Abstract
The NEDD8 conjugation pathway modulates the ubiquitination, stability and activity of a wide range of intracellular proteins, and its blockade by pevonedistat is emerging as a promising ...therapeutic approach in various cancer settings. However, systematic characterization of pevonedistat efficacy in specific tumor types and definition of molecular predictors of response are still missing. We investigated the in vitro sensitivity to pevonedistat in a large panel of molecularly and functionally annotated colorectal cancer (CRC) cell lines, and exploited global gene expression profiles to define a transcriptional predictor. Out of 122 tested cell lines, 16 (13%) displayed a marked response to pevonedistat, featuring DNA re-replication, proliferative block and apoptosis. Pevonedistat sensitivity did not significantly correlate with microsatellite instability or mutations in KRAS or BRAF, but was functionally associated with resistance to EGFR pathway blockade. A 184-gene transcriptional predictor generated in cell lines was applied to 87 metastatic CRC clinical samples for which patient-derived xenografts (PDX) were available. For in vivo tests, pevonedistat was provided by Millennium Pharmaceuticals, Inc., a subsidiary of Takeda Pharmaceutical Company Ltd. In vivo administration of pevonedistat did not affect the growth of any predicted resistant PDX; whereas, it significantly impaired growth of five out of six predicted sensitive models. In human CRC gene expression datasets, transcriptional prediction of pevonedistat sensitivity was associated with poor prognosis after surgery and early progression under cetuximab treatment. Histological and immunohistochemical analyses revealed that pevonedistat sensitivity signature captures transcriptional traits of poor differentiation and high-grade mucinous adenocarcinoma. These results highlight NEDD8-pathway inhibition by pevonedistat as a potentially effective strategy to treat poorly differentiated, clinically aggressive CRC and identify transcriptional and histological response predictors with possible clinical applicability.
Citation Format: Gabriele Picco, Francesco Sassi, Claudio Isella, Federica Di Nicolantonio, Anna Sapino, Alberto Bardelli, Livio Trusolino, Andrea Bertotti, Enzo Medico. NEDD8 pathway inhibition is effective in preclinical models of poorly differentiated, clinically aggressive colorectal cancer. abstract. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-213.
The authors report on high speed operation of a Ge/SiGe multiple quantum-well waveguide photodetector. At -3 V, 10 Gb/s operation is demonstrated at wavelengths of 1405 and 1420 nm with a ...responsivity as high as 0.8 A/W. The device, 3 μm wide and 80 μm long, exhibits a dark current of 474 nA at a reverse bias of -1 V. These results pave the way for the use of Ge/SiGe multiple quantum-well structures as efficient active waveguide devices in silicon compatible integrated circuits.
We target the nanofabrication of free-standing nanostructures made of epitaxial semiconductor material layers of high crystallinity quality and high heterostructure complexity for optical ...applications at the nanoscale. Here we demonstrate the fabrication method in the case of epitaxial germanium grown on a silicon substrate but the method can be applied to any heterostructure material. The nanostructures are fabricated out of planar epitaxial wafers in the form of pillars with arbitrary section and high aspect ratio by electron-beam lithography and deep reactive-ion etching. The patterned SiGe structures are then released by focused ion-beam milling of the pillar base. In this way, they become free-standing and can be relocated on a suitable substrate by using a nanomanipulator. Microscopic characterizations are ongoing to verily that the high crystal quality typical of epitaxial layers grown on a large-area substrate is preserved throughout the different fabrication steps.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Silicon-based photonics has generated a strong interest in recent years, mainly for optical interconnects and sensing on photonic integrated circuits. The main rationales of silicon photonics are the ...reduction of energy consumption and photonic system costs via integration on a standard Si chip. Waveguide-integrated silicon based-optoelectronic modulators have been particularly studied as a key building block. Ge-rich Ge/SiGe quantum well waveguides are promising for compact and low energy consumption modulators thanks to the demonstration of direct gap related optical transitions in these structures, while silicon nitride (SiN) waveguide could be a promising alternative to Si waveguide. This paper studies an integration approach between passive SiN waveguide and active Ge/SiGe multiple quantum wells (MQWs) optoelectronic modulators. Photocurrent measurements at different bias voltages demonstrated strong optical modulation within the O-band wavelength (1.26 - 1.36 µm) from Ge/SiGe MQWs, while 3D-FDTD calculations confirm a compact and efficient integration with SiN waveguide on Si wafer.
In this paper we report on the defects formed in Ge crystals grown on Si(001) pillars upon strain relaxation. The analysis is performed by high-angle annular dark-field scanning transmission electron ...microscopy. The strain relaxation happens by means of 60° and 90° misfit dislocations with Burgers vectors b→=12⟨110⟩. Misfit dislocations may split forming partial dislocations with Burgers vectors b→=16⟨112⟩, and are separated by a stacking fault. Besides, intrinsic stacking faults in different {111} planes interact and annihilate each other forming stair rod dislocations. Coherent and incoherent twin boundaries of the Σ3{111} and Σ3{112} types are also found in the Ge.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
A method for growing suspended Ge films on micron-sized Si pillars in Si(001) is discussed. In C.V. Falub et al., Science 335 (2012) 1330 vertically aligned three-dimensional Ge crystals, separated ...by a few tens of nanometers, were obtained by depositing several micrometers of Ge using Low-Energy Plasma-Enhanced Chemical Vapor Deposition. Here a different regime of high growth temperature is exploited in order to induce the merging of the crystals into a connected structure eventually forming a continuous, two-dimensional film. The mechanisms leading to such a behavior are discussed with the aid of an effective model of crystal growth. Both the effects of deposition and curvature-driven surface diffusion are considered to reproduce the main features of coalescence. The key enabling role of high temperature is identified with the activation of the diffusion process on a time scale competitive with the deposition rate. We demonstrate the versatility of the deposition process, which allows to switch between the formation of individual crystals and a continuous suspended film simply by tuning the growth temperature.
•Growth temperature permits to switch from individual crystals to suspended films.•A continuum model including both deposition and surface diffusion is discussed.•The activation of surface diffusion plays the major role in the merging process.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Background
Drug–drug interactions are a major concern in oncology and may potentially affect the outcome of patients with cancer.
Objective
In this study, we aimed to determine whether the ...concomitant use of statins, metformin, or proton pump inhibitors affects survival in patients with metastatic renal cell carcinoma treated with first-line combination therapies.
Methods
Medical records of patients with documented metastatic renal cell carcinoma between January 2016 and November 2021 were reviewed at 17 participating centers. This research was conducted in ten institutions, including both referral centers and local hospitals. Patients were assessed for overall survival, progression-free survival, and overall clinical benefit. Univariate and multivariate analyses were conducted to explore the association of variables of interest with overall survival and progression-free survival.
Results
A total of 304 patients receiving dual immunotherapy (51%) or immunotherapy/vascular endothelial growth factor-tyrosine kinase inhibitor (49%) combinations were eligible for inclusion in this retrospective study. Statin use was a significant prognostic factor for longer overall survival in a univariate analysis (hazard ratio 0.48, 95% confidence interval 0.26–0.87;
p
= 0.016) and a multivariate analysis (hazard ratio 0.48, 95% confidence interval 0.31–0.74;
p
< 0.001) and was significantly associated with an overall clinical benefit (83% in statin users vs 71% in non-users;
p
= 0.045). Otherwise, the use of metformin or proton pump inhibitors did not affect the outcome of these patients.
Conclusions
Our study suggests a prognostic impact of statin use in patients receiving first-line immuno-oncology combinations. The mechanism of this interaction warrants further elucidation.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
In this paper we present the exceptional thermal strain release provided by micrometric Si pillar arrays to Ge epitaxial patches suspended on them, for different pillar aspect ratios and patch sizes. ...By combining 3D and 2D Finite Element Method simulations, low-energy plasma-enhanced chemical vapor deposition on patterned Si substrates, μ-Raman, μ-photoluminescence and XRD measurements, we provide a quantitative and consistent picture of this effect with the patch sizes. Strain relaxation up to 85% of the value for the corresponding planar films can be obtained for a squared patch 100μm in size. Finally, the enhanced thermal strain relaxation is analytically explained in terms of the Si pillar lateral tilting, critically dependent on the pillar aspect ratio, very similarly to the well-known case of a deflected beam. Our results are transferable to any material deposited, or wafer bonded at high temperature, on any patterned substrate: wafer bowing can be controlled by micrometric patterned features well within the present capabilities of deep reactive ion etching.
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•Quantitative proof by simulations and experiments that the rotation of Si pillars sustaining a continuous Ge film is crucial.•An accurate analysis demonstrates how strain relaxation depends on pillar aspect ratio.•Quantitative indication by simulations and experiments of the role played by the array size in setting the strain relaxation.•Our continuum findings are general, valid for any heteroepitaxial system, independently of crystal orientation.•Our results are valid also for non-epitaxial films, such as polycrystalline, amorphous or wafer-bonded structures.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The integration of germanium (Ge)-rich active devices in photonic integrated circuits is challenging due to the lattice mismatch between silicon (Si) and Ge. A new Ge-rich silicon-germanium (SiGe) ...waveguide on graded buffer was investigated as a platform for integrated photonic circuits. At a wavelength of 1550 nm, low loss bends with radii as low as 12 µm and Multimode Interferometer beam splitter based on Ge-rich SiGe waveguide on graded buffer were designed, fabricated and characterized. A Mach Zehnder interferometer exhibiting a contrast of more than 10 dB has been demonstrated.
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