Depth concentrations of deuterium ions implanted into some pure metals and alloys

Pure metals (Cu, Ti, Zr, V, Pd) and diluted Pd-alloys (Pd-Ag, Pd-Pt, Pd-Ru, Pd-Rh) were implanted by 25 keV deuterium ions at fluences in the range (1.2{\div}2.3)x1022 D+/m2. The post-treatment depth distributions of deuterium ions were measured 10 days and three months after the implantation using Elastic Recoil Detection Analysis (ERDA) and Rutherford Backscattering (RBS). Comparison of the obtained results allowed to make conclusions about relative stability of deuterium and hydrogen gases in pure metals and diluted Pd alloys. Very high diffusion rates of implanted deuterium ions from V and Pd pure metals and Pd alloys were observed. Small-angle X-ray scattering revealed formation of nanosized defects in implanted corundum and titanium.Comment: 12 pages, 9 figure

Intratumoral Delivery of Plasmid Interleukin-12 Via Electroporation Leads to Regression of Injected and Non-Injected Tumors in Merkel Cell Carcinoma

Purpose: Interleukin-12 (IL12) promotes adaptive type I immunity and has demonstrated antitumor efficacy, but systemic administration leads to severe adverse events (AE), including death. This pilot trial investigated safety, efficacy, and immunologic activity of intratumoral delivery of IL12 plasmid DNA (tavo) via in vivo electroporation (i.t.-tavo-EP) in patients with Merkel cell carcinoma (MCC), an aggressive virus-associated skin cancer. Experimental Design: Fifteen patients with MCC with superficial injectable tumor(s) received i.t.-tavo-EP on days 1, 5, and 8 of each cycle. Patients with locoregional MCC (cohort A, N = 3) received one cycle before definitive surgery in week 4. Patients with metastatic MCC (cohort B, N = 12) received up to four cycles total, administered at least 6 weeks apart. Serial tumor and blood samples were collected. Results: All patients successfully completed at least one cycle with transient, mild (grades 1 and 2) AEs and without significant systemic toxicity. Sustained (day 22) intratumoral expression of IL12 protein was observed along with local inflammation and increased tumor-specific CD8+ T-cell infiltration, which led to systemic immunologic and clinical responses. The overall response rate was 25% (3/12) in cohort B, with 2 patients experiencing durable clinical benefit (16 and 55+ months, respectively). Two cohort A patients (1 with pathologic complete remission) were recurrence-free at 44+ and 75+ months. Conclusions: I.t.-tavo-EP was safe and feasible without systemic toxicity. Sustained local expression of IL12 protein and local inflammation led to systemic immune responses and clinically meaningful benefit in some patients. Gene electrotransfer, specifically i.t.-tavo-EP, warrants further investigation for immunotherapy of cancer

FAM123A Binds to Microtubules and Inhibits the Guanine Nucleotide Exchange Factor ARHGEF2 to Decrease Actomyosin Contractility

The FAM123 gene family comprises three members, FAM123A, the tumor suppressor WTX(FAM123B) and FAM123C. WTX is required for normal development and causally contributes to human disease, in part through its regulation of β-catenin-dependent WNT signaling. The roles of FAM123A and FAM123C in signaling, cell behavior and human disease remain less understood. We defined and compared the protein-protein interaction networks for each member of the FAM123 family by affinity purification and mass spectrometry. Protein localization and functional studies suggest that the FAM123 family members have conserved and divergent cellular roles. In contrast to WTX and FAM123C, we found that microtubule-associated proteins were enriched in the FAM123A protein interaction network. FAM123A interacted with and tracked dynamic microtubules in a plus-end direction. Domain interaction experiments revealed a ‘SKIP’ amino acid motif in FAM123A that mediated interaction with the microtubule tip tracking proteins EB1 and EB3, and therefore with microtubules. Cells depleted of FAM123A showed compartment-specific effects on microtubule dynamics, increased actomyosin contractility, larger focal adhesions and decreased cell migration. These effects required binding of FAM123A to and inhibition of the guanine nucleotide exchange factor ARHGEF2, a microtubule-associated activator of RhoA. Together, these data suggest that the ‘family-unique’ SKIP motif enables FAM123A to bind EB proteins, localize to microtubules and coordinate microtubule dynamics and actomyosin contractility

WNT7B mediates autocrine Wnt/β-catenin signaling and anchorage-independent growth in pancreatic adenocarcinoma

Developmental and cancer models show Wnt/β-catenin-dependent signaling mediates diverse phenotypic outcomes in the pancreas that are dictated by context, duration and strength of activation. While generally assumed to be pro-tumorigenic, it is unclear to what extent dysregulation of Wnt/β-catenin signaling impacts tumor progression in pancreatic adenocarcinoma (PDAC). In the present study, Wnt/β-catenin activity was characterized across a spectrum of PDAC cell lines and primary tumors. Reporter and gene expression based assays revealed wide heterogeneity in Wnt/β-catenin transcriptional activity across PDAC cell lines and patient tumors, as well as variable responsiveness to exogenous Wnt ligand stimulation. An experimentally-generated, pancreas-specific gene expression signature of Wnt/β-catenin transcriptional activation was used to stratify pathway activation across a cohort of resected, early stage PDAC tumors (N=41). In this cohort, higher Wnt/β-catenin activation was found to significantly correlate with lymphvascular invasion and worse disease specific survival (median survival time 20.3 versus 43.9 months, log rank P=0.03). Supporting the importance of Wnt ligand in mediating autocrine Wnt signaling, Wnt/β-catenin activity was significantly inhibited in PDAC cell lines by WLS gene silencing and the small molecule inhibitor IWP-2, both of which functionally block Wnt ligand processing and secretion. Transcriptional profiling revealed elevated expression of WNT7B occurred in PDAC cell lines with high levels of cell autonomous Wnt/β-catenin activity. Gene knockdown studies in AsPC-1 and HPAF-2 cell lines confirmed WNT7B mediated cell autonomous Wnt/β-catenin activation, as well as an anchorage-independent growth phenotype. Our findings indicate WNT7B can serve as a primary determinant of differential Wnt/β-catenin activation in PDAC. Disrupting the interaction between Wnt ligands and their receptors may be a particularly suitable approach for therapeutic modulation of Wnt/β-catenin signaling in PDAC and other cancer contexts where Wnt activation is mediated by ligand expression rather than mutations in canonical pathway members

WNT/β-catenin signaling regulates mitochondrial activity to alter the oncogenic potential of melanoma in a PTEN-dependent manner

Aberrant regulation of WNT/β-catenin signaling has a crucial role in the onset and progression of cancers, where the effects are not always predictable depending on tumor context. In melanoma, for example, models of the disease predict differing effects of the WNT/β-catenin pathway on metastatic progression. Understanding the processes that underpin the highly context-dependent nature of WNT/β-catenin signaling in tumors is essential to achieve maximal therapeutic benefit from WNT inhibitory compounds. In this study, we have found that expression of the tumor suppressor, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), alters the invasive potential of melanoma cells in response to WNT/β-catenin signaling, correlating with differing metabolic profiles. This alters the bioenergetic potential and mitochondrial activity of melanoma cells, triggered through regulation of pro-survival autophagy. Thus, WNT/β-catenin signaling is a regulator of catabolic processes in cancer cells, which varies depending on the metabolic requirements of tumors

Direct confirmation of the radial-velocity planet β Pictoris c

Context. Methods used to detect giant exoplanets can be broadly divided into two categories: indirect and direct. Indirect methods are more sensitive to planets with a small orbital period, whereas direct detection is more sensitive to planets orbiting at a large distance from their host star. This dichotomy makes it difficult to combine the two techniques on a single target at once. Aims: Simultaneous measurements made by direct and indirect techniques offer the possibility of determining the mass and luminosity of planets and a method of testing formation models. Here, we aim to show how long-baseline interferometric observations guided by radial-velocity can be used in such a way. Methods: We observed the recently-discovered giant planet β Pictoris c with GRAVITY, mounted on the Very Large Telescope Interferometer. Results: This study constitutes the first direct confirmation of a planet discovered through radial velocity. We find that the planet has a temperature of T = 1250 ± 50 K and a dynamical mass of M = 8.2 ± 0.8 M[SUB]Jup[/SUB]. At 18.5 ± 2.5 Myr, this puts β Pic c close to a `hot start' track, which is usually associated with formation via disk instability. Conversely, the planet orbits at a distance of 2.7 au, which is too close for disk instability to occur. The low apparent magnitude (M[SUB]K[/SUB] = 14.3 ± 0.1) favours a core accretion scenario. Conclusions: We suggest that this apparent contradiction is a sign of hot core accretion, for example, due to the mass of the planetary core or the existence of a high-temperature accretion shock during formation

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