Context: Kisspeptin, encoded by the KISS1 gene, is a key stimulatory factor of GnRH secretion and puberty onset. Inactivating mutations of its receptor (KISS1R) cause isolated hypogonadotropic ...hypogonadism (IHH). A unique KISS1R-activating mutation was described in central precocious puberty (CPP).
Objective: Our objective was to investigate KISS1 mutations in patients with idiopathic CPP and normosmic IHH.
Patients: Eighty-three children with CPP (77 girls) and 61 patients with IHH (40 men) were studied. The control group consisted of 200 individuals with normal pubertal development.
Methods: The promoter region and the three exons of KISS1 were amplified and sequenced. Cells expressing KISS1R were stimulated with synthetic human wild-type or mutant kisspeptin-54 (kp54), and inositol phosphate accumulation was measured. In a second set of experiments, kp54 was preincubated in human serum before stimulation of the cells.
Results: Two novel KISS1 missense mutations, p.P74S and p.H90D, were identified in three unrelated children with idiopathic CPP. Both mutations were absent in 400 control alleles. The p.P74S mutation was identified in the heterozygous state in a boy who developed CPP at 1 yr of age. The p.H90D mutation was identified in the homozygous state in two unrelated girls with CPP. In vitro studies revealed that the capacity of the P74S and H90D mutants to stimulate IP production was similar to the wild type. After preincubation of wild-type and mutant kp54 in human serum, the capacity to stimulate signal transduction was significantly greater for P74S compared with the wild type, suggesting that the p.P74S variant is more stable. Only polymorphisms were found in the IHH group.
Conclusion: Two KISS1 mutations were identified in unrelated patients with idiopathic CPP. The p.P74S variant was associated with higher kisspeptin resistance to degradation in comparison with the wild type, suggesting a role for this mutation in the precocious puberty phenotype.
A mutation in the KISS1 gene (P74S), identified in a boy with central precocious puberty, results in higher kisspeptin resistance to degradation in vitro.
Since its inception, laparoscopic surgery has evolved and new techniques have been developed due to technological advances. This requires a different and more complex skill set in comparison with ...open surgery. Reduced working hours, less training time and patient safety factors demand that such skills need to be achieved outside the operating theatre environment. Several studies have been published and have determined the effectiveness of virtual reality training. We aimed to compare virtual reality training with the traditional apprenticeship method of training and determine whether it can supplement or replace the traditional apprenticeship model. We also aimed to perform a meta-analysis of the literature and develop conclusions with respect to the benefits achieved by adding virtual reality training on a regular basis to surgical training programmes.
A literature search was carried out on PubMed, MEDLINE, EMBASE and Google Scholar academic search engines using the MESH terms 'randomised controlled trials', 'virtual reality', 'laparoscopy', 'surgical education' and 'surgical training'. All randomised controlled trials published to January 2018 comparing virtual reality training to apprenticeship training were included. Data were collected on improved dexterity, operative performance and operating times. Each outcome was calculated with 95% confidence intervals and with intention-to-treat analysis; 24 randomised controlled trials were analysed.
Meta-analytical data were extracted for time, path length, instrument handling, tissue handling, error scores and objective structure assessment of technical skills scoring. There was significant improvement in individual trainee skill in all meta-analyses (
0.0002).
This meta-analysis shows that virtual reality not only improves efficiency in the trainee's surgical practice but also improves quality with reduced error rates and improved tissue handling.
Purinergic signaling is involved in inflammation and cancer. Extracellular ATP accumulates in tumor interstitium, reaching hundreds micromolar concentrations, but its functional role on tumor ...vasculature and endothelium is unknown. Here we show that high ATP doses (>20 μM) strongly inhibit migration of endothelial cells from human breast carcinoma (BTEC), but not of normal human microvascular EC. Lower doses (1-10 μM result ineffective. The anti-migratory activity is associated with cytoskeleton remodeling and is significantly prevented by hypoxia. Pharmacological and molecular evidences suggest a major role for P2X7R and P2Y11R in ATP-mediated inhibition of TEC migration: selective activation of these purinergic receptors by BzATP mimics the anti-migratory effect of ATP, which is in turn impaired by their pharmacological or molecular silencing. Downstream pathway includes calcium-dependent Adenilyl Cyclase 10 (AC10) recruitment, cAMP release and EPAC-1 activation. Notably, high ATP enhances TEC-mediated attraction of human pericytes, leading to a decrease of endothelial permeability, a hallmark of vessel normalization. Finally, we provide the first evidence of in vivo P2X7R expression in blood vessels of murine and human breast carcinoma. In conclusion, we have identified a purinergic pathway selectively acting as an antiangiogenic and normalizing signal for human tumor-derived vascular endothelium.
Liver receptor homolog-1 (LRH-1, NR5A2) is an orphan nuclear receptor that has an essential role in cancer progression, notably in breast cancer. Although its role in promoting cancer cell ...proliferation and migration is well documented, the molecular basis is not completely established. Here, we report that LRH-1 inhibition affects two- and three-dimensional cell proliferation of different types of breast cancer cells, including estrogen receptor α (ERα)-positive and triple-negative cells. This phenotype is accompanied by the upregulation of the cyclin-dependent kinase inhibitor CDKN1A (aka p21(CIP1/WAF1)) in a p53-independent manner. Chromatin immunoprecipitation analysis shows that LRH-1 cooperates with FOXA1 and binds directly to CDKN1A promoter and a distal regulatory region found at -62 kb from its transcriptional start sites, allowing repression of CDKN1A transcription. LRH-1 or FOXA1 depletion induces CDKN1A upregulation by removing histone deacetylase 2 from the promoter and distal regulatory elements and permitting histone acetylation in these regions. Analysis of breast cancer samples reveals that a high LRH-1 level is inversely correlated with CDKN1A expression in breast cancer patients and is associated with poor prognosis. This study reveals a novel mechanism of control of cell proliferation by LRH-1 regulating CDKN1A transcription in breast cancer cells, independent of ERα and p53 status. Targeting LRH-1 may provide an attractive prospect for treatment of tumors that are resistant to hormonal and targeted therapy.
In this work, we investigate how illuminant estimation techniques can be improved taking into account intrinsic, low level properties of the images. We show how these properties can be used to drive, ...given a set of illuminant estimation algorithms, the selection of the best algorithm for a given image. The algorithm selection is made by a decision forest composed of several trees on the basis of the values of a set of heterogeneous features. The features represent the image content in terms of low-level visual properties. The trees are trained to select the algorithm that minimizes the expected error in illuminant estimation. We also designed a combination strategy that estimates the illuminant as a weighted sum of the different algorithms’ estimations. Experimental results on the widely used Ciurea and Funt dataset demonstrate the effectiveness of our approach.
Recent advances in machine learning research, combined with the reduced sequencing costs enabled by modern next-generation sequencing, paved the way to the implementation of precision medicine ...through routine multi-omics molecular profiling of tumours. Thus, there is an emerging need of reliable models exploiting such data to retrieve clinically useful information. Here, we introduce an original consensus clustering approach, overcoming the intrinsic instability of common clustering methods based on molecular data. This approach is applied to the case of non-small cell lung cancer (NSCLC), integrating data of an ongoing clinical study (PROMOLE) with those made available by The Cancer Genome Atlas, to define a molecular-based stratification of the patients beyond, but still preserving, histological subtyping. The resulting subgroups are biologically characterized by well-defined mutational and gene-expression profiles and are significantly related to disease-free survival (DFS). Interestingly, it was observed that (1) cluster B, characterized by a short DFS, is enriched in KEAP1 and SKP2 mutations, that makes it an ideal candidate for further studies with inhibitors, and (2) over- and under-representation of inflammation and immune systems pathways in squamous-cell carcinomas subgroups could be potentially exploited to stratify patients treated with immunotherapy.
We present a simple and effective technique for absolute colorimetric camera characterization, invariant to changes in exposure/aperture and scene irradiance, suitable in a wide range of applications ...including image‐based reflectance measurements, spectral pre‐filtering and spectral upsampling for rendering, to improve colour accuracy in high dynamic range imaging. Our method requires a limited number of acquisitions, an off‐the‐shelf target and a commonly available projector, used as a controllable light source, other than the reflected radiance to be known. The characterized camera can be effectively used as a 2D tele‐colorimeter, providing the user with an accurate estimate of the distribution of luminance and chromaticity in a scene, without requiring explicit knowledge of the incident lighting power spectra. We validate the approach by comparing our estimated absolute tristimulus values (XYZ data in cd/m2) with the measurements of a professional 2D tele‐colorimeter, for a set of scenes with complex geometry, spatially varying reflectance and light sources with very different spectral power distribution.
We present a simple and effective technique for absolute colorimetric camera characterization, invariant to changes in exposure/aperture and scene irradiance, suitable in a wide range of applications including image‐based reflectance measurements, spectral pre‐filtering and spectral upsampling for rendering, to improve colour accuracy in high dynamic range imaging. Our method requires a limited number of acquisitions, an off‐the‐shelf target and a commonly available projector, used as a controllable light source, other than the reflected radiance to be known. The characterized camera can be effectively used as a 2D tele‐colorimeter, providing the user with an accurate estimate of the distribution of luminance and chromaticity in a scene, without requiring explicit knowledge of the incident lighting power spectra.
Resistive switching (RS) devices based on self-assembled nanowires (NWs) and nanorods (NRs) represent a fascinating alternative to conventional devices with thin film structure. The high ...surface-to-volume ratio may indeed provide the possibility of modulating their functionalities through surface effects. However, devices based on NWs usually suffer from low resistive switching performances in terms of operating voltages, endurance and retention capabilities. In this work, we report on the resistive switching behaviour of ZnO NW arrays, grown by hydrothermal synthesis, that exhibit stable, bipolar resistive switching characterized by SET/RESET voltages lower than 3 V, endurance higher than 1100 cycles and resistance state retention of more than 105 s. The physical mechanism underlying these RS performances can be ascribed to nanoionic processes involving the formation/rupture of conductive paths assisted by oxygen-related species in the ZnO active layer. The reported results represent, to the best of our knowledge, the best resistive switching performances observed in ZnO NW arrays in terms of endurance and retention.
Flexible supercapacitors have emerged as one of the more promising and efficient space-saving energy storage system for portable and wearable electronics. Laser-induced graphenization has been ...recently proposed as a powerful and scalable method to directly convert a polymeric substrate into a 3D network of few layer graphene as high-performance supercapacitor electrode. Unfortunately this outstanding process has been reported to be feasible only for few thermoplastic polymers, strongly limiting its future developments. Here we show that laser induced graphenization of sulfonated poly(ether ether ketone) (SPEEK) can be obtained and the mechanism of this novel process is proposed. The resulting material can act at the same time as binder-free electrode and current collector. Moreover SPEEK is also used both as separator and polymeric electrolyte allowing the assembling of an all-SPEEK flexible supercapacitor. Chemico-physical characterization provides deep understanding of the laser-induced graphenization process, reported on this polymer for the first time, while the device performance studied by cyclic voltammetry, charging-discharging, and impedance spectroscopy prove the enormous potential of the proposed approach.
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