Zeta function regularization for a scalar field in a compact domain

We express the zeta function associated to the Laplacian operator on $S^1_r\times M$ in terms of the zeta function associated to the Laplacian on $M$, where $M$ is a compact connected Riemannian manifold. This gives formulas for the partition function of the associated physical model at low and high temperature for any compact domain $M$. Furthermore, we provide an exact formula for the zeta function at any value of $r$ when $M$ is a $D$-dimensional box or a $D$-dimensional torus; this allows a rigorous calculation of the zeta invariants and the analysis of the main thermodynamic functions associated to the physical models at finite temperature.Comment: 19 pages, no figures, to appear in J. Phys.

Efficacy and safety of the anti-IL-12/23 p40 monoclonal antibody, ustekinumab, in patients with active psoriatic arthritis despite conventional non-biological and biological anti-tumour necrosis factor therapy: 6-month and 1-year results of the phase 3, multicentre, double-blind, placebo-controlled, randomised PSUMMIT 2 trial

Objective: Assess ustekinumab efficacy (week 24/week 52) and safety (week 16/week 24/week 60) in patients with active psoriatic arthritis (PsA) despite treatment with conventional and/or biological anti-tumour necrosis factor (TNF) agents. Methods: In this phase 3, multicentre, placebo-controlled trial, 312 adults with active PsA were randomised (stratified by site, weight (≤100 kg/>100 kg), methotrexate use) to ustekinumab 45 mg or 90 mg at week 0, week 4, q12 weeks or placebo at week 0, week 4, week 16 and crossover to ustekinumab 45 mg at week 24, week 28 and week 40. At week 16, patients with <5% improvement in tender/swollen joint counts entered blinded early escape (placebo→45 mg, 45 mg→90 mg, 90 mg→90 mg). The primary endpoint was ≥20% improvement in American College of Rheumatology (ACR20) criteria at week 24. Secondary endpoints included week 24 Health Assessment Questionnaire-Disability Index (HAQ-DI) improvement, ACR50, ACR70 and ≥75% improvement in Psoriasis Area and Severity Index (PASI75). Efficacy was assessed in all patients, anti-TNF-naïve (n=132) patients and anti-TNF-experienced (n=180) patients. Results: More ustekinumab-treated (43.8% combined) than placebo-treated (20.2%) patients achieved ACR20 at week 24 (p<0.001). Significant treatment differences were observed for week 24 HAQ-DI improvement (p<0.001), ACR50 (p≤0.05) and PASI75 (p<0.001); all benefits were sustained through week 52. Among patients previously treated with ≥1 TNF inhibitor, sustained ustekinumab efficacy was also observed (week 24 combined vs placebo: ACR20 35.6% vs 14.5%, PASI75 47.1% vs 2.0%, median HAQ-DI change −0.13 vs 0.0; week 52 ustekinumab-treated: ACR20 38.9%, PASI75 43.4%, median HAQ-DI change −0.13). No unexpected adverse events were observed through week 60. Conclusions: The interleukin-12/23 inhibitor ustekinumab (45/90 mg q12 weeks) yielded significant and sustained improvements in PsA signs/symptoms in a diverse population of patients with active PsA, including anti-TNF-experienced PsA patients

Spoken term detection ALBAYZIN 2014 evaluation: overview, systems, results, and discussion

The electronic version of this article is the complete one and can be found online at: http://dx.doi.org/10.1186/s13636-015-0063-8Spoken term detection (STD) aims at retrieving data from a speech repository given a textual representation of the search term. Nowadays, it is receiving much interest due to the large volume of multimedia information. STD differs from automatic speech recognition (ASR) in that ASR is interested in all the terms/words that appear in the speech data, whereas STD focuses on a selected list of search terms that must be detected within the speech data. This paper presents the systems submitted to the STD ALBAYZIN 2014 evaluation, held as a part of the ALBAYZIN 2014 evaluation campaign within the context of the IberSPEECH 2014 conference. This is the first STD evaluation that deals with Spanish language. The evaluation consists of retrieving the speech files that contain the search terms, indicating their start and end times within the appropriate speech file, along with a score value that reflects the confidence given to the detection of the search term. The evaluation is conducted on a Spanish spontaneous speech database, which comprises a set of talks from workshops and amounts to about 7 h of speech. We present the database, the evaluation metrics, the systems submitted to the evaluation, the results, and a detailed discussion. Four different research groups took part in the evaluation. Evaluation results show reasonable performance for moderate out-of-vocabulary term rate. This paper compares the systems submitted to the evaluation and makes a deep analysis based on some search term properties (term length, in-vocabulary/out-of-vocabulary terms, single-word/multi-word terms, and in-language/foreign terms).This work has been partly supported by project CMC-V2 (TEC2012-37585-C02-01) from the Spanish Ministry of Economy and Competitiveness. This research was also funded by the European Regional Development Fund, the Galician Regional Government (GRC2014/024, “Consolidation of Research Units: AtlantTIC Project” CN2012/160)

Comparison of gene expression during in vivo and in vitro postnatal retina development

Retina explants are widely used as a model of neural development. To define the molecular basis of differences between the development of retina in vivo and in vitro during the early postnatal period, we carried out a series of microarray comparisons using mouse retinas. About 75% of 8,880 expressed genes from retina explants kept the same expression volume and pattern as the retina in vivo. Fewer than 6% of the total gene population was changed at two consecutive time points, and only about 1% genes showed more than a threefold change at any time point studied. Functional Gene Ontology (GO) mapping for both changed and unchanged genes showed similar distribution patterns, except that more genes were changed in the GO clusters of response to stimuli and carbohydrate metabolism. Three distinct expression patterns of genes preferentially expressed in rod photoreceptors were observed in the retina explants. Some genes showed a lag in increased expression, some showed no change, and some continued to have a reduced level of expression. An early downregulation of cyclin D1 in the explanted retina might explain the reduction in numbers of precursors in explanted retina and suggests that external factors are required for maintenance of cyclin D1. The global view of gene profiles presented in this study will help define the molecular changes in retina explants over time and will provide criteria to define future changes that improve this model system

Self-renewal and chemotherapy resistance of p75NTR positive cells in esophageal squamous cell carcinomas

<p>Abstract</p> <p>Background</p> <p>p75^NTRhas been used to isolate esophageal and corneal epithelial stem cells. In the present study, we investigated the expression of p75^NTRin esophageal squamous cell carcinoma (ESCC) and explored the biological properties of p75^NTR+cells.</p> <p>Methods</p> <p>p75^NTRexpression in ESCC was assessed by immunohistochemistry. p75^NTR+and p75^NTR-cells of 4 ESCC cell lines were separated by fluorescence-activated cell sorting. Differentially expressed genes between p75^NTR+and p75^NTR-cells were determined by real-time quantitative reverse transcription-PCR. Sphere formation assay, DDP sensitivity assay, ⁶⁴copper accumulation assay and tumorigenicity analysis were performed to determine the capacity of self-renewal, chemotherapy resistance and tumorigenicity of p75^NTR+cells.</p> <p>Results</p> <p>In ESCC specimens, p75^NTRwas found mainly confined to immature cells and absent in cells undergoing terminal differentiation. The percentage of p75^NTR+cells was 1.6%–3.7% in Eca109 and 3 newly established ESCC cell lines. The expression of Bmi-1, which is associated with self-renewal of stem cells, was significantly higher in p75^NTR+cells. p63, a marker identified in keratinocyte stem cells, was confined mainly to p75^NTR+cells. The expression of CTR1, which is associated with cisplatin (DDP)-resistance, was significantly decreased in p75^NTR+cells. Expression levels of differentiation markers, such as involucrin, cytokeratin 13, β1-integrin and β4-integrin, were lower in p75^NTR+cells. In addition, p75^NTR+cells generated both p75^NTR+and p75^NTR-cells, and formed nonadherent spherical clusters in serum-free medium supplemented with growth factors. Furthermore, p75^NTR+cells were found to be more resistant to DDP and exhibited lower ⁶⁴copper accumulation than p75^NTR-cells.</p> <p>Conclusion</p> <p>Our results demonstrated that p75^NTR+cells possess some characteristics of CSCs, namely, self-renewal and chemotherapy resistance. Chemotherapy resistance of p75^NTR+cells may probably be attributable to decreased expression of CTR1.</p

Loss of pigment epithelium-derived factor enables migration, invasion and metastatic spread of human melanoma

Pigment epithelium-derived factor (PEDF) is a multifunctional secreted glycoprotein that displays broad anti-tumor activity based on dual targeting of the tumor microenvironment (anti-angiogenic action) and the tumor cells (direct anti-tumor action). Here, we show that PEDF expression is high in melanocytes, but it is lost during malignant progression of human melanoma. Using a high-throughput analysis of the data from microarray studies of molecular profiling of human melanoma, we found that PEDF expression is lost in highly invasive melanomas. In paired cell lines established from the same lesion but representing the high and low extremes of malignant potential, abundant PEDF expression was restricted to the poorly aggressive counterparts. We used RNA interference to directly address the functional consequences of PEDF silencing. PEDF knockdown in poorly aggressive melanoma cell lines augmented migration, invasion and vasculogenic mimicry, which translated into an increased in vivo metastatic potential. PEDF interference also significantly enhanced the migratory and invasive capability of normal melanocytes and moderately increased their proliferative potential. Our results show that loss of PEDF enables melanoma cells to acquire an invasive phenotype and, therefore, modulation of this multifunctional factor could be critical for the malignant progression of human melanoma. © 2009 Macmillan Publishers Limited All rights reservedSupported by grants: Ministerio de Educación y Ciencia grant SAF2007-62292 (BJ), Comunidad de Madrid SAL-0311-2006 (BJ), NIH grant RO1 HL68033 (OV), NIH merit grant CA59702 (MJCH). JL Orgaz has been supported by a Ministerio de Educación y Ciencia fellowship, O Ladhani by an NIH/NCI training grant T32CA009560 and A Fernández-Barral by a Consejo Superior de Investigaciones Científicas fellowshi

Tissue-Specific Target Analysis of Disease-Associated MicroRNAs in Human Signaling Pathways

MicroRNAs are a large class of post-transcriptional regulators that bind to the 3′ untranslated region of messenger RNAs. They play a critical role in many cellular processes and have been linked to the control of signal transduction pathways. Recent studies indicate that microRNAs can function as tumor suppressors or even as oncogenes when aberrantly expressed. For more general insights of disease-associated microRNAs, we analyzed their impact on human signaling pathways from two perspectives. On a global scale, we found a core set of signaling pathways with enriched tissue-specific microRNA targets across diseases. The function of these pathways reflects the affinity of microRNAs to regulate cellular processes associated with apoptosis, proliferation or development. Comparing cancer and non-cancer related microRNAs, we found no significant differences between both groups. To unveil the interaction and regulation of microRNAs on signaling pathways locally, we analyzed the cellular location and process type of disease-associated microRNA targets and proteins. While disease-associated proteins are highly enriched in extracellular components of the pathway, microRNA targets are preferentially located in the nucleus. Moreover, targets of disease-associated microRNAs preferentially exhibit an inhibitory effect within the pathways in contrast to disease proteins. Our analysis provides systematic insights into the interaction of disease-associated microRNAs and signaling pathways and uncovers differences in cellular locations and process types of microRNA targets and disease-associated proteins

RNA-Binding Protein Musashi1 Modulates Glioma Cell Growth through the Post-Transcriptional Regulation of Notch and PI3 Kinase/Akt Signaling Pathways

Musashi1 (MSI1) is an RNA-binding protein that plays critical roles in nervous-system development and stem-cell self-renewal. Here, we examined its role in the progression of glioma. Short hairpin RNA (shRNA)-based MSI1-knock down (KD) in glioblastoma and medulloblastoma cells resulted in a significantly lower number of self renewing colony on day 30 (a 65% reduction), compared with non-silencing shRNA-treated control cells, indicative of an inhibitory effect of MSI1-KD on tumor cell growth and survival. Immunocytochemical staining of the MSI1-KD glioblastoma cells indicated that they ectopically expressed metaphase markers. In addition, a 2.2-fold increase in the number of MSI1-KD cells in the G2/M phase was observed. Thus, MSI1-KD caused the prolongation of mitosis and reduced the cell survival, although the expression of activated Caspase-3 was unaltered. We further showed that MSI1-KD glioblastoma cells xenografted into the brains of NOD/SCID mice formed tumors that were 96.6% smaller, as measured by a bioluminescence imaging system (BLI), than non-KD cells, and the host survival was longer (49.3±6.1 days vs. 33.6±3.6 days; P<0.01). These findings and other cell biological analyses suggested that the reduction of MSI1 in glioma cells prolonged the cell cycle by inducing the accumulation of Cyclin B1. Furthermore, MSI1-KD reduced the activities of the Notch and PI3 kinase-Akt signaling pathways, through the up-regulation of Numb and PTEN, respectively. Exposure of glioma cells to chemical inhibitors of these pathways reduced the number of spheres and living cells, as did MSI1-KD. These results suggest that MSI1 increases the growth and/or survival of certain types of glioma cells by promoting the activation of both Notch and PI3 kinase/Akt signaling

Lens stem cells may reside outside the lens capsule: an hypothesis

In this paper, we consider the ocular lens in the context of contemporary developments in biological ideas. We attempt to reconcile lens biology with stem cell concepts and a dearth of lens tumors