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Glioblastoma (GBM) is the most aggressive and invasive primary brain tumor. Current therapies are not curative, and patients' outcomes remain poor with an overall survival of 20.9 months after surgery. The typical growing pattern of GBM develops by infiltrating the surrounding apparent normal brain tissue within which the recurrence is expected to appear in the majority of cases. Thus, in the last decades, an increased interest has developed to investigate the cellular and molecular interactions between GBM and the peritumoral brain zone (PBZ) bordering the tumor tissue. The aim of this review is to provide up-to-date knowledge about the oncogenic properties of the PBZ to highlight possible druggable targets for more effective treatment of GBM by limiting the formation of recurrence, which is almost inevitable in the majority of patients. Starting from the description of the cellular components, passing through the illustration of the molecular profiles, we finally focused on more clinical aspects, represented by imaging and radiological details. The complete picture that emerges from this review could provide new input for future investigations aimed at identifying new effective strategies to eradicate this still incurable tumor.

Background: One intrastriatal administration of quinolinic acid (QA) in rats induces a lesion with features resembling those observed in Huntington's disease. Our aim is to evaluate the effects of the cysteinyl leukotriene receptor antagonist montelukast (MLK), which exhibited neuroprotection in different preclinical models of neurodegeneration, on QA-induced neuroinflammation and regional metabolic functions. Methods: The right and left striatum of Sprague Dawley and athymic nude rats were injected with QA and vehicle (VEH), respectively. Starting from the day before QA injection, animals were treated with 1 or 10 mg/kg of MLK or VEH for 14 days. At 14 and 30 days post-lesion, animals were monitored with magnetic resonance imaging (MRI) and positron emission tomography (PET) using [18F]-VC701, a translocator protein (TSPO)-specific radiotracer. Striatal neuroinflammatory response was measured post-mortem in rats treated with 1 mg/kg of MLK by immunofluorescence. Rats treated with 10 mg/kg of MLK also underwent a [18F]-FDG PET study at baseline and 4 months after lesion. [18F]-FDG PET data were then used to assess metabolic connectivity between brain regions by applying a covariance analysis method. Results: MLK treatment was not able to reduce the QA-induced increase in striatal TSPO PET signal and MRI lesion volume, where we only detected a trend towards reduction in animals treated with 10 mg/kg of MLK. Post-mortem immunofluorescence analysis revealed that MLK attenuated the increase in striatal markers of astrogliosis and activated microglia in the lesioned hemisphere. We also found a significant increase in a marker of anti-inflammatory activity (MannR) and a trend towards reduction in a marker of pro-inflammatory activity (iNOS) in the lesioned striatum of MLK-compared to VEH-treated rats. [18F]-FDG uptake was significantly reduced in the striatum and ipsilesional cortical regions of VEH-treated rats at 4 months after lesion.

Glioblastoma is the most common and aggressive brain tumor, associated with poor prognosis and survival, representing a challenging medical issue for neurooncologists. Dysregulation of histone-modifying enzymes (HDACs) is commonly identified in many tumors and has been linked to cancer proliferation, changes in metabolism, and drug resistance. These findings led to the development of HDAC inhibitors, which are limited by their narrow therapeutic index. In this work, we provide the proof of concept for a delivery system that can improve the in vivo half-life and increase the brain delivery of Givinostat, a pan-HDAC inhibitor. Here, 150-nm-sized liposomes composed of cholesterol and sphingomyelin with or without surface decoration with mApoE peptide, inhibited human glioblastoma cell growth in 2D and 3D models by inducing a time-and dose-dependent reduction in cell viability, reduction in the receptors involved in cholesterol metabolism (from −25% to −75% of protein levels), and reduction in HDAC activity (−25% within 30 min). In addition, liposome-Givinostat formulations showed a 2.5-fold increase in the drug half-life in the bloodstream and a 6-fold increase in the amount of drug entering the brain in healthy mice, without any signs of overt toxicity. These features make liposomes loaded with Givinostat valuable as potential candidates for glioblastoma therapy.

We examined effects of exposing female and male mice for 33 weeks to 45% or 60% high fat diet (HFD). Males fed with either diet were more vulnerable than females, displaying higher and faster increase in body weight and more elevated cholesterol and liver enzymes levels. Higher glucose metabolism was revealed by PET in the olfactory bulbs of both sexes. However, males also displayed altered anterior cortex and cerebellum metabolism, accompanied by a more prominent brain inflammation relative to females. Although both sexes displayed reduced transcripts of neuronal and synaptic genes in anterior cortex, only males had decreased protein levels of AMPA and NMDA receptors. Oppositely, to anterior cortex, cerebellum of HFD-exposed mice displayed hypometabolism and transcriptional up-regulation of neuronal and synaptic genes. These results indicate that male brain is more susceptible to metabolic changes induced by HFD and that the anterior cortex versus cerebellum display inverse susceptibility to HFD.

Paolo Rainone,1– 3 Antonella De Palma,4 Francesco Sudati,5 Valentina Roffia,4 Valentina Rigamonti,6 Lucia Salvioni,6 Miriam Colombo,6 Marilena Ripamonti,2 Antonello Enrico Spinelli,7 Davide Mazza,7 Pierluigi Mauri,4 Rosa Maria Moresco,1,2,7 Davide Prosperi,6 Sara Belloli2,7 1Department of Medicine and Surgery, University of Milano-Bicocca, Monza, 20900, Italy; 2Institute of Molecular Bioimaging and Physiology of CNR, Segrate, 20090, Italy; 3Doctorate School of Molecular and Translational Medicine, University of Milan, Milan, Italy; 4Institute of Biomedical Technologies of CNR, Segrate, 20090, Italy; 5PET and Nuclear Medicine Unit, San Raffaele Scientific Institute, Milan, 20132, Italy; 6NanoBioLab, Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, 20126, Italy; 7Experimental Imaging Center, San Raffaele Scientific Institute, Milan, 20132, ItalyCorrespondence: Sara BelloliInstitute of Molecular Bioimaging and Physiology of CNR, Via Fratelli Cervi 93, Segrate, 20090, ItalyTel +39 02 26433640Fax +39 02 26432717Email belloli.sara@hsr.itIntroduction: The overexpression of Human Epidermal Growth Factor Receptor 2 (HER2) is usually associated with aggressive and infiltrating breast cancer (BC) phenotype, and metastases. Functionalized silica-based nanocarriers (SiNPs) can be labeled for in vivo imaging applications and loaded with chemotherapy drugs, making possible the simultaneous noninvasive diagnosis and treatment (theranostic) for HER2-positive BC.Methods: Firstly, FITC-filled SiNPs, were engineered with two different amounts of Hc-TZ (trastuzumab half-chain) per single nanoparticle (1:2 and 1:8, SiNPs to Hc-TZ ratio), which was 99mTc-radiolabeled at histidine residues for ex vivo and in vivo biodistribution evaluations. Secondly, nanoparticles were loaded with DOX and their in vitro and ex vivo/in vivo delivery was assessed, in comparison with liposomal Doxorubicin (Caelyx). Finally, the treatment efficacy of DOX-SiNPs-TZ (1

L'elevata prevalenza di disturbi metabolici e cognitivi rappresenta uno dei maggiori problemi della salute umana. Recenti scoperte indicano che l'obesità può influenzare le funzioni cerebrali, tuttavia l'effetto di una dieta ricca di grassi sul sistema nervoso centrale non è ancora completamente compreso. Lo scopo di questo studio è la valutazione dell'influenza della dieta grassa sulla neuro infiammazione e sulla funzione cerebrale regionale in un modello murino di insulino-resistenza, con particolare attenzione alle differenze dipendenti dal sesso. I topi maschi e femmine C57BL/6J sono stati nutriti con dieta standard o dieta grassa (due tenori: 45% / 60% di grassi) per 35 settimane. Gli animali sono stati monitorati settimanalmente per analizzare le variazioni di peso corporeo, analisi ematochimiche (glucosio circolante, colesterolo totale, ALT e AST) e test di tolleranza al glucosio. Gli studi di imaging con tomografia a emissione di positroni (PET) sono stati eseguiti longitudinalmente utilizzando [18F] -FDG e [18F] -VC701 come radio-traccianti, per misurare rispettivamente il consumo di glucosio e l'attivazione di microglia / macrofagi all'interno del cervello. La risonanza magnetica (RM) e la spettroscopia a risonanza magnetica (SRM) sono state utilizzate per misurare gli effetti della dieta sul contenuto lipidico epatico e sull'accumulo di grasso peri addominale. Infine, l'analisi della trascrittomica post-mortem è stata applicata alla corteccia anteriore al fine di rivelare potenziali modifiche nell'espressione genica. La dieta grassa introduce in modo significativo un aumento del peso corporeo, della tolleranza al glucosio e dei parametri ematochimici che variano in base al sesso. Anche l'accumulo di grasso peri addominale nel maschio e il contenuto di lipidi nel fegato, come rivelato alla spettroscopia RM, sono stati osservati in tale modello. Quest'ultimo effetto è stato particolarmente evidente nelle femmine. La PET [18F]-FDG ha mostrato un aument, The high prevalence of metabolic and cognitive disorders represents one of the major issues of health systems. Recent findings indicate that obesity may affect brain functions however the effect of a high-fat diet (HFD) on the central nervous system is not fully understood. The aim of this study is the evaluation of the influence of HFD on neuroinflammation and regional brain function in a mouse model of Insulin Resistance (IR) focusing on sex-dependent differences induced by peripheral metabolic impairment. C57BL/6J male and female mice were fed with standard chow or HFD (45%/60%) for 35 weeks. Animals were monitored weekly for body weight, haemato-chemical analysis (circulating glucose, total cholesterol, ALT, and AST), and glucose tolerance test (GTT). Positron Emission Tomography (PET) imaging studies were performed longitudinally using [18F]-FDG and [18F]-VC701 as radiotracers, to measure respectively glucose consumption and microglia/macrophages activation within the brain. Magnetic Resonance Imaging (MRI) and Magnetic Resonance Spectroscopy (MRS) was used to measure the effects of diet on hepatic lipid content and peri abdominal fat accumulation. Finally, post-mortem transcriptome analysis was applied to the anterior cortex to reveal potential modification in gene expression. HFD induced a significant increase in body weight, glucose tolerance, and haemato-chemical parameter in a sex dependent manner. HFD diet increased peri abdominal fat accumulation in male and lipid content in the liver as revealed at MR spectroscopy. This last effect was particularly evident in females. PET [18F]-FDG showed a relative increase in glucose metabolism in the anterior region of the brain including the olfactory bulbs in both male and female mice while an increase in the anterior cortex was found in males mice fed with 60% HFD. Moreover, correlation analysis between glucose uptake and different metabolic biomarkers revealed, mainly in male mice, regional brain metabolic modifi

The high glycolytic activity of multiple myeloma (MM) cells is the rationale for use of Positron Emission Tomography (PET) with 18F-fluorodeoxyglucose ([18F]FDG) to detect both bone marrow (BM) and extramedullary disease. However, new tracers are actively searched because [18F]FDG-PET has some limitations and there is a portion of MM patients who are negative. Glutamine (Gln) addiction has been recently described as a typical metabolic feature of MM cells. Yet, the possible exploitation of Gln as a PET tracer in MM has never been assessed so far and is investigated in this study in preclinical models. Firstly, we have synthesized enantiopure (2S,4R)-4-fluoroglutamine (4-FGln) and validated it as a Gln transport analogue in human MM cell lines, comparing its uptake with that of 3H-labelled Gln. We then radiosynthesized [18F]4-FGln, tested its uptake in two different in vivo murine MM models, and checked the effect of Bortezomib, a proteasome inhibitor currently used in the treatment of MM. Both [18F]4-FGln and [18F]FDG clearly identified the spleen as site of MM cell colonization in C57BL/6 mice, challenged with syngeneic Vk12598 cells and assessed by PET. NOD.SCID mice, subcutaneously injected with human MM JJN3 cells, showed high values of both [18F]4-FGln and [18F]FDG uptake. Bortezomib significantly reduced the uptake of both radiopharmaceuticals in comparison with vehicle at post treatment PET. However, a reduction of glutaminolytic, but not of glycolytic, tumor volume was evident in mice showing the highest response to Bortezomib. Our data indicate that [18F](2S,4R)-4-FGln is a new PET tracer in preclinical MM models, yielding a rationale to design studies in MM patients.

Understanding the molecular mechanisms of metastatic dissemination, the leading cause of death in cancer patients, is required to develop novel, effective therapies. Extravasation, an essential rate-limiting process in the metastatic cascade, includes three tightly coordinated steps: cancer cell adhesion to the endothelium, trans-endothelial migration, and early invasion into the secondary site. Focal adhesion proteins, including Tln1 and FAK, regulate the cytoskeleton dynamics: dysregulation of these proteins is often associated with metastatic progression and poor prognosis.