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Purpose Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease leading to neuromuscular palsy and death. We propose a computational approach to [18F]-fluorodeoxyglucose (FDG) PET/CT images to analyze the structure and metabolic pattern of skeletal muscle in ALS and its relationship with disease aggressiveness. Materials and methods A computational 3D method was used to extract whole psoas muscle’s volumes and average attenuation coefficient (AAC) from CT images obtained by FDG PET/CT performed in 62 ALS patients and healthy controls. Psoas average standardized uptake value (normalized on the liver, N-SUV) and its distribution heterogeneity (defined as N-SUV variation coefficient, VC-SUV) were also extracted. Spinal cord and brain motor cortex FDG uptake were also estimated. Results As previously described, FDG uptake was significantly higher in the spinal cord and lower in the brain motor cortex, in ALS compared to controls. While psoas AAC was similar in patients and controls, in ALS a significant reduction in psoas volume (3.6 ± 1.02 vs 4.12 ± 1.33 mL/kg; p < 0.01) and increase in psoas N-SUV (0.45 ± 0.19 vs 0.29 ± 0.09; p < 0.001) were observed. Higher heterogeneity of psoas FDG uptake was also documented in ALS (VC-SUV 8 ± 4%, vs 5 ± 2%, respectively, p < 0.001) and significantly predicted overall survival at Kaplan–Meier analysis. VC-SUV prognostic power was confirmed by univariate analysis, while the multivariate Cox regression model identified the spinal cord metabolic activation as the only independent prognostic biomarker. Conclusion The present data suggest the existence of a common mechanism contributing to disease progression through the metabolic impairment of both second motor neuron and its effector.

Background The close connection between neuronal activity and glucose consumption accounts for the clinical value of 18F-fluoro-2-deoxyglucose (FDG) imaging in neurodegenerative disorders. Nevertheless, brain metabolic response to starvation (STS) might hamper the diagnostic accuracy of FDG PET/CT when the cognitive impairment results in a severe food deprivation. Methods Thirty six-week-old BALB/c female mice were divided into two groups: “control” group (n = 15) were kept under standard conditions and exposed to fasting for 6 h before the study; the remaining “STS” mice were submitted to 48 h STS (absence of food and free access to water) before imaging. In each group, nine mice were submitted to dynamic micro-PET imaging to estimate brain and skeletal muscle glucose consumption (C- and SM-MRGlu*) by Patlak approach, while six mice were sacrificed for ex vivo determination of the lumped constant, defined as the ratio between CMRGlu* and glucose consumption measured by glucose removal from the incubation medium (n = 3) or biochemical analyses (n = 3), respectively. Results CMRGlu* was lower in starved than in control mice (46.1 ± 23.3 vs 119.5 ± 40.2 nmol × min−1 × g−1, respectively, p

BACKGROUND: The close connection between neuronal activity and glucose consumption accounts for the clinical value of 18F-fluoro-2-deoxyglucose (FDG) imaging in neurodegenerative disorders. Nevertheless, brain metabolic response to starvation (STS) might hamper the diagnostic accuracy of FDG PET/CT when the cognitive impairment results in a severe food deprivation. METHODS: Thirty six-week-old BALB/c female mice were divided into two groups: "control" group (n = 15) were kept under standard conditions and exposed to fasting for 6 h before the study; the remaining "STS" mice were submitted to 48 h STS (absence of food and free access to water) before imaging. In each group, nine mice were submitted to dynamic micro-PET imaging to estimate brain and skeletal muscle glucose consumption (C- and SM-MRGlu*) by Patlak approach, while six mice were sacrificed for ex vivo determination of the lumped constant, defined as the ratio between CMRGlu* and glucose consumption measured by glucose removal from the incubation medium (n = 3) or biochemical analyses (n = 3), respectively. RESULTS: CMRGlu* was lower in starved than in control mice (46.1 ± 23.3 vs 119.5 ± 40.2 nmol × min-1 × g-1, respectively, p < 0.001). Ex vivo evaluation documented a remarkable stability of lumped constant as documented by the stability of GLUT expression, G6Pase activity, and kinetic features of hexokinase-catalyzed phosphorylation. However, brain SUV in STS mice was even (though not significantly) higher with respect to control mice. Conversely, a marked decrease in both SM-MRGlu* and SM-SUV was documented in STS mice with respect to controls. CONCLUSIONS: STS markedly decreases brain glucose consumption without altering measured FDG SUV in mouse experimental models. This apparent paradox does not reflect any change in lumped constant. Rather, it might be explained by the metabolic response of the whole body: the decrease in FDG sequestration by the skeletal muscle is as profound as to prolong tracer persistence in the bloodstream and thus its availability for brain uptake.

Background/Aim The metabolic properties of cancer cells are significantly different from those of normal cells. Energy production in cancer cells is dependent on aerobic glycolysis, fatty acid synthesis and increased rates of glutamine metabolism. Emerging evidences indicate that these features are linked to therapeutic resistance in cancer treatment. Thus, novel therapeutic strategies able to modify tumor metabolism are warranted. Aim of this study is to investigate the effects and underlying mechanisms of fasting in combination with chemotherapy on tumor metabolism. Methods The in vitro citotoxicity of chemodrugs in combination with short-term-starvation (STS) was tested in various colon cancer cell lines by Trypan Blue staining and Annexin V apoptosis assay. Cancer cell proliferation by BrdUdr and CFSE staining was also evaluated. Reactive oxygen species production were evaluated by DCFDA staining. The effects of STS on the regulation of tumor metabolism were evaluated by 2-[(18)F]-Fluoro-2-deoxyglucose uptake. Expression of different proteins involved in metabolic and signaling pathways were studied by western blot and proteomic analyses. In vivo studies were performed using syngeneic BALB/c mice which were subcutaneously injected with CT26 cells. The in vivo STS protocol allowed mice to consume water but not food for 48 hours before chemotherapy. All mice were monitored daily for weight loss and side effects. Tumor growth was monitored every two days by caliper. The effects of STS in combination with chemotherapy (CT), in terms of glucose uptake/consumption and tumor growth inhibition were also evaluated by dynamic micro-Positron Emission Tomography (micro-PET). Results In vitro experiments showed that STS+CT maximally reduced cell viability and glucose uptake. A metabolic switch from anaerobic glycolysis to oxidative phosphorilation (OXPHOSPH) and beta-lipidic oxidation was induced by STS+CT. Down-regulation of PI3K/AKT pathway by STS+CT was found to be involved in the reduction of different glycolytic enzymes including hexokinases, phosphofructokinase and piruvate kinase. Furthermore, tumor cells treated with STS+CT exhibited a significant induction of respiratory chain complexes I, III, IV associated to a striking uncoupling between oxygen consumption which was induced and ATP synthesis that was reduced. This latter event was related to significant increase of ROS generation by STS+CT, leading to tumor cell apoptosis. Accordingly, in vivo experiments demonstrated that STS in combination with high-dose CT maximally reduced tumor glucose consumption in parallel with tumor cell growth. Conclusions Taken together, these results demonstrated that STS+CT affected tumor metabolism leading to a significant decrease of tumor growth. These findings open a novel scenario in cancer treatment. Citation Format: Giovanna Bianchi, Roberto Martella, Silvia Ravera, Andrea Petretto, Danilo Marimpietri, Laura Emionite, Selene Capitanio, Gianluca Bottone, Annamaria Orengo, Cecilia Marini, Gianmario Sambuceti, Vito Pistoia, Valter D. Longo, Lizzia Raffaghello. Fasting chemosensitizes tumor cells by affecting their metabolism. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3374. doi:10.1158/1538-7445.AM2014-3374

// Giovanna Bianchi 1,* , Roberto Martella 1,* , Silvia Ravera 2 , Cecilia Marini 3 , Selene Capitanio 4 , Annamaria Orengo 4 , Laura Emionite 5 , Chiara Lavarello 6 , Adriana Amaro 7 , Andrea Petretto 6 , Ulrich Pfeffer 7 , Gianmario Sambuceti 4 , Vito Pistoia 1 , Lizzia Raffaghello 1,** and Valter D. Longo 8,9,10,** 1 Laboratorio di Oncologia Istituto G. Gaslini, Genoa, Italy 2 Department of Pharmacy, University of Genoa, Genova, Italy 3 CNR Institute of Bioimages and Molecular Physiology, Milan, Section of Genoa, Genoa, Italy 4 Nuclear Medicine Unit, Department of Health Sciences, University of Genoa and IRCCS AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy 5 Animal facility, IRCCS AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy 6 Core Facility, Istituto G. Gaslini, Genoa, Italy 7 Functional Genomics, IRCCS AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy 8 Longevity Institute, School of Gerontology, Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA 9 Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA 10 IFOM, FIRC Institute of Molecular Oncology, Milan, Italy * These authors have contributed equally as first authors ** These authors have contributed equally as last authors Correspondence to: Valter D. Longo, email: // Keywords : fasting, Warburg effect, colon cancer, oxidative phosphorylation, glucose uptake Received : March 04, 2015 Accepted : March 11, 2015 Published : March 30, 2015 Abstract Tumor chemoresistance is associated with high aerobic glycolysis rates and reduced oxidative phosphorylation, a phenomenon called “Warburg effect” whose reversal could impair the ability of a wide range of cancer cells to survive in the presence or absence of chemotherapy. In previous studies, Short-term-starvation (STS) was shown to protect normal cells and organs but to sensitize different cancer cell types to chemotherapy but the mechanisms responsible for these effects are poorly understood. We tested the cytotoxicity of Oxaliplatin (OXP) combined with a 48hour STS on the progression of CT26 colorectal tumors. STS potentiated the effects of OXP on the suppression of colon carcinoma growth and glucose uptake in both in vitro and in vivo models. In CT26 cells, STS down-regulated aerobic glycolysis, and glutaminolysis, while increasing oxidative phosphorylation. The STS-dependent increase in both Complex I and Complex II-dependent O 2 consumption was associated with increased oxidative stress and reduced ATP synthesis. Chemotherapy caused additional toxicity, which was associated with increased succinate/Complex II-dependent O 2 consumption, elevated oxidative stress and apoptosis . These findings indicate that the glucose and amino acid deficiency conditions imposed by STS promote an anti-Warburg effect characterized by increased oxygen consumption but failure to generate ATP, resulting in oxidative damage and apoptosis.