Effects of 1,25 Dihydroxyvitamin D3 and Calcium on Growth and Differentiation and on c-fos and p53 Gene Expression in Normal Human Keratinocytes

Calcium enhances keratinocyte differentiation, and 1,25 dihydroxyvitamin D3 (1,25(OH)2D3) is both antiproliferative and prodifferentiative in many cell types, including normal human keratinocytes. In the present study, we examined the combined effects of calcium and 1,25(OH)2D3 on parameters of growth and differentiation and on c-fos and p53 gene expression in normal human keratinocytes. Exposure of normal human keratinocytes to 1,25(OH)2D3 markedly reduced [3H] thymidine incorporation and cell number at low and high medium Ca++ concentrations. Simultaneously, cells in the G0/G1 phase of the cell cycle increased significantly and those in the S phase fell precipitously. l,25(OH)2D3 and calcium also induced keratinocyte differentiation independently, as assessed by iminuno- cytochemistry and by induction of involucrin mRNA. Both Ca++ and 1,25(OH)2D3 were shown, by nuclear run-on assays, to increase involucrin gene transcription. A rapid, transient elevation in c-fos protooncogene expression preceded these effects when epidermal growth factor was present alone. When 1,25(OH)2D3 was added to quiescent keratinocytes, there was a marked augmentation of c-fos mRNA accumulation at low and high medium Ca++ concentrations. Varying medium Ca++ concentrations had no effect on c-fos mRNA levels. Increasing medium Ca++ concentrations from 0.15 to 2.0mM produced marked elevations of p53 mRNA accumulation and of the rate of p53 gene transcription, whereas 1,25(OH)2D3 had no effect.These results, therefore, suggest that 1,25(OH)2D3 and calcium act in concert to modulate the expression of two important cell-cycle-associated genes, which may be important components in the initial programming of growth and differentiation of normal human keratinocytes

Collaborative hyperparameter tuning

International audienceHyperparameter learning has traditionally been a manual task because of the limited number of trials. Today's computing infrastructures allow bigger evaluation budgets, thus opening the way for algorithmic approaches. Recently, surrogate-based optimization was successfully applied to hyperparameter learning for deep belief networks and to WEKA classifiers. The methods combined brute force computational power with model building about the behavior of the error function in the hyperparameter space, and they could significantly improve on manual hyperparameter tuning. What may make experienced practitioners even better at hyperparameter optimization is their ability to generalize across similar learning problems. In this paper, we propose a generic method to incorporate knowledge from previous experiments when simultaneously tuning a learning algorithm on new problems at hand. To this end, we combine surrogate-based ranking and optimization techniques for surrogate-based collaborative tuning (SCoT). We demonstrate SCoT in two experiments where it outperforms standard tuning techniques and single-problem surrogate-based optimization

Extreme compass and Dynamic Multi-Armed Bandits for Adaptive Operator Selection

The goal of adaptive operator selection is the on-line control of the choice of variation operators within evolutionary algorithms. The control process is based on two main components, the credit assignment, that defines the reward that will be used to evaluate the quality of an operator after it has been applied, and the operator selection mechanism, that selects one operator based on some operators qualities. Two previously developed adaptive operator selection methods are combined here: Compass evaluates the performance of operators by considering not only the fitness improvements from parent to offspring, but also the way they modify the diversity of the population, and their execution time; dynamic multi-armed bandit proposes a selection strategy based on the well-known UCB algorithm, achieving a compromise between exploitation and exploration, while nevertheless quickly adapting to changes. Tests with the proposed method, called ExCoDyMAB, are carried out using several hard instances of the satisfiability problem (SAT). Results show the good synergetic effect of combining both approaches

Investigating the association of rs2910164 with cancer predisposition in an Irish cohort.

IntroductionMicroRNAs (miRNAs) are small noncoding RNA molecules that exert post-transcriptional effects on gene expression by binding with cis-regulatory regions in target messenger RNA (mRNA). Polymorphisms in genes encoding miRNAs or in miRNA-mRNA binding sites confer deleterious epigenetic effects on cancer risk. miR-146a has a role in inflammation and may have a role as a tumour suppressor. The polymorphism rs2910164 in the MIR146A gene encoding pre-miR-146a has been implicated in several inflammatory pathologies, including cancers of the breast and thyroid, although evidence for the associations has been conflicting in different populations. We aimed to further investigate the association of this variant with these two cancers in an Irish cohort.MethodsThe study group comprised patients with breast cancer (BC), patients with differentiated thyroid cancer (DTC) and unaffected controls. Germline DNA was extracted from blood or from saliva collected using the DNA Genotek Oragene 575 collection kit, using crystallisation precipitation, and genotyped using TaqMan-based PCR. Data were analysed using SPSS, v22.ResultsThe total study group included 1516 participants. This comprised 1386 Irish participants; 724 unaffected individuals (controls), 523 patients with breast cancer (BC), 136 patients with differentiated thyroid cancer (DTC) and three patients with dual primary breast and thyroid cancer. An additional cohort of 130 patients with DTC from the South of France was also genotyped for the variant. The variant was detected with a minor allele frequency (MAF) of 0.19 in controls, 0.22 in BC and 0.27 and 0.26 in DTC cases from Ireland and France, respectively. The variant was not significantly associated with BC (per allele odds ratio = 1.20 (0.98-1.46), P  = 0.07), but was associated with DTC in Irish patients (per allele OR = 1.59 (1.18-2.14), P = 0.002).ConclusionThe rs2910164 variant in MIR146A is significantly associated with DTC, but is not significantly associated with BC in this cohort

Light Scattering by Vitreous of Humans With Vision Degrading Myodesopsia From Floaters

PURPOSE: Vision-degrading myodesopsia (VDM) from vitreous floaters significantly degrades vision and impacts visual quality of life (VQOL), but the relationship to light scattering is poorly understood. This study compared in vitro measures of light scatter and transmission in surgically excised human vitreous to preoperative indexes of vitreous structure, visual function, and VQOL. METHODS: Pure vitreous collected during vitrectomy from 8 patients with VDM had wide-angle straylight measurements and dark-field imaging, performed within 36 hours of vitrectomy. Preoperative VQOL assessment with VFQ-25, contrast sensitivity (CS) measurements with Freiburg acuity contrast testing, and quantitative ultrasonography were compared to light scattering and transmission in vitro. RESULTS: All indices of vitreous echodensity in vivo correlated positively with straylight at 0.5° (R = 0.708 to 0.775, P = 0.049 and 0.024, respectively). Straylight mean scatter index correlated with echodensity (R = 0.71, P = 0.04) and VQOL (R = -0.82, P = 0.0075). Dark-field measures in vitro correlated with degraded CS in vivo (R = -0.69, P = 0.04). VQOL correlated with straylight mean scatter index (R = -0.823, P = 0.012). CONCLUSIONS: Increased vitreous echodensity in vivo is associated with more straylight scattering in vitro, validating ultrasonography as a clinical surrogate for light scattering. Contrast sensitivity in vivo is more degraded in the presence of dark-field scattering in vitro and VQOL is decreased in patients whose vitreous has increased light scattering. These findings could form the basis for the development of optical corrections for VDM or support new laser treatments, as well as novel pharmacotherapy

Scaling Analysis of Affinity Propagation

We analyze and exploit some scaling properties of the Affinity Propagation (AP) clustering algorithm proposed by Frey and Dueck (2007). First we observe that a divide and conquer strategy, used on a large data set hierarchically reduces the complexity ${\cal O}(N^2)$ to ${\cal O}(N^{(h+2)/(h+1)})$, for a data-set of size $N$ and a depth $h$ of the hierarchical strategy. For a data-set embedded in a $d$-dimensional space, we show that this is obtained without notably damaging the precision except in dimension $d=2$. In fact, for $d$ larger than 2 the relative loss in precision scales like $N^{(2-d)/(h+1)d}$. Finally, under some conditions we observe that there is a value $s^*$ of the penalty coefficient, a free parameter used to fix the number of clusters, which separates a fragmentation phase (for $s<s^*$) from a coalescent one (for $s>s^*$) of the underlying hidden cluster structure. At this precise point holds a self-similarity property which can be exploited by the hierarchical strategy to actually locate its position. From this observation, a strategy based on \AP can be defined to find out how many clusters are present in a given dataset.Comment: 28 pages, 14 figures, Inria research repor

Patient-reported outcomes in PROSPECT trial (Alliance N1048) – FOLFOX is not a panacea

The PROSPECT was a randomized phase III trial that included patients with resectable rectal cancer (clinical stage cT2-3N+ or cT3N0). The trial aimed to test the hypothesis that pre-operative chemotherapy consisting of 6 cycles of FOLFOX given over a 12-week period, followed by total mesorectal excision (TME) surgery, was non-inferior to pre-operative long-course chemoradiotherapy (CRT). The primary endpoint of the study was disease-free survival (DFS), and patients were also monitored for other relevant oncological outcomes such and health-related quality of life (HRQoL) using patient-reported outcome (PRO) tools [1, 2]