighted ensemble approach. We further propose that this ensemble forecasting is conducted within a hierarchic multi-scale framework. We present two ensemble models for a test species, one at regional and one at local scale, each based on the combination of 630 models. In both cases, we obtained excellent spatial projections, unusual when modelling rare species. Model results highlight, from a statistically sound approach, the effects of multiple drivers in a same modelling framework and at two distinct scales. From this added information, regional models can support accurate forecasts of range dynamics under climate change scenarios, whereas local models allow the assessment of isolated or synergistic impacts of changes in multiple predictors. This novel framework provides a baseline for adaptive conservation, management and monitoring of rare species at distinct spatial and temporal scales.

Use of the comet test to assess DNA damage in children with ataxia-telangiectasia and their relatives.

The electrophoresis of cells in alkaline medium (comet assay) is a valid technique for quantifying DNA damage in patients with ataxia-telangiectasia and their relatives.

Disentangling the attention network test: behavioral, event related potentials, and neural source analyses.

BACKGROUND The study of the attentional system remains a challenge for current neuroscience. The "Attention Network Test" (ANT) was designed to study simultaneously three different attentional networks (alerting, orienting, and executive) based in subtraction of different experimental conditions. However, some studies recommend caution with these calculations due to the interactions between the attentional networks. In particular, it is highly relevant that several interpretations about attentional impairment have arisen from these calculations in diverse pathologies. Event related potentials (ERPs) and neural source analysis can be applied to disentangle the relationships between these attentional networks not specifically shown by behavioral measures. RESULTS This study shows that there is a basic level of alerting (tonic alerting) in the no cue (NC) condition, represented by a slow negative trend in the ERP trace prior to the onset of the target stimuli. A progressive increase in the CNV amplitude related to the amount of information provided by the cue conditions is also shown. Neural source analysis reveals specific modulations of the CNV related to a task-related expectancy presented in the NC condition; a late modulation triggered by the central cue (CC) condition and probably representing a generic motor preparation; and an early and late modulation for spatial cue (SC) condition suggesting specific motor and sensory preactivation. Finally, the first component in the information processing of the target stimuli modulated by the interaction between orienting network and the executive system can be represented by N1. CONCLUSIONS The ANT is useful as a paradigm to study specific attentional mechanisms and their interactions. However, calculation of network effects is based in subtractions with non-comparable experimental conditions, as evidenced by the present data, which can induce misinterpretations in the study of the attentional capacity in human subjects.

Quantifying rock fabrics: a test of autocorrelation of the spatial distribution of cristals

A novel test of spatial independence of the distribution of crystals or phases in rocksbased on compositional statistics is introduced. It improves and generalizes the commonjoins-count statistics known from map analysis in geographic information systems.Assigning phases independently to objects in RD is modelled by a single-trial multinomialrandom function Z(x), where the probabilities of phases add to one and areexplicitly modelled as compositions in the K-part simplex SK. Thus, apparent inconsistenciesof the tests based on the conventional joins{count statistics and their possiblycontradictory interpretations are avoided. In practical applications we assume that theprobabilities of phases do not depend on the location but are identical everywhere inthe domain of de nition. Thus, the model involves the sum of r independent identicalmultinomial distributed 1-trial random variables which is an r-trial multinomialdistributed random variable. The probabilities of the distribution of the r counts canbe considered as a composition in the Q-part simplex SQ. They span the so calledHardy-Weinberg manifold H that is proved to be a K-1-affine subspace of SQ. This isa generalisation of the well-known Hardy-Weinberg law of genetics. If the assignmentof phases accounts for some kind of spatial dependence, then the r-trial probabilitiesdo not remain on H. This suggests the use of the Aitchison distance between observedprobabilities to H to test dependence. Moreover, when there is a spatial uctuation ofthe multinomial probabilities, the observed r-trial probabilities move on H. This shiftcan be used as to check for these uctuations. A practical procedure and an algorithmto perform the test have been developed. Some cases applied to simulated and realdata are presented.Key words: Spatial distribution of crystals in rocks, spatial distribution of phases,joins-count statistics, multinomial distribution, Hardy-Weinberg law, Hardy-Weinbergmanifold, Aitchison geometry

Assessment of melanocytic skin lesions with a high-definition laser Doppler imaging system.

BACKGROUND: Early detection is a major goal in the management of malignant melanoma. Besides clinical assessment many noninvasive technologies such as dermoscopy, digital dermoscopy and in vivo laser scanner microscopy are used as additional methods. Herein we tested a system to assess lesional perfusion as a tool for early melanoma detection.¦METHODS: Laser Doppler flow (FluxExplorer) and mole analyser (MA) score (FotoFinder) were applied to histologically verified melanocytic nevi (33) and malignant melanomas (12).¦RESULTS: Mean perfusion and MA scores were significantly increased in melanoma compared to nevi. However, applying an empirically determined threshold of 16% perfusion increase only 42% of the melanomas fulfilled the criterion of malignancy, whereas with the mole analyzer score 82% of the melanomas fulfilled the criterion of malignancy.¦CONCLUSION: Laser Doppler imaging is a highly sensitive technology to assess skin and skin tumor perfusion in vivo. Although mean perfusion is higher in melanomas compared to nevi the high numbers of false negative results hamper the use of this technology for early melanoma detection.

Euromelanoma: a dermatology-led European campaign against nonmelanoma skin cancer and cutaneous melanoma: past, present and future.

Euromelanoma is a dermatologist-led skin cancer prevention programme conducting an annual screening and public education campaign in over 20 European countries. Within its 10-year history, Euromelanoma has screened over 260,000 individuals across Europe, detecting a significant number of cutaneous melanomas and nonmelanoma skin cancers, identifying high-risk individuals for further surveillance and promoting awareness on the suspicious features of melanoma and the hazardous effects of ultraviolet exposure. In this review article, we summarize the history of the Euromelanoma campaign, present its organizational structure and discuss the results of the campaign in individual countries and on a European scale. Euromelanoma has had a significant impact on melanoma prevention and early diagnosis in participating countries and, despite many challenges, has positively influenced public health attitudes towards regular mole examination and the implementation of preventive measures against skin cancer.

Cancers du sein : comment associer l'hormonothérapie et la radiothérapie en situation adjuvante [How to combine hormonotherapy and radiation treatment in adjuvant breast cancer?]

Combined radiation and hormone therapies have become common clinical practice in recent years for locally-advanced prostate cancers. The use of such concomitant therapy in the treatment of breast disease has been infrequently reported in the literature, but seems justified given the common hormonal dependence of breast cancer and the potential synergistic effect of these two treatment modalities. As adjuvant therapy, two strategies are used in daily clinical practice: upfront aromatase inhibitors or sequentially after a variable delay of tamoxifen. These molecules may, thus, interact with radiotherapy. Retrospectives studies recently published did not show any differences in terms of locoregional recurrences between concurrent or sequential radiohormonotherapy. Lung and skin fibroses due to concurrent treatment are still under debate. Nevertheless, late side effects appeared to be increased by such a treatment, particularly in hypersensitive patients identified at risk by the lymphocyte predictive test. Concurrent radiohormonotherapy should, thus, be delivered cautiously at least for these patients. This article details the potent advantages and risks of concurrent use of adjuvant hormonotherapy and radiotherapy in localized breast cancers.

The Effect Of Induced Intraocular Straylight (cataract Simulation) On Sensitivity Measures Of Standard Automated Perimetry, Pulsar Perimetry And Moorfields Motion Displacement Test

Purpose: To investigate the effect of incremental increases in intraocular straylight on threshold measurements made by three modern forms of perimetry: Standard Automated Perimetry (SAP) using Octopus (Dynamic, G-Pattern), Pulsar Perimetry (PP) (TOP, 66 points) and the Moorfields Motion Displacement Test (MDT) (WEBS, 32 points).Methods: Four healthy young observers were recruited (mean age 26yrs [25yrs, 28yrs]), refractive correction [+2 D, -4.25D]). Five white opacity filters (WOF), each scattering light by different amounts were used to create incremental increases in intraocular straylight (IS). Resultant IS values were measured with each WOF and at baseline (no WOF) for each subject using a C-Quant Straylight Meter (Oculus, Wetzlar, Germany). A 25 yr old has an IS value of ~0.85 log(s). An increase of 40% in IS to 1.2log(s) corresponds to the physiological value of a 70yr old. Each WOFs created an increase in IS between 10-150% from baseline, ranging from effects similar to normal aging to those found with considerable cataract. Each subject underwent 6 test sessions over a 2-week period; each session consisted of the 3 perimetric tests using one of the five WOFs and baseline (both instrument and filter were randomised).Results: The reduction in sensitivity from baseline was calculated. A two-way ANOVA on mean change in threshold (where subjects were treated as rows in the block and each increment in fog filters was treated as column) was used to examine the effect of incremental increases in straylight. Both SAP (p<0.001) and Pulsar (p<0.001) were significantly affected by increases in straylight. The MDT (p=0.35) remained comparatively robust to increases in straylight.Conclusions: The Moorfields MDT measurement of threshold is robust to effects of additional straylight as compared to SAP and PP.

Aplicació web de generació i autoavaluació d'exàmens tipus test basat en el criptosistema knapsack

Creació d'una aplicació web que genera exàmens tipus test agafant les preguntes d'un banc de preguntes. Genera una versió per cada alumne del mateix exàmen, amb les preguntes desordenades i les opcions també desordenades. A cada resposta se li associa un número. El resultat de l'exàmen és la suma de les repostes. Mitjançant el criptosistema Knapsack ficant a l'aplicació el número resultat de l'exàmen s'obté la nota.

Oxygen uptake of isolated toad skin epithelium: micromeasurement and effect of ionic acclimation.

Oxidative metabolism of isolated toad skin epithelium (Bufo viridis) was investigated in vitro under open-circuit conditions using the spectrophotometric oxyhemoglobin micromethod. This highly sensitive technique has been adapted for studying several epithelia in parallel and for detecting possible regional variations of oxygen uptake in individual epithelium. Changes in the proportion of mitochondria-rich cells (MRC) by ionic acclimation affected oxidative metabolism under nontransporting condition. After acclimation of animals to either NaNO3 or NaCl solutions (100 mmol/l, for greater than 2 wk), the number of MRC per square millimeter in epithelia from nonacclimated and NaNO3- and NaCl-acclimated animals was 350 +/- 113, 460 +/- 196, and 107 +/- 52, respectively. O2 uptake of nonacclimated and NaNO3-acclimated epithelia was significantly higher than that of NaCl-acclimated epithelia (i.e., 0.89 and 0.90 vs. 0.57 nmol O2.h-1.mm-2, respectively). The correlation established between O2 uptake and number of MRC allowed evaluation of the respiration rate of one single MRC, i.e., approximately 1 pmol O2/h. The lowest mitochondrial oxidative activity was found in the epithelia from NaCl-acclimated toads where the uncoupler 2,4-dinitrophenol (50 mumols/l) had the highest relative stimulatory effect (+114%). Acetazolamide (50 mumols/l), a potent inhibitor of carbonic anhydrase mainly present in the MRC, reduced selectively by 31% O2 uptake of the MRC-rich epithelia (NaNO3 acclimated). O2 uptake increased significantly by approximately 80% when basolateral pH increased from 5.8 to 7.8, but did not depend on apical pH. These findings indicate that under nontransporting (open-circuit) conditions, aerobic metabolism of the isolated toad skin epithelium is related to the density and/or characteristics of the MRC.(ABSTRACT TRUNCATED AT 250 WORDS)