FGFR3 expression in primary and metastatic urothelial carcinoma of the bladder

While fibroblast growth factor receptor 3 (FGFR3) is frequently mutated or overexpressed in nonmuscle-invasive urothelial carcinoma (UC), the prevalence of FGFR3 protein expression and mutation remains unknown in muscle-invasive disease. FGFR3 protein and mRNA expression, mutational status, and copy number variation were retrospectively analyzed in 231 patients with formalin-fixed paraffin-embedded primary UCs, 33 metastases, and 14 paired primary and metastatic tumors using the following methods: immunohistochemistry, NanoString nCounterTM, OncoMap or Affymetrix OncoScanTM array, and Gain and Loss of Analysis of DNA and Genomic Identification of Significant Targets in Cancer software. FGFR3 immunohistochemistry staining was present in 29% of primary UCs and 49% of metastases and did not impact overall survival (P = 0.89, primary tumors; P = 0.78, metastases). FGFR3 mutations were observed in 2% of primary tumors and 9% of metastases. Mutant tumors expressed higher levels of FGFR3 mRNA than wild-type tumors (P < 0.001). FGFR3 copy number gain and loss were rare events in primary and metastatic tumors (0.8% each; 3.0% and 12.3%, respectively). FGFR3 immunohistochemistry staining is present in one third of primary muscle-invasive UCs and half of metastases, while FGFR3 mutations and copy number changes are relatively uncommon

Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma

This randomised phase III trial compared standard of care Everolimus with the anti-PD1 monoclonal antibody Nivolumab in previously treated patients with locally advanced inoperable or metastatic clear cell renal cancer. 810 patients were randomised to receive either Everolimus 10 mg orally daily or 3 mg/kg of Nivolumab intravenously every two weeks. Patients were treated until unacceptable toxicity or disease progression. Patients could be treated beyond progression if the investigator believed that the patient was gaining clinical benefit. The primary endpoint was overall survival. The median survival was 25 months for Nivolumab and 19.8 months for Everolimus (p=0.002). The objective response rate was higher for Nivolumab (25 versus 5%; p=&#60;0.001).The median progression free survivals were 4.6 & 4.4 months (p=0.11). Grade 3 & 4 treatment related toxicities were observed in 19 & 37% of patients on Nivolumab or Everolimus respectively. In patients with previously treated renal cell carcinoma Nivolumab produced superior survival and more tolerable treatment than Everolimus

Design and Characterization of a Human Monoclonal Antibody that Modulates Mutant Connexin 26 Hemichannels Implicated in Deafness and Skin Disorders

Background: Mutations leading to changes in properties, regulation, or expression of connexin-made channels have been implicated in 28 distinct human hereditary diseases. Eight of these result from variants of connexin 26 (Cx26), a protein critically involved in cell-cell signaling in the inner ear and skin. Lack of non-toxic drugs with defined mechanisms of action poses a serious obstacle to therapeutic interventions for diseases caused by mutant connexins. In particular, molecules that specifically modulate connexin hemichannel function without affecting gap junction channels are considered of primary importance for the study of connexin hemichannel role in physiological as well as pathological conditions. Monoclonal antibodies developed in the last three decades have become the most important class of therapeutic biologicals. Recombinant methods permit rapid selection and improvement of monoclonal antibodies from libraries with large diversity.Methods: By screening a combinatorial library of human single-chain fragment variable (scFv) antibodies expressed in phage, we identified a candidate that binds an extracellular epitope of Cx26. We characterized antibody action using a variety of biochemical and biophysical assays in HeLa cells, organotypic cultures of mouse cochlea and human keratinocyte-derived cells.Results: We determined that the antibody is a remarkably efficient, non-toxic, and completely reversible inhibitor of hemichannels formed by connexin 26 and does not affect direct cell-cell communication via gap junction channels. Importantly, we also demonstrate that the antibody efficiently inhibits hyperative mutant Cx26 hemichannels implicated in autosomal dominant non-syndromic hearing impairment accompanied by keratitis and hystrix-like ichthyosis-deafness (KID/HID) syndrome. We solved the crystal structure of the antibody, identified residues that are critical for binding and used molecular dynamics to uncover its mechanism of action.Conclusions: Although further studies will be necessary to validate the effect of the antibody in vivo, the methodology described here can be extended to select antibodies against hemichannels composed by other connexin isoforms and, consequently, to target other pathologies associated with hyperactive hemichannels. Our study highlights the potential of this approach and identifies connexins as therapeutic targets addressable by screening phage display libraries expressing human randomized antibodies

BAAV Mediated GJB2 Gene Transfer Restores Gap Junction Coupling in Cochlear Organotypic Cultures from Deaf Cx26Sox10Cre Mice

The deafness locus DFNB1 contains GJB2, the gene encoding connexin26 and GJB6, encoding connexin30, which appear to be coordinately regulated in the inner ear. In this work, we investigated the expression and function of connexin26 and connexin30 from postnatal day 5 to adult age in double transgenic Cx26Sox10Cre mice, which we obtained by crossing connexin26 floxed mice with a deleter Sox10–Cre line. Cx26Sox10Cre mice presented with complete connexin26 ablation in the epithelial gap junction network of the cochlea, whereas connexin30 expression was developmentally delayed; immunolabeling patterns for both connexins were normal in the cochlear lateral wall. In vivo electrophysiological measurements in Cx26Sox10Cre mice revealed profound hearing loss accompanied by reduction of endocochlear potential, and functional experiments performed in postnatal cochlear organotypic cultures showed impaired gap junction coupling. Transduction of these cultures with a bovine adeno associated virus vector restored connexin26 protein expression and rescued gap junction coupling. These results suggest that restoration of normal connexin levels by gene delivery via recombinant adeno associated virus could be a way to rescue hearing function in DFNB1 mouse models and, in future, lead to the development of therapeutic interventions in humans

Are men universally more dismissing than women? Gender differences in romantic attachment across 62 cultural regions

The authors thank Susan Sprecher (USA), Del Paulhus (Canada), Glenn D. Wilson (England), Qazi Rahman (England), Alois Angleitner (Germany), Angelika Hofhansl (Austria), Tamio Imagawa (Japan), Minoru Wada (Japan), Junichi Taniguchi (Japan), and Yuji Kanemasa (Japan) for helping with data collection and contributing significantly to the samples used in this study.Gender differences in the dismissing form of adult romantic attachment were investigated as part of the International Sexuality Description Project—a survey study of 17,804 people from 62 cultural regions. Contrary to research findings previously reported in Western cultures, we found that men were not significantly more dismissing than women across all cultural regions. Gender differences in dismissing romantic attachment were evident in most cultures, but were typically only small to moderate in magnitude. Looking across cultures, the degree of gender differentiation in dismissing romantic attachment was predictably associated with sociocultural indicators. Generally, these associations supported evolutionary theories of romantic attachment, with smaller gender differences evident in cultures with high–stress and high–fertility reproductive environments. Social role theories of human sexuality received less support in that more progressive sex–role ideologies and national gender equity indexes were not cross–culturally linked as expected to smaller gender differences in dismissing romantic attachment.peer-reviewe

Buffered high charge spectrally-peaked proton beams in the relativistic-transparency regime

Spectrally-peaked proton beams of high charge (Ep » 8 MeV, DE » 4 MeV, N » 50 nC ) have been observed from the interaction of an intense laser (>1019 W cm−2) with ultrathin CH foils, as measured by spectrally-resolved full beam profiles. These beams are reproducibly generated for foil thicknesses 5–100 nm, and exhibit narrowing divergence with decreasing target thickness down to »8 for 5 nm. Simulations demonstrate that the narrow energy spread feature is a result of buffered acceleration of protons. The radiation pressure at the front of the target results in asymmetric sheath fields which permeate throughout the target, causing preferential forward acceleration. Due to their higher charge- to-mass ratio, the protons outrun a carbon plasma driven in the relativistic transparency regime

Comprehensive all-sky search for periodic gravitational waves in the sixth science run LIGO data

We report on a comprehensive all-sky search for periodic gravitational waves in the frequency band 100–1500 Hz and with a frequency time derivative in the range of [−1.18,+1.00]×10−8  Hz/s. Such a signal could be produced by a nearby spinning and slightly nonaxisymmetric isolated neutron star in our galaxy. This search uses the data from the initial LIGO sixth science run and covers a larger parameter space with respect to any past search. A Loosely Coherent detection pipeline was applied to follow up weak outliers in both Gaussian (95% recovery rate) and non-Gaussian (75% recovery rate) bands. No gravitational wave signals were observed, and upper limits were placed on their strength. Our smallest upper limit on worst-case (linearly polarized) strain amplitude h0 is 9.7×10−25 near 169 Hz, while at the high end of our frequency range we achieve a worst-case upper limit of 5.5×10−24. Both cases refer to all sky locations and entire range of frequency derivative values

A directed search for gravitational waves from Scorpius X-1 with initial LIGO

19 pages, 8 figuresInternational audienceWe present results of a search for continuously-emitted gravitational radiation, directed at the brightest low-mass X-ray binary, Scorpius X-1. Our semi-coherent analysis covers 10 days of LIGO S5 data ranging from 50-550 Hz, and performs an incoherent sum of coherent $\mathcal{F}$-statistic power distributed amongst frequency-modulated orbital sidebands. All candidates not removed at the veto stage were found to be consistent with noise at a 1% false alarm rate. We present Bayesian 95% confidence upper limits on gravitational-wave strain amplitude using two different prior distributions: a standard one, with no a priori assumptions about the orientation of Scorpius X-1; and an angle-restricted one, using a prior derived from electromagnetic observations. Median strain upper limits of 1.3e-24 and 8e-25 are reported at 150 Hz for the standard and angle-restricted searches respectively. This proof of principle analysis was limited to a short observation time by unknown effects of accretion on the intrinsic spin frequency of the neutron star, but improves upon previous upper limits by factors of ~1.4 for the standard, and 2.3 for the angle-restricted search at the sensitive region of the detector