Fasting glucose and body mass index as predictors of activity in breast cancer patients treated with everolimus-exemestane: the EverExt study

Evidence on everolimus in breast cancer has placed hyperglycemia among the most common high grade adverse events. Anthropometrics and biomarkers of glucose metabolism were investigated in a observational study of 102 postmenopausal, HR + HER2- metastatic breast cancer patients treated with everolimus-exemestane in first and subsequent lines. Best overall response (BR) and clinical benefit rate (CBR) were assessed across subgroups defined upon fasting glucose (FG) and body mass index (BMI). Survival was estimated by Kaplan-Meier method and log-rank test. Survival predictors were tested in Cox models. Median follow up was 12.4 months (1.0-41.0). The overall cohort showed increasing levels of FG and decreasing BMI (p < 0.001). Lower FG fasting glucose at BR was more commonly associated with C/PR or SD compared with PD (p < 0.001). We also observed a somewhat higher BMI associated with better response (p = 0.052). More patients in the lowest FG category achieved clinical benefit compared to the highest (p < 0.001), while no relevant differences emerged for BMI. Fasting glucose at re-assessment was also predictive of PFS (p = 0.037), as confirmed in models including BMI and line of therapy (p = 0.049). Treatment discontinuation was significantly associated with changes in FG (p = 0.014). Further research is warranted to corroborate these findings and clarify the underlying mechanisms

The identification of informative genes from multiple datasets with increasing complexity

Background In microarray data analysis, factors such as data quality, biological variation, and the increasingly multi-layered nature of more complex biological systems complicates the modelling of regulatory networks that can represent and capture the interactions among genes. We believe that the use of multiple datasets derived from related biological systems leads to more robust models. Therefore, we developed a novel framework for modelling regulatory networks that involves training and evaluation on independent datasets. Our approach includes the following steps: (1) ordering the datasets based on their level of noise and informativeness; (2) selection of a Bayesian classifier with an appropriate level of complexity by evaluation of predictive performance on independent data sets; (3) comparing the different gene selections and the influence of increasing the model complexity; (4) functional analysis of the informative genes. Results In this paper, we identify the most appropriate model complexity using cross-validation and independent test set validation for predicting gene expression in three published datasets related to myogenesis and muscle differentiation. Furthermore, we demonstrate that models trained on simpler datasets can be used to identify interactions among genes and select the most informative. We also show that these models can explain the myogenesis-related genes (genes of interest) significantly better than others (P < 0.004) since the improvement in their rankings is much more pronounced. Finally, after further evaluating our results on synthetic datasets, we show that our approach outperforms a concordance method by Lai et al. in identifying informative genes from multiple datasets with increasing complexity whilst additionally modelling the interaction between genes. Conclusions We show that Bayesian networks derived from simpler controlled systems have better performance than those trained on datasets from more complex biological systems. Further, we present that highly predictive and consistent genes, from the pool of differentially expressed genes, across independent datasets are more likely to be fundamentally involved in the biological process under study. We conclude that networks trained on simpler controlled systems, such as in vitro experiments, can be used to model and capture interactions among genes in more complex datasets, such as in vivo experiments, where these interactions would otherwise be concealed by a multitude of other ongoing events

Rab3D is critical for secretory granule maturation in PC12 cells.

Neuropeptide- and hormone-containing secretory granules (SGs) are synthesized at the trans-Golgi network (TGN) as immature secretory granules (ISGs) and complete their maturation in the F-actin-rich cell cortex. This maturation process is characterized by acidification-dependent processing of cargo proteins, condensation of the SG matrix and removal of membrane and proteins not destined to mature secretory granules (MSGs). Here we addressed a potential role of Rab3 isoforms in these maturation steps by expressing their nucleotide-binding deficient mutants in PC12 cells. Our data show that the presence of Rab3D(N135I) decreases the restriction of maturing SGs to the F-actin-rich cell cortex, blocks the removal of the endoprotease furin from SGs and impedes the processing of the luminal SG protein secretogranin II. This strongly suggests that Rab3D is implicated in the subcellular localization and maturation of ISGs

Triplet Exciton Generation in Bulk-Heterojunction Solar Cells based on Endohedral Fullerenes

Organic bulk-heterojunctions (BHJ) and solar cells containing the trimetallic nitride endohedral fullerene 1-[3-(2-ethyl)hexoxy carbonyl]propyl-1-phenyl-Lu3N@C80 (Lu3N@C80-PCBEH) show an open circuit voltage (VOC) 0.3 V higher than similar devices with [6,6]-phenyl-C[61]-butyric acid methyl ester (PC61BM). To fully exploit the potential of this acceptor molecule with respect to the power conversion efficiency (PCE) of solar cells, the short circuit current (JSC) should be improved to become competitive with the state of the art solar cells. Here, we address factors influencing the JSC in blends containing the high voltage absorber Lu3N@C80-PCBEH in view of both photogeneration but also transport and extraction of charge carriers. We apply optical, charge carrier extraction, morphology, and spin-sensitive techniques. In blends containing Lu3N@C80-PCBEH, we found 2 times weaker photoluminescence quenching, remainders of interchain excitons, and, most remarkably, triplet excitons formed on the polymer chain, which were absent in the reference P3HT:PC61BM blends. We show that electron back transfer to the triplet state along with the lower exciton dissociation yield due to intramolecular charge transfer in Lu3N@C80-PCBEH are responsible for the reduced photocurrent

p130Cas is an essential transducer element in ErbB2 transformation

The ErbB2 oncogene is often overexpressed in breast tumors and associated with poor clinical outcome. p130Cas represents a nodal scaffold protein regulating cell survival, migration, and proliferation in normal and pathological cells. The functional role of p130Cas in ErbB2-dependent breast tumorigenesis was assessed by its silencing in breast cancer cells derived from mouse mammary tumors overexpressing ErbB2 (N202-1A cells), and by its reexpression in ErbB2-transformed p130Cas-null mouse embryonic fibroblasts. We demonstrate that p130Cas is necessary for ErbB2-dependent foci formation, anchorage-independent growth, and in vivo growth of orthotopic N202-1A tumors. Moreover, intranipple injection of p130Cas-stabilized siRNAs in the mammary gland of Balbc-NeuT mice decreases the growth of spontaneous tumors. In ErbB2-transformed cells, p130Cas is a crucial component of a functional molecular complex consisting of ErbB2, c-Src, and Fak. In human mammary cells, MCF10A.B2, the concomitant activation of ErbB2, and p130Cas overexpression sustain and strengthen signaling, leading to Rac1 activation and MMP9 secretion, thus providing invasive properties. Consistently, p130Cas drives N202-1A cell in vivo lung metastases colonization. These results demonstrate that p130Cas is an essential transducer in ErbB2 transformation and highlight its potential use as a novel therapeutic target in ErbB2 positive human breast cancers.-Cabodi, S., Tinnirello, A., Bisaro, B., Tornillo, G., Camacho-Leal, M. P., Forni, G., Cojoca, R., Iezzi, M., Amici, A., Montani, M., Eva, A., Di Stefano, P., Muthuswamy, S. K., Tarone, G., Turco, E., Defilippi, P. p130Cas is an essential transducer element in ErbB2 transformation

Physico-Mechanical Performances of Mortars Prepared with Sorted Earthquake Rubble: The Role of CDW Type and Contained Crystalline Phases

Construction and demolition waste (CDW) from earthquake rubbles was used here as recycled aggregates (RA) in cementitious binders. The materials were sorted in six groups: concrete (CO), natural stone (NS), tile (TI), brick (BR), perforated brick (PF) and roof tile (RT). The abundance (wt.%) of crystalline phases in each RA type was determined by X-ray Powder Diffraction (XRPD). Each group of RAs was used alone (100 wt.% of RA) and mixed with quartz-rich virgin aggregates (VA) to prepare 13 types of mortars (12 specimens per type): one reference mortar (RM) with only VA, six recycled aggregate mortars (RAM) and six recycled-plus-virgin aggregate mortars (RVAM). The physical and mechanical properties of aggregates and mortars reflect the type and abundance of crystalline phases in each CDW group. Recycled mortars rich in concrete, natural stones and tiles have better mechanical performance than mortars prepared with recycled bricks, perforated bricks and roof tiles. For each RA, RVAMs have superior mechanical characteristics than the corresponding RAM. Since the type and amount of phases contained in recycled aggregates strongly control the mechanical performance of new construction materials, they should be routinely quantified as reported here, in addition to other physical features (water absorption, density, etc.). The separation of heterogeneous CDW into homogeneous RA groups is necessary for the production of new construction materials with stable and predictable performances to ensure CDW recycling, especially in areas hit by major adverse events, where large amounts of still valuable materials could be used for reconstruction processes

ESEM-EDX Mineralization and Morphological Analysis of Human Retrieved Maxillary Sinus Bone Graft Biopsies before Loading

This study aimed to analyze the morphology of bone graft granules, the presence of granule demineralization, and bone morphology in retrieved human maxillary sinus bone graft biopsies. Healthy patients underwent sinus bone augmentation using lateral access. Two different dimensions of the antrostomy were performed, a 4 mm or 8 mm height. After 6 months, all sites received one implant using a flap technique, crestal positioning, and submerged healing. Implant biopsies were retrieved after 3 months and were histologically processed. The ESEM analysis was performed on the entire portion of the peri-implant bone (up to 750 μm from the implant thread). Three different regions of interest (ROIs) were selected: the coronal, middle, and apical portions of the implant. In these areas, EDX was performed, and calcium (Ca), phosphate (P), nitrogen (N), and their atomic ratios (Ca/P, Ca/N, and P/N) were calculated. Different bone tissue electron-dense areas were detected through grayscale intensity quantification of ESEM images with different organic (N) or inorganic (Ca,P) compositions. A total of 16 biopsies from 16 healthy patients were analyzed. Bone graft granules were mostly detected in the apical ROI. New bone tissue bridges were detected in the apical and middle ROI. These structures, with lower Ca/N and P/N ratios, were connected and enveloped the bone graft granules. Cortical ROI revealed the most mineralized bone tissue. Conclusions: After 9 months, bone graft resorption was only partially completed and new bone tissue appeared less mineralized in the middle and apical ROI than in the coronal ROI

Retrieving magma composition from TIR spectra: implications for terrestrial planets investigations

Emissivity and reflectance spectra have been investigated on two series of silicate glasses, having compositions belonging to alkaline and subalkaline series, covering the most common terrestrial igneous rocks. Glasses were synthesized starting from natural end-members outcropping at Vulcano Island (Aeolian Islands, Italy) and on Snake River Plain (USA). Results show that the shift of the spectra, by taking Christiansen feature (CF) as a reference point, is correlated with SiO2 content, the SCFM factor and/or the degree of polymerization state via the NBO/T and temperature. The more evolved is the composition, the more polymerized the structure, the shorter the wavelength at which CF is observable. CF shift is also dependent on temperature. The shape of the spectra discriminates alkaline character, and it is related to the evolution of Qn structural units. Vulcano alkaline series show larger amount of Q4 and Q3 species even for mafic samples compared to the subalkaline Snake River Plain series. Our results provide new and robust insights for the geochemical characterization of volcanic rocks by remote sensing, with the outlook to infer origin of magmas both on Earth as well as on terrestrial planets or rocky bodies, from emissivity and reflectance spectra