Pathogenetic, Prognostic, and Therapeutic Role of Fatty Acid Synthase in Human Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is one of the most common solid tumors worldwide, characterized by clinical aggressiveness, resistance to conventional chemotherapy, and high lethality. Consequently, there is an urgent need to better delineate the molecular pathogenesis of HCC to develop new preventive and therapeutic strategies against this deadly disease. Noticeably, emerging evidence indicates that proteins involved in lipid biosynthesis are important mediators along the development and progression of HCC in humans and rodents. Here, we provide a comprehensive overview of: (a) The pathogenetic relevance of lipogenic proteins involved in liver carcinogenesis, with a special emphasis on the master fatty acid regulator, fatty acid synthase (FASN); (b) The molecular mechanisms responsible for unrestrained activation of FASN and related fatty acid biosynthesis in HCC; (c) The findings in experimental mouse models of liver cancer and their possible clinical implications; (d) The existing potential therapies targeting FASN. A consistent body of data indicates that elevated levels of lipogenic proteins, including FASN, characterize human hepatocarcinogenesis and are predictive of poor prognosis of HCC patients. Pharmacological or genetic blockade of FASN is highly detrimental for the growth of HCC cells in both in vitro and in vivo models. In conclusion, FASN is involved in the molecular pathogenesis of HCC, where it plays a pivotal role both in tumor onset and progression. Thus, targeted inhibition of FASN and related lipogenesis could be a potentially relevant treatment for human HCC. Introduction: Human Hepatocellular Carcinom

Polimeri conduttori e metallopolimeri redox

Il nostro gruppo di ricerca è da anni attivo nella sintesi e caratterizzazione elettrochimica di polimeri conduttori a base tiofenica. In particolare la nostra attenzione è rivolta verso materiali costituiti da un backbone di tipo tertiofenico, che consente la polimerizzazione nelle posizioni 2 e 5, e da unità chelanti all’azoto, (terpiridine o fenantroline), che possono consentire la coordinazione con metalli di transizione all’interno del polimero ed incrementarne ulteriormente le proprietà conduttive

DNA-based Self-Assembly of Chiral Plasmonic Nanostructures with Tailored Optical Response

Surface plasmon resonances generated in metallic nanostructures can be utilized to tailor electromagnetic fields. The precise spatial arrangement of such structures can result in surprising optical properties that are not found in any naturally occurring material. Here, the designed activity emerges from collective effects of singular components equipped with limited individual functionality. Top-down fabrication of plasmonic materials with a predesigned optical response in the visible range by conventional lithographic methods has remained challenging due to their limited resolution, the complexity of scaling, and the difficulty to extend these techniques to three-dimensional architectures. Molecular self-assembly provides an alternative route to create such materials which is not bound by the above limitations. We demonstrate how the DNA origami method can be used to produce plasmonic materials with a tailored optical response at visible wavelengths. Harnessing the assembly power of 3D DNA origami, we arranged metal nanoparticles with a spatial accuracy of 2 nm into nanoscale helices. The helical structures assemble in solution in a massively parallel fashion and with near quantitative yields. As a designed optical response, we generated giant circular dichroism and optical rotary dispersion in the visible range that originates from the collective plasmon-plasmon interactions within the nanohelices. We also show that the optical response can be tuned through the visible spectrum by changing the composition of the metal nanoparticles. The observed effects are independent of the direction of the incident light and can be switched by design between left- and right-handed orientation. Our work demonstrates the production of complex bulk materials from precisely designed nanoscopic assemblies and highlights the potential of DNA self-assembly for the fabrication of plasmonic nanostructures.Comment: 5 pages, 4 figure

The Hippo pathway effector TAZ induces intrahepatic cholangiocarcinoma in mice and is ubiquitously activated in the human disease

Background Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive primary liver tumor with increasing incidence worldwide, dismal prognosis, and few therapeutic options. Mounting evidence underlines the role of the Hippo pathway in this disease; however, the molecular mechanisms whereby the Hippo cascade contributes to cholangiocarcinogenesis remain poorly defined. Methods We established novel iCCA mouse models via hydrodynamic transfection of an activated form of transcriptional coactivator with PDZ-binding motif (TAZ), a Hippo pathway downstream effector, either alone or combined with the myristoylated AKT (myr-AKT) protooncogene, in the mouse liver. Hematoxylin and eosin staining, immunohistochemistry, electron microscopy, and quantitative real-time RT-PCR were applied to characterize the models. In addition, in vitro cell line studies were conducted to address the growth-promoting roles of TAZ and its paralog YAP. Results Overexpression of TAZ in the mouse liver triggered iCCA development with very low incidence and long latency. In contrast, co-expression of TAZ and myr-AKT dramatically increased tumor frequency and accelerated cancer formation in mice, with 100% iCCA incidence and high tumor burden by 10 weeks post hydrodynamic injection. AKT/TAZ tumors faithfully recapitulated many of the histomolecular features of human iCCA. At the molecular level, the development of the cholangiocellular lesions depended on the binding of TAZ to TEAD transcription factors. In addition, inhibition of the Notch pathway did not hamper carcinogenesis but suppressed the cholangiocellular phenotype of AKT/TAZ tumors. Also, knockdown of YAP, the TAZ paralog, delayed cholangiocarcinogenesis in AKT/TAZ mice without affecting the tumor phenotype. Furthermore, human preinvasive and invasive iCCAs and mixed hepatocellular carcinoma/iCCA displayed widespread TAZ activation and downregulation of the mechanisms protecting TAZ from proteolysis. Conclusions Overall, the present data underscore the crucial role of TAZ in cholangiocarcinogenesi

Cosmology with the Laser Interferometer Space Antenna

254 pags:, 44 figs.The Laser Interferometer Space Antenna (LISA) has two scientific objectives of cosmological focus: to probe the expansion rate of the universe, and to understand stochastic gravitational-wave backgrounds and their implications for early universe and particle physics, from the MeV to the Planck scale. However, the range of potential cosmological applications of gravitational-wave observations extends well beyond these two objectives. This publication presents a summary of the state of the art in LISA cosmology, theory and methods, and identifies new opportunities to use gravitational-wave observations by LISA to probe the universe.This work is partly supported by: A.G. Leventis Foundation; Academy of Finland Grants 328958 and 345070; Alexander S. Onassis Foundation, Scholarship ID: FZO 059-1/2018-2019; Amaldi Research Center funded by the MIUR program “Dipartimento di Eccellenza” (CUP: B81I18001170001); ASI Grants No. 2016-24-H.0 and No. 2016-24-H.1-2018; Atracción de Talento Grant 2019-T1/TIC-15784; Atracción de Talento contract no. 2019-T1/TIC-13177 granted by the Comunidad de Madrid; Ayuda ‘Beatriz Galindo Senior’ by the Spanish ‘Ministerio de Universidades’, Grant BG20/00228; Basque Government Grant (IT-979-16); Belgian Francqui Foundation; Centre national d’Etudes spatiales; Ben Gurion University Kreitman Fellowship, and the Israel Academy of Sciences and Humanities (IASH) & Council for Higher Education (CHE) Excellence Fellowship Program for International Postdoctoral Researchers; Centro de Excelencia Severo Ochoa Program SEV-2016-0597; CERCA program of the Generalitat de Catalunya; Cluster of Excellence “Precision Physics, Fundamental Interactions, and Structure of Matter” (PRISMA? EXC 2118/1); Comunidad de Madrid, Contrato de Atracción de Talento 2017-T1/TIC-5520; Czech Science Foundation GAČR, Grant No. 21-16583M; Delta ITP consortium; Department of Energy under Grant No. DE-SC0008541, DE-SC0009919 and DESC0019195; Deutsche Forschungsgemeinschaft (DFG), Project ID 438947057; Deutsche Forschungsgemeinschaft under Germany’s Excellence Strategy - EXC 2121 Quantum Universe - 390833306; European Structural and Investment Funds and the Czech Ministry of Education, Youth and Sports (Project CoGraDS - CZ.02.1.01/0.0/0.0/15 003/0000437); European Union’s H2020 ERC Consolidator Grant “GRavity from Astrophysical to Microscopic Scales” (Grant No. GRAMS-815673); European Union’s H2020 ERC, Starting Grant Agreement No. DarkGRA-757480; European Union’s Horizon 2020 programme under the Marie Sklodowska-Curie Grant Agreement 860881 (ITN HIDDeN); European Union’s Horizon 2020 Research and Innovation Programme Grant No. 796961, “AxiBAU” (K.S.); European Union’s Horizon 2020 Research Council grant 724659 MassiveCosmo ERC-2016-COG; FCT through national funds (PTDC/FIS-PAR/31938/2017) and through project “BEYLA – BEYond LAmbda” with Ref. Number PTDC/FIS-AST/0054/2021; FEDER-Fundo Europeu de Desenvolvimento Regional through COMPETE2020 - Programa Operacional Competitividade e Internacionalização (POCI-01-0145- FEDER-031938) and research Grants UIDB/04434/2020 and UIDP/04434/2020; Fondation CFM pour la Recherche in France; Foundation for Education and European Culture in Greece; French ANR project MMUniverse (ANR-19-CE31-0020); FRIA Grant No.1.E.070.19F of the Belgian Fund for Research, F.R. S.-FNRS Fundação para a Ciência e a Tecnologia (FCT) through Contract No. DL 57/2016/CP1364/ CT0001; Fundação para a Ciência e a Tecnologia (FCT) through Grants UIDB/04434/2020, UIDP/04434/ 2020, PTDC/FIS-OUT/29048/2017, CERN/FIS-PAR/0037/2019 and “CosmoTests – Cosmological tests of gravity theories beyond General Relativity” CEECIND/00017/2018; Generalitat Valenciana Grant PROMETEO/2021/083; Grant No. 758792, project GEODESI; Government of Canada through the Department of Innovation, Science and Economic Development and Province of Ontario through the Ministry of Colleges and Universities; Grants-in-Aid for JSPS Overseas Research Fellow (No. 201960698); I?D Grant PID2020-118159GB-C41 of the Spanish Ministry of Science and Innovation; INFN iniziativa specifica TEONGRAV; Israel Science Foundation (Grant No. 2562/20); Japan Society for the Promotion of Science (JSPS) KAKENHI Grant Nos. 20H01899 and 20H05853; IFT Centro de Excelencia Severo Ochoa Grant SEV-2; Kavli Foundation and its founder Fred Kavli; Minerva Foundation; Ministerio de Ciencia e Innovacion Grant PID2020-113644GB-I00; NASA Grant 80NSSC19K0318; NASA Hubble Fellowship grants No. HST-HF2-51452.001-A awarded by the Space Telescope Science Institute with NASA contract NAS5-26555; Netherlands Organisation for Science and Research (NWO) Grant Number 680-91-119; new faculty seed start-up grant of the Indian Institute of Science, Bangalore, the Core Research Grant CRG/2018/002200 of the Science and Engineering; NSF Grants PHY-1820675, PHY-2006645 and PHY-2011997; Polish National Science Center Grant 2018/31/D/ ST2/02048; Polish National Agency for Academic Exchange within the Polish Returns Programme under Agreement PPN/PPO/2020/1/00013/U/00001; Pró-Reitoria de Pesquisa of Universidade Federal de Minas Gerais (UFMG) under Grant No. 28359; Ramón y Cajal Fellowship contract RYC-2017-23493; Research Project PGC2018-094773-B-C32 [MINECO-FEDER]; Research Project PGC2018-094773-B-C32 [MINECO-FEDER]; ROMFORSK Grant Project. No. 302640; Royal Society Grant URF/R1/180009 and ERC StG 949572: SHADE; Shota Rustaveli National Science Foundation (SRNSF) of Georgia (Grant FR/18-1462); Simons Foundation/SFARI 560536; SNSF Ambizione grant; SNSF professorship Grant (No. 170547); Spanish MINECO’s “Centro de Excelencia Severo Ochoa” Programme Grants SEV-2016- 0597 and PID2019-110058GB-C22; Spanish Ministry MCIU/AEI/FEDER Grant (PGC2018-094626-BC21); Spanish Ministry of Science and Innovation (PID2020-115845GB-I00/AEI/10.13039/ 501100011033); Spanish Proyectos de I?D via Grant PGC2018-096646-A-I00; STFC Consolidated Grant ST/T000732/1; STFC Consolidated Grants ST/P000762/1 and ST/T000791/1; STFC Grant ST/ S000550/1; STFC Grant ST/T000813/1; STFC Grants ST/P000762/1 and ST/T000791/1; STFC under the research Grant ST/P000258/1; Swiss National Science Foundation (SNSF), project The Non-Gaussian Universe and Cosmological Symmetries, Project Number: 200020-178787; Swiss National Science Foundation Professorship Grants No. 170547 and No. 191957; SwissMap National Center for Competence in Research; “The Dark Universe: A Synergic Multi-messenger Approach” Number 2017X7X85K under the MIUR program PRIN 2017; UK Space Agency; UKSA Flagship Project, Euclid.Peer reviewe

Search for eccentric black hole coalescences during the third observing run of LIGO and Virgo

Despite the growing number of confident binary black hole coalescences observed through gravitational waves so far, the astrophysical origin of these binaries remains uncertain. Orbital eccentricity is one of the clearest tracers of binary formation channels. Identifying binary eccentricity, however, remains challenging due to the limited availability of gravitational waveforms that include effects of eccentricity. Here, we present observational results for a waveform-independent search sensitive to eccentric black hole coalescences, covering the third observing run (O3) of the LIGO and Virgo detectors. We identified no new high-significance candidates beyond those that were already identified with searches focusing on quasi-circular binaries. We determine the sensitivity of our search to high-mass (total mass M>70 M⊙) binaries covering eccentricities up to 0.3 at 15 Hz orbital frequency, and use this to compare model predictions to search results. Assuming all detections are indeed quasi-circular, for our fiducial population model, we place an upper limit for the merger rate density of high-mass binaries with eccentricities 0<e≤0.3 at 0.33 Gpc−3 yr−1 at 90\% confidence level

Search for gravitational-lensing signatures in the full third observing run of the LIGO-Virgo network

Gravitational lensing by massive objects along the line of sight to the source causes distortions of gravitational wave-signals; such distortions may reveal information about fundamental physics, cosmology and astrophysics. In this work, we have extended the search for lensing signatures to all binary black hole events from the third observing run of the LIGO--Virgo network. We search for repeated signals from strong lensing by 1) performing targeted searches for subthreshold signals, 2) calculating the degree of overlap amongst the intrinsic parameters and sky location of pairs of signals, 3) comparing the similarities of the spectrograms amongst pairs of signals, and 4) performing dual-signal Bayesian analysis that takes into account selection effects and astrophysical knowledge. We also search for distortions to the gravitational waveform caused by 1) frequency-independent phase shifts in strongly lensed images, and 2) frequency-dependent modulation of the amplitude and phase due to point masses. None of these searches yields significant evidence for lensing. Finally, we use the non-detection of gravitational-wave lensing to constrain the lensing rate based on the latest merger-rate estimates and the fraction of dark matter composed of compact objects

Ultralight vector dark matter search using data from the KAGRA O3GK run

Among the various candidates for dark matter (DM), ultralight vector DM can be probed by laser interferometric gravitational wave detectors through the measurement of oscillating length changes in the arm cavities. In this context, KAGRA has a unique feature due to differing compositions of its mirrors, enhancing the signal of vector DM in the length change in the auxiliary channels. Here we present the result of a search for U(1)B−L gauge boson DM using the KAGRA data from auxiliary length channels during the first joint observation run together with GEO600. By applying our search pipeline, which takes into account the stochastic nature of ultralight DM, upper bounds on the coupling strength between the U(1)B−L gauge boson and ordinary matter are obtained for a range of DM masses. While our constraints are less stringent than those derived from previous experiments, this study demonstrates the applicability of our method to the lower-mass vector DM search, which is made difficult in this measurement by the short observation time compared to the auto-correlation time scale of DM