A fully joint Bayesian quantitative trait locus mapping of human protein abundance in plasma.

Molecular quantitative trait locus (QTL) analyses are increasingly popular to explore the genetic architecture of complex traits, but existing studies do not leverage shared regulatory patterns and suffer from a large multiplicity burden, which hampers the detection of weak signals such as trans associations. Here, we present a fully multivariate proteomic QTL (pQTL) analysis performed with our recently proposed Bayesian method LOCUS on data from two clinical cohorts, with plasma protein levels quantified by mass-spectrometry and aptamer-based assays. Our two-stage study identifies 136 pQTL associations in the first cohort, of which >80% replicate in the second independent cohort and have significant enrichment with functional genomic elements and disease risk loci. Moreover, 78% of the pQTLs whose protein abundance was quantified by both proteomic techniques are confirmed across assays. Our thorough comparisons with standard univariate QTL mapping on (1) these data and (2) synthetic data emulating the real data show how LOCUS borrows strength across correlated protein levels and markers on a genome-wide scale to effectively increase statistical power. Notably, 15% of the pQTLs uncovered by LOCUS would be missed by the univariate approach, including several trans and pleiotropic hits with successful independent validation. Finally, the analysis of extensive clinical data from the two cohorts indicates that the genetically-driven proteins identified by LOCUS are enriched in associations with low-grade inflammation, insulin resistance and dyslipidemia and might therefore act as endophenotypes for metabolic diseases. While considerations on the clinical role of the pQTLs are beyond the scope of our work, these findings generate useful hypotheses to be explored in future research; all results are accessible online from our searchable database. Thanks to its efficient variational Bayes implementation, LOCUS can analyze jointly thousands of traits and millions of markers. Its applicability goes beyond pQTL studies, opening new perspectives for large-scale genome-wide association and QTL analyses. Diet, Obesity and Genes (DiOGenes) trial registration number: NCT00390637.

Bone regeneration response in an experimental long bone defect orthotopically implanted with alginate-pullulan-glass-ceramic composite scaffolds.

In the present study, scaffolds based on alginate-pullulan-bioactive glass-ceramic with 0.5 and 1.5 mol % copper oxide were orthotopically implanted in experimental rat models to assess their ability to heal an induced bone defect. By implying magnetic resonance and imaging scans together with histological evaluation of the processed samples, a progressive healing of bone was observed within 5 weeks. Furthermore, as the regenerative process continued, new bone tissue was formed, enhancing the growth of irregular bone spicules around the scaffolds. A significantly higher amount of new bone was formed (37%) in the defect that received the composite with 1.5 mol % CuO (in glass-ceramic matrix) content implant. Nevertheless, the bone regeneration obtained by scaffold with 0.5 mol % CuO implanted is comparable with the alginate-pullulan-ß-tricalcium phosphate/hydroxiapatite composite implant. The assessed amount of new bone formed was found to be between 29.75 and 37.15% for all the composition involved in the present study. During this process a regeneration process was shown when the alginate-pullulan composite materials were involved, fact that indicate the great potential of these materials to be used in tissue engineering.

New alginate-pullulan-bioactive glass composites with copper oxide for bone tissue regeneration trials.

Composites based on sodium alginate, pullulan, and bioactive SiO2 -CaO-P2 O5 glass-ceramics with copper oxide were prepared as capsules. The obtained samples were structurally characterized by Fourier transform infrared (FT-IR) spectroscopy, X-ray diffraction (XRD), and scanning electron microscopy (SEM), and their bioactivity and biocompatibility properties were also tested both in vitro and in vivo by XRD, FT-IR, SEM, and high-resolution transmission electron microscopy. The fibroblast and osteoblast cell viability assays have shown good proliferation rates for all investigated samples, whereas all composites exhibited a good in vivo tolerance. The recovered composites after 5 weeks' in vivo and in vitro trials evidenced clear macroscopic alterations; particularly, after soaking in simulated body fluid, they have a corn flake aspect, and after their in vivo inoculation, a globular shape is retained. Different crystalline shapes of hydroxyapatite were formed after in vitro and in vivo trials for the glass-ceramic-polymer composites, the in vitro precipitated apatite was found to be nodular, and the in vivo experiment led to needlelike crystallites formation. Histopathological results showed a good biocompatibility with no significant signs of rejection by the host tissue. These assessments performed on the composites indicate that the studied materials can be considered without any doubt suitable candidates for future bone regeneration applications.

The Role of EGFR and HER2- Activating Mutations in Maxillary Sinus Cancer.

Head and neck cancers account for less than 5% of all cancers worldwide and for less than 1% of all cancer deaths in Romania. Sinonasal squamous cell carcinomas are malignant tumors with origin in the respiratory mucosa of the paranasal sinuses and the nasal cavity. Because of the proximity to different important structures such as the brain, the eye the relevance of a multimodal therapy is well known. We take into discussion not only the most recent data from novel agents targeting EGF receptor (EGFR), VEGF and p53 pathways for the management of sinonasal cancer, but also further development of multimodal approach, and the use of biomarkers to appreciate the progression of the disease and the prognostic and overall survival rate in clinical practice. EGFR alterations have been implicated in the pathogenesis and progression of many malignancies. EGFR overexpression has been studied extensively regarding its clinical use but the results are yet to be analyzed.

Sentinel lymph node - work hypothesis in sinonasal carcinoma treatment.

Although rare, sinonasal malignancies (SNM) can be lesions of immense importance. Approximately 60-70% of sinonasal malignancies (SNM) occur in the maxillary sinus and 20-30% occurs in the nasal cavity itself. The lymphatic drainage of the sinuses and nasal cavity include levels I-III as well as the parapharyngian nodes. Elective regional lymph node dissections became controversial because of overtreatment of the many patients without lymph node metastases. Lymphatic metastasis is the most important mechanism of spread in sinonasal squamous cell carcinoma considering the vast network of vessels in this area. The indications and type of neck dissection to be performed in the positive node neck and management of the N0 neck remain controversial. The sentinel lymph node concept is based on the Halsted theory that stressed the importance of locoregional cancer treatment because of the far site spread. Each patient with head and neck malignancies, including sinonasal carcinoma have about 2-3 sentinel lymph nodes of which up to 40% of them contain metastases.

An assessment of VELACS "Class A" predictions

A method to compare numerical predictions with experimental recordings is presented. Two comparison indices are proposed:(1) the root mean square error of the predictions with respect to the mean of the experimental results; and (2) the size of a confidence interval centered at the predicted value which contains the estimated true value of the experimental results with a 75

probability. The reliability of experimental results is accounted for by the second index. The method is used to compare numerical "Class A" predictions perfomed within the framework of the VELACS Project with experimental results recorded in centrifuge experiments. The comparison is made in terms of excess pore pressures.(AU)

Numerical simulations of soil liquefaction

The paper emphasizes the capabilities of the mathematical model to simulate the recorded phenomena, providing that a proper evaluation of the constitutive parameter values is achieved. Some of the results of an extended analysis for the Kawagishi-cho apartment, to account for various drainage conditions at the base of the structure and to study the effects of the foundation soil improvement, are also presented.(AU)