High-Fat Diet Leads to Reduced Protein O-GlcNAcylation and Mitochondrial Defects Promoting the Development of Alzheimer’s Disease Signatures

The disturbance of protein O-GlcNAcylation is emerging as a possible link between altered brain metabolism and the progression of neurodegeneration. As observed in brains with Alzheimer’s disease (AD), flaws of the cerebral glucose uptake translate into reduced protein O-GlcNAcylation, which promote the formation of pathological hallmarks. A high-fat diet (HFD) is known to foster metabolic dysregulation and insulin resistance in the brain and such effects have been associated with the reduction of cognitive performances. Remarkably, a significant role in HFD-related cognitive decline might be played by aberrant protein O-GlcNAcylation by triggering the development of AD signature and mitochondrial impairment. Our data support the impairment of total protein O-GlcNAcylation profile both in the brain of mice subjected to a 6-week high-fat-diet (HFD) and in our in vitro transposition on SH-SY5Y cells. The reduction of protein O-GlcNAcylation was associated with the development of insulin resistance, induced by overfeeding (i.e., defective insulin signaling and reduced mitochondrial activity), which promoted the dysregulation of the hexosamine biosynthetic pathway (HBP) flux, through the AMPK-driven reduction of GFAT1 activation. Further, we observed that a HFD induced the selective impairment of O-GlcNAcylated-tau and of O-GlcNAcylated-Complex I subunit NDUFB8, thus resulting in tau toxicity and reduced respiratory chain functionality respectively, highlighting the involvement of this posttranslational modification in the neurodegenerative process.     

Trastuzumab Deruxtecan: Changing the Destiny of HER2 Expressing Solid Tumors

HER2 targeted therapies have significantly improved prognosis of HER2-positive breast and gastric cancer. HER2 overexpression and mutation is the pathogenic driver in non-small cell lung cancer (NSCLC) and colorectal cancer, however, to date, there are no approved HER2-targeted therapies with these indications. Trastuzumab deruxtecan (T-DXd) is a novel HER2-directed antibody drug conjugate showing significant anti-tumor activity in heavily pre-treated HER2-positive breast and gastric cancer patients. Preliminary data have shown promising objective response rates in patients with HER2-positive NSCLC and colorectal cancer. T-DXd has an acceptable safety profile, however with concerns regarding potentially serious treatment-emergent adverse events. In this review we focus on the pharmacologic characteristics and toxicity profile of T-Dxd, and provide an update on the most recent results of clinical trials of T-DXd in solid tumors. The referenced papers were selected through a PubMed search performed on 16 March 2021 with the following searching terms: T-DXd and breast cancer, or gastric cancer, or non-small cell lung cancer (NSCLC), or colorectal cancer. Oral presentation, abstracts, and posters presented at the American Society of Clinical Oncology (ASCO, Alexandria, VA, USA) 2020 and the European Society for Medical Oncology (ESMO, Lugano, Switzerland) 2020 annual meetings were retrieved for data on T-DXd. We also overview ongoing research and data of combination therapies currently under investigation, which will impact on future therapeutic strategies. Clinicaltrials.gov was searched to identify ongoing clinical trials of T-DXd alone or in combination in solid tumors.     

The AFLATOX® Project: Approaching the Development of New Generation,Natural-Based Compounds for the Containment of the Mycotoxigenic Phytopathogen Aspergillus flavus and Aflatoxin Contamination

The control of the fungal contamination on crops is considered a priority by the sanitary authorities of an increasing number of countries, and this is also due to the fact that the geographic areas interested in mycotoxin outbreaks are widening. Among the different pre- and post-harvest strategies that may be applied to prevent fungal and/or aflatoxin contamination, fungicides still play a prominent role; however, despite of countless efforts, to date the problem of food and feed contamination remains unsolved, since the essential factors that affect aflatoxins production are various and hardly to handle as a whole. In this scenario, the exploitation of bioactive natural sources to obtain new agents presenting novel mechanisms of action may represent a successful strategy to minimize, at the same time, aflatoxin contamination and the use of toxic pesticides. The Aflatox^® Project was aimed at the development of new-generation inhibitors of aflatoxigenic Aspergillus spp. proliferation and toxin production, through the modification of naturally occurring molecules: a panel of 177 compounds, belonging to the thiosemicarbazones class, have been synthesized and screened for their antifungal and anti-aflatoxigenic potential. The most effective compounds, selected as the best candidates as aflatoxin containment agents, were also evaluated in terms of cytotoxicity, genotoxicity and epi-genotoxicity to exclude potential harmful effect on the human health, the plants on which fungi grow and the whole ecosystem.     

A hybrid dynamic motion prediction method for multibody digital human models based on a motion database and motion knowledge

In this paper, we present a novel method to predict human motion, seeking to combine the advantages of both data-based and knowledge-based motion prediction methods. Our method relies on a database of captured motions for reference and introduces knowledge in the prediction in the form of a motion control law, which is followed while resembling the actually performed reference motion. The prediction is carried out by solving an optimization problem in which the following conditions are imposed to the motion: must fulfill the goals of the task; resemble the reference motion selected from the database; follow a knowledge-based dynamic motion control law; and ensure the dynamic equilibrium of the human model, considering its interactions with the environment. In this work, we apply the proposed method to a database of clutch pedal depression motions, and we present the results for three predictions. The method is validated by comparing the results of the prediction to motions actually performed in similar conditions. The predicted motions closely resemble the motions in the validation database and no significant differences have been noted either in the motion’s kinematics or in the motion’s dynamics.     

Recommending multimedia visiting paths in cultural heritage applications

The valorization and promotion of worldwide Cultural Heritage by the adoption of Information and Communication Technologies represent nowadays some of the most important research issues with a large variety of potential applications. This challenge is particularly perceived in the Italian scenario, where the artistic patrimony is one of the most diverse and rich of the world, able to attract millions of visitors every year to monuments, archaeological sites and museums. In this paper, we present a general recommendation framework able to uniformly manage heterogeneous multimedia data coming from several web repositories and to provide context-aware recommendation techniques supporting intelligent multimedia services for the users—i.e. dynamic visiting paths for a given environment. Specific applications of our system within the cultural heritage domain are proposed by means of real case studies in the mobile environment related both to an outdoor and indoor scenario, together with some results on user’s satisfaction and system accuracy.     

Gingival recession and exposure of barrier membrane: effect on guided tissue regeneration of Class II furcation defects

The purpose of the present study was to evaluate the effect of barrier membrane exposure on the success of guided tissue regeneration in Class II furcation defects. Twenty-six subjects with mandibular Class II furcation defects received initial periodontal therapy followed by guided tissue regeneration surgery. The membrane was placed and the flaps were repositioned so that the membrane was totally submerged. Membranes were removed 4 to 6 weeks later, at which time the extent of their exposure was recorded. An overall improvement in all clinical parameters was observed for all subjects 1 year after surgery. Half of the patients had experienced no membrane exposure, while the other 13 subjects had experienced mild to pronounced exposure; both groups showed similar improvement in all clinical and surgical parameters. In light of the comparable results obtained in exposed sites, and the anatomic difficulties sometimes encountered in covering a membrane completely, in some of these cases the membrane may be left only partially submerged. This approach will allow for tighter occlusal "seal" of the tooth-membrane interface and preservation of the keratinized gingiva.     

Sorafenib delivery nanoplatform based on superparamagnetic iron oxide nanoparticles magnetically targets hepatocellular carcinoma

Currently,sorafenib is the only systemic therapy capable of increasing overall survival of hepatocellular carcinoma patients.Unfortunately,its side effects,particularly its overall toxicity,limit the therapeutic response that can be achieved.Superparamagnetic iron oxide nanoparticles (SPIONs) are very attractive for drug delivery because they can be targeted to specific sites in the body through application of a magnetic field,thus improving intratumoral accumulation and reducing adverse effects.Here,nanoformulations based on polyethylene glycol modified phospholipid micelles,loaded with both SPIONs and sorafenib,were successfully prepared and thoroughly investigated by complementary techniques.This nanovector system provided effective drug delivery,had an average hydrodynamic diameter of about 125 nm,had good stability in aqueous medium,and allowed controlled drug loading.Magnetic analysis allowed accurate determination of the amount of SPIONs embedded in each micelle.An in vitro system was designed to test whether the SPION micelles can be efficiently held using a magnetic field under typical flow conditions found in the human liver.Human hepatocellular carcinoma (HepG2) cells were selected as an in vitro system to evaluate tumor cell targeting efficacy of the superparamagnetic micelles loaded with sorafenib.These experiments demonstrated that this delivery platform is able to enhance sorafenib's antitumor effectiveness by magnetic targeting.The magnetic nanovectors described here represent promising candidates for targeting specific hepatic tumor sites,where selective release of sorafenib can improve its efficacy and safety profile.     

Preface: Volume 16, Issue 2

This volume contains the Proceedings of the fifth EXPRESS workshop. The workshop was held in Nice, France, on 7 September 1998, as a satellite event to CONCUR '98.The EXPRESS workshops aim at bringing together researchers interested in the relations between various formal systems, particularly in the field of Concurrency. More specifically, they focus on the comparison between programming concepts (such as concurrent, functional, imperative, logic and object-oriented programming) and between mathematical models of computation (such as process algebras, Petri nets, event structures, modal logics, rewrite systems etc.) on the basis of their relative expressive power.These workshops were originally held as meetings of the HCM project EXPRESS, which has been active with the same focus from January 1994 till December 1997. The first three workshops were held respectively in Amsterdam (1994, chaired by Frits Vaandrager), Tarquinia (1995, chaired by Rocco de Nicola), and Dagstuhl (1996, chaired by Ursula Goltz, Frits Vaandrager and Rocco de Nicola). The fourth workshop, which took place in Santa Margherita Ligure in 1997 and was co-chaired by Catuscia Palamidessi and Joachim Parrow, was organized as a conference with a call for papers and a significant attendance from outside the project. The fifth workshop, EXPRESS '98, was again organised as a (one day) conference, and was also meant as an occasion to discuss on the inheritance of the Express project and possible directions of future research. We had 17 submissions, out of which we selected 7 for inclusion in these proceedings (41%). Additionally, this collection contains the contribution of the two invited speakers, Matthew Hennessy (University of Sussex, UK) and P.S. Thiagarajan (SPIC Mathematical Institute, IN).We would like to thank the authors of the submitted papers, the invited speakers, and the members of the program committee for their contribution to both the meeting and this volume. We also would like to thank INRIA for their help with the local organization, and Michael Mislove for his help with the editing of the proceedings.

EXPRESS '98 Programme Committee
Ilaria Castellani (co-chair, INRIA)	Catuscia Palamidessi (co-chair, PSU)
Luca Aceto (Aalborg Univ.)	Roberto Amadio (Univ. Marseille)
Eike Best (Oldenburg Univ.)	Steve Brookes (CMU)
Philippe Darondeau (INRIA)	Rocco De Nicola (Univ. Firenze)
Jan Willem Klop (CWI)	Patrick Lincoln (SRI)
Frits Vaandrager (Nijmegen Univ.)	Glynn Winskel (Aarhus Univ.)

Full-size table

17 October 1998, Ilaria Castellani and Catuscia Palamidessi