Increased Glucose Metabolism Research Articles

Dihydromyricetin Ameliorates 3NP-induced Behavioral Deficits and Striatal Injury in Rats

Oxidative stress is closely involved in neurodegenerative diseases. The present study aimed to examine the effect of anti-oxidant DHM (dihydromyricetin) on 3NP (3-nitropropionic acid) -induced behavioral deficits of experimental rats and striatal histopathological injury by using behavioral, imaging, biochemistry, histochemistry and molecular biology technologies. The experimental results showed that both motor dysfunctions and learning and memory impairments induced by 3NP were significantly reduced after DHM treatment. 3NP-induced striatal metabolic abnormality was also remarkably improved by DHM treatment, showed as the increased glucose metabolism in PET/CT scan, decreased MDA (malondialdehyde) and increased SOD (superoxide dismutase) activity in enzyme histochemical staining. In addition, the cell apoptosis was evidently detected in the striatum of the 3NP group, while in the 3NP + DHM group, the number of apoptotic cells was remarkably reduced. 3NP treatment obviously induced down-regulation of Bcl-2, and up-regulations of Bax and Cleaved Caspase-3, while these changes were significantly reversed by DHM treatment. The present results suggested that DHM showed its protective effect by anti-oxidant and anti-apoptosis mechanisms.

Karin Bornfeldt

Karin Bornfeldt is stubborn. Once she gets curious about something, she does not let it go—turning questions around in her head, examining the issue from varying perspectives, thinking about alternative solutions, and applying a variety of tools to the problem. The question that sparked Bornfeldt’s curiosity during her PhD research at the University of Linkoping was how diabetes mellitus accelerates atherosclerosis. She has never lost interest, and in 3 decades of research, she has worked to uncomplicate the most deadly of diabetic complications. Bornfeldt, joint professor of medicine and pathology at the University of Washington in Seattle, arrived at the university in 1991 as a postdoc to work with Russell Ross, PhD, and Edwin Krebs, MD. She joined the faculty in 1995 and is now associate director of the Diabetes and Obesity Center of Excellence, deputy director of the Diabetes Research Center, and director of the Viral Vector and Transgenic Mouse Core at the university. Karin Bornfeldt When Bornfeldt established her independent laboratory in 1997, she recognized the need for a mouse model of diabetes mellitus–accelerated atherosclerosis that could separate the effects of diabetes mellitus per se from the effects of diabetes mellitus–induced hyperlipidemia. The laboratory created a transgenic mouse that develops type 1 diabetes mellitus in a process similar to that of type 1 in humans, with viral infection inducing T-cell–mediated destruction of beta cells, and also develops atherosclerosis. Using that model, the team showed that, even with no lipid abnormalities or cholesterol in the diet, diabetes mellitus accelerates the initiation of atherosclerotic lesions by stimulating macrophage accumulation within the vascular wall. In contrast, when the mice are fed a cholesterol-rich diet and then given diabetes mellitus, they develop severe hypertriglyceridemia and advanced atherosclerotic plaques.1 Later, when the team induced type 1 diabetes mellitus in mice after they …

Increased Expression of the Glucose Transporter Type 1 Gene Is Associated With Worse Overall Survival in Resected Pancreatic Adenocarcinoma.

There is currently no reliable method to predict the risk of relapse after curative resection of early-stage pancreatic adenocarcinoma. Increased glucose metabolism observed on F-fluorodeoxyglucose positron emission tomography (PET) by malignant cells, the Warburg effect, is a well-known characteristic of the malignant phenotype. We investigated the role of glucose transporter type 1 (GLUT-1) gene expression, a glucose cell plasma membrane transporter, in early-stage pancreatic cancer. Associations between GLUT-1 gene expression with PET maximum standardized uptake values and histologic grade were investigated in early-stage pancreatic adenocarcinoma patients. Multivariate analysis was conducted to determine predictors of prognosis. Cox proportional hazard model was used for survival analysis. Sixty-three patients had GLUT-1 gene analysis performed, and 50 patients had both GLUT-1 analysis and PET scan. Patients with high GLUT-1 gene expression had a decreased overall survival by univariate analysis using Cox proportional hazard model (hazard ratio, 2.82; P = 0.001) and remained significant on multivariate analysis (hazard ratio, 2.54; P = 0.03). There was no correlation of GLUT-1 gene expression with histologic grade or PET maximum standardized uptake values. Increased GLUT-1 gene expression was associated with a decreased overall survival in pancreatic adenocarcinoma. This supports increased GLUT-1 gene expression as a potential prognostic marker in resected pancreatic adenocarcinoma.

Abstract 557: Taking the sweet out of Th17 cells to potentiate immuno-oncology drugs

Abstract The major subsets of T cells that produce IL-17 include adaptive CD4+ Th17 cells and innate γδ T17 cells. IL-17 and both cellular sources are elevated in multiple human cancers and have been found to correlate with decreased patient survival. IL-17 produced by these cells promotes tumor growth by increasing the tumor infiltration and function of myeloid-derived suppressor cells (MDSCs), which in turn stimulate angiogenesis and suppress CD4+ and CD8+ T cell tumor homing and activation. Recently, two independent groups discovered that Th17 cell differentiation requires the transcription factor, hypoxia inducible factor 1α (HIF-1α), which promotes glycolytic enzymes and increases glucose metabolism. An established transcriptional target of HIF-1α and stimulator of glucose metabolism is 6-phosphofructo-2-kinase (PFKFB3) which synthesizes fructose 2,6-bisphosphate (F2,6BP), a potent allosteric activator of the rate-limiting enzyme 6-phosphofructo-1-kinase (PFK-1). In unpublished studies, we have found that human Th17 cells generated ex vivo produce increased PFKFB3 and F2,6BP relative to total T cells. We postulate that Th17 cells may selectively require the activity of PFKFB3 for their differentiation and tumor-promoting functions. We examined the immunomodulatory effects of a first-in-class PFKFB3 inhibitor, (E)-1-(pyridyn-4-yl)-3-(7-(trifluoromethyl)quinolin-2-yl)-prop-2-en-1-one (PFK-158) on Th17 cells in vitro, in B16 melanoma-bearing mice and in cancer patients participating in a phase 1 multi-center clinical trial (clinicaltrials.gov # NCT02044861) and found that PFK-158: (i) suppresses human Th17 cell differentiation in vitro (200 nM); (ii) decreases splenic and tumor-infiltrating Th17 cells, γδ T17 cells and MDSCs, and increases CD4+ and CD8+ T cells in the tumors of B16-F10 melanoma-bearing mice (0.06 mg/gm QD x 3 days); and (iii) decreases peripheral blood Th17 cells, γδ T cells and MDSCs and increases activated effector CD4+ and CD8+ T cells in cancer patients. Furthermore, we observed that homozygous genomic deletion of Pfkfb3 in C57Bl/6 mice (but not in implanted B16 melanoma cells) reduces B16 tumor growth, decreases splenic and tumor-infiltrating Th17 cells, γδ T17 cells and MDSCs, and increases tumor-filtrating CD4+ and CD8+ T cells. Based on these immunological effects, we predicted that PFK-158 would improve the anti-tumor activity of an immune checkpoint inhibitor, anti-CTLA4, in the B16-F10 model - we observed a marked increase in tumor growth inhibition by anti-CTLA4 when combined with PFK-158 in vivo. Taken together, these studies provide the first pre-clinical and clinical rationale for the conduct of phase 1/2 trials to examine the anti-cancer efficacy of PFKFB3 inhibitors in combination with FDA-approved immune checkpoint inhibitors and other immunostimulatory agents such as the GM-CSF-producing oncolytic herpes virus talimogene laherparepvec. Citation Format: Sucheta Telang, Kavitha Yaddanadupi, Gilles Tapolsky, Rebecca Redman, Jason Chesney. Taking the sweet out of Th17 cells to potentiate immuno-oncology drugs. [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 557.

Thoracic [18F]fluorodeoxyglucose uptake measured by positron emission tomography/computed tomography in pulmonary hypertension.

Positron emission tomography (PET) visualizes increased cellular [F]fluorodeoxyglucose ([F]FDG) uptake. Pulmonary hypertension (PH) is conceived of a proliferative disease of the lung vessels. Increased glucose uptake can be quantified as pulmonary [F]FDG uptake via PET imaging. Because the angioproliferative mechanisms in PH are still in need of further description, the aim of the present study was to investigate whether [F]FDG PET/CT imaging can elucidate these pathophysiologic mechanisms in different etiologies of PH.Patients (n = 109) with end-stage pulmonary disease being evaluated for lung transplant were included in this observational study. Mean standardized uptake value (SUVmean) of predefined regions of interest in lung parenchyma (LP), left (LV), and right ventricle (RV) of the heart, and SUVmax in pulmonary artery (PA) were determined and normalized to liver uptake. These SUV ratios (SUVRs) were compared with results from right heart catheterization (mean pulmonary artery pressure [mPAP], pulmonary vascular resistance [PVR]), and serum N-terminal pro-brain natriuretic peptide. Group comparisons were performed and Pearson correlation coefficients (r) were calculated.The [F]FDG uptake ratios in LP, RV, RV/LV, and PA, but not in LV, were found to be significantly higher in both patients with mPAP ≥25 mm Hg (P = 0.013, P = 0.006, P = 0.049, P = 0.002, P = 0.68, respectively) and with PVR ≥480 dyn·s/cm (P < 0.001, P = 0.045, P < 0.001, P < 0.001, P = 0.26, respectively). The [F]FDG uptake in these regions positively correlated also with mPAP, PVR, and N-terminal pro-brain natriuretic peptide. The SUVR of PA positively correlated with the SUVR of LP and RV (r = 0.55, r = 0.42, respectively).Pulmonary and cardiac [F]FDG uptake in PET imaging positively correlated with the presence and severity of PH in patients with end-stage pulmonary disease. Increased glucose metabolism in the central PAs seems to play a certain role in terms of severity of PH. These results suggest that [F]FDG-PET imaging can help understand the pathophysiology of PH as a proliferative pulmonary disease.

Neural stem cell transplantation for the treatment of primary torsion dystonia: A case report.

Primary torsion dystonia (PTD) occurs due to a genetic mutation and often advances gradually. Currently, there is no therapy available that is able to inhibit progression. Neural stem cells (NSCs) are being investigated as potential therapies for neurodegenerative diseases, such as stroke and trauma. The present study evaluated the clinical effectiveness of NSC transplantation in an 18-year-old male patient with PTD, to assess the ability of this therapy to inhibit PTD progression. Genetic testing of the patient revealed a mutation in the torsion dystonia-1 (DYT1) gene (907–909 delGAG). NSCs were bilaterally implanted in the globus pallidus of the patient through stereotactic surgery. Prior to surgery, the patient's Burke-Fahn-Marsden dystonia movement score (BFMDMS) was 21, which progressively decreased after surgery to 18, 17, 15 and 13 at 1, 2, 3 and 4 postoperative years, respectively. BFMDMS was improved by 38.1% over the 4 postoperative years. Although computed tomography and magnetic resonance imaging examinations showed no significant changes prior to and following surgery, postoperative brain positron emission tomography scans revealed increased glucose metabolism in the transplanted region. The clinical efficacy of NSC transplantation in this patient suggests its potential for the treatment of DYT1-positive patients with PTD.

Longitudinal Changes in Glucose Metabolism of Denervated Muscle after Complete Peripheral Nerve Injury.

Electrodiagnostic studies can obtain information 2 or 3weeks after an acute nerve injury. Previous studies have shown increased glucose metabolism in denervated muscles 1week after injury using 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) positron emission tomography (PET). Therefore, this study aimed to evaluate the changes in glucose metabolism in denervated muscles using serial monitoring by [(18)F]FDG PET scans. Denervation was induced in eight male Sprague-Dawley rats (aged 7weeks old) weighing 200-250g. The right legs of the rats were denervated by resecting the sciatic nerve in the thigh after the initial skin incision. Two rats were sacrificed 1 and 10weeks after denervation. Skeletal muscles (gastrocnemius and tibialis anterior) were excised from both the right and left legs of the rats. Staining with hematoxylin and eosin, glucose transporter (GLUT)-1, GLUT-4, and hexokinase II was undertaken. PET/computed tomography (CT) scans were performed on the six remaining rats a total of five times at 1, 2, 5, 8, and 10weeks after denervation. Regions of interest were drawn on integrated PET/CT images to measure the degree of [(18)F]FDG uptake in the right and left lower leg muscles. Target-to-background ratios (TBRs) were calculated by dividing the FDG uptake of the lower leg muscles by that of the upper leg muscles. The TBRs of the denervated muscles were higher than those of the control muscles at both 1 (6.84 ± 1.98 vs. 1.18 ± 0.11, p = 0.009) and 2 (4.10 ± 2.05 vs. 1.86 ± 0.73, p = 0.0374) weeks after denervation. After 5 (2.18 ± 0.78 vs. 1.35 ± 0.47, p = 0.1489), 8 (1.76 ± 0.18 vs. 1.69 ± 0.18, p = 0.5127), and 10 (1.76 ± 0.52 vs. 1.56 ± 0.37, p = 0.5637) weeks, the difference in the TBRs between the denervated and controls became non-significant. [(18)F]FDG PET can visualize increased glucose metabolism in a denervated muscle early as 1week after injury. Therefore, PET could be adopted as a noninvasive imaging modality for acute nerve injuries. In addition, [(18)F]FDG PET may help to understand the role of the nervous system in the control of peripheral tissues.

Neuroprotective effects of bee venom phospholipase A2 in the 3xTg AD mouse model of Alzheimer's disease.

BackgroundAlzheimer’s disease (AD) is a severe neuroinflammatory disease. CD4+Foxp3+ regulatory T cells (Tregs) modulate various inflammatory diseases via suppressing Th cell activation. There are increasing evidences that Tregs have beneficial roles in neurodegenerative diseases. Previously, we found the population of Treg cells was significantly increased by bee venom phospholipase A2 (bvPLA2) treatment in vivo and in vitro.MethodsTo examine the effects of bvPLA2 on AD, bvPLA2 was administered to 3xTg-AD mice, mouse model of Alzheimer’s disease. The levels of amyloid beta (Aβ) deposits in the hippocampus, glucose metabolism in the brain, microglia activation, and CD4+ T cell infiltration were analyzed to evaluate the neuroprotective effect of bvPLA2.ResultsbvPLA2 treatment significantly enhanced the cognitive function of the 3xTg-AD mice and increased glucose metabolism, as assessed with 18F-2 fluoro-2-deoxy-D-glucose ([F-18] FDG) positron emission tomography (PET). The levels of Aβ deposits in the hippocampus were dramatically decreased by bvPLA2 treatment. This neuroprotective effect of bvPLA2 was associated with microglial deactivation and reduction in CD4+ T cell infiltration. Interestingly, the neuroprotective effects of bvPLA2 were abolished in Treg-depleted mice.ConclusionsThe present studies strongly suggest that the increase of Treg population by bvPLA2 treatment might inhibit progression of AD in the 3xTg AD mice.

Lin28: an emerging important oncogene connecting several aspects of cancer.

RNA-binding protein Lin28 was originally found as a heterochronic gene which played a significant role in the development of Caenorhabditis elegans. The tumor suppressor let-7 is a downstream target of Lin28, which has a wide variety of target genes which are involved in many aspects of cellular activities. By inhibition of let-7 and directly binding the target RNAs, Lin28 plays an important role in different biological and pathological processes including differentiation, metabolism, proliferation, pluripotency, and tumorigenesis. Overexpression of Lin28 has been reported in several kinds of cancers and is correlated with poor outcomes. It has been shown that Lin28 could affect the progression of cancers in several ways, such as promoting proliferation, increasing glucose metabolism, and inducing epithelial-mesenchymal transition (EMT) and cancer stem cells. Decrease of Lin28 expression or reactivation of let-7 in cancer cells could induce a reverse effect, indicating their therapeutic values in developing novel strategies for cancer treatment. Here, we will overview the regulatory mechanisms and functions of Lin28 in cancers.

Utility of 18F-fluorodeoxy glucose and 18F-sodium fluoride positron emission tomography/computed tomography in the diagnosis of medication-related osteonecrosis of the jaw: A preclinical study in a rat model.

The aim of this study was to determine the clinical utility of positron emission tomography/computed tomography (PET/CT) using 18F-FDG and 18F-NaF for the diagnosis of osteonecrosis of the jaw (ONJ), by observing characteristics in rat models treated with zoledronic acid (ZA) and/or dexamethasone (DX) followed by tooth extraction. A total of 48 rats were divided randomly into four groups: Group 1, rats treated with ZA and DX; Group 2, rats treated with ZA; Group 3, rats treated with DX; and Group 4, rats treated with vehicle as normal controls. They underwent examinations with both 18F-FDG and 18F-NaF PET/CT at 4 weeks prior to tooth extraction (baseline) and 4 weeks after tooth extraction. Rats were then sacrificed to evaluate the histological incidence and characteristics of ONJ. Histological and radiological characteristics of all groups were compared to assess the effects of medication and tooth extraction. Baseline PET/CT studies using 18F-FDG and 18F-NaF showed no difference in uptake among the groups. However, 18F-FDG PET/CT performed at 4 weeks after tooth extraction showed increased glucose metabolism at the extraction site in both the ZA/DX and the ZA-only groups compared with that in the vehicle-treated group, in accordance with the higher incidence of histological ONJ (p < 0.05, respectively). 18F-NaF PET/CT performed at 4 weeks after tooth extraction showed decreased bone uptake in the extraction site in the ZA/DX, ZA, and DX groups versus the vehicle group (all p < 0.05), but this was not correlated with the incidence of histological ONJ. The incidence of ONJ was highest in the ZA/DX group (66.7%), followed by the ZA group, both of which were significantly higher than in the DX and vehicle groups (both p < 0.05). 18F-FDG PET/CT as an inflammatory marker appeared to be a more appropriate imaging modality than 18F-NaF PET/CT in diagnosing ONJ in a rat model including a ZA/DX group. However, the decreased bone remodeling tendency highlighted by 18F-NaF PET/CT may be an indicator of a possible risk of ONJ before the onset of clinical signs and symptoms.

Pharmacological inhibition of S6K1 increases glucose metabolism and Akt signalling in vitro and in diet-induced obese mice.

The mammalian target of rapamycin complex 1 (mTORC1)/p70 ribosomal S6 kinase (S6K)1 pathway is overactivated in obesity, leading to inhibition of phosphoinositide 3-kinase (PI3K)/Akt signalling and insulin resistance. However, chronic mTORC1 inhibition by rapamycin impairs glucose homeostasis because of robust induction of liver gluconeogenesis. Here, we compared the effect of rapamycin with that of the selective S6K1 inhibitor, PF-4708671, on glucose metabolism in vitro and in vivo. We used L6 myocytes and FAO hepatocytes to explore the effect of PF-4708671 on the regulation of glucose uptake, glucose production and insulin signalling. We also treated high-fat (HF)-fed obese mice for 7days with PF-4708671 in comparison with rapamycin to assess glucose tolerance, insulin resistance and insulin signalling in vivo. Chronic rapamycin treatment induced insulin resistance and impaired glucose metabolism in hepatic and muscle cells. Conversely, chronic S6K1 inhibition with PF-4708671 reduced glucose production in hepatocytes and enhanced glucose uptake in myocytes. Whereas rapamycin treatment inhibited Akt phosphorylation, PF-4708671 increased Akt phosphorylation in both cell lines. These opposite effects of the mTORC1 and S6K1 inhibitors were also observed in vivo. Indeed, while rapamycin treatment induced glucose intolerance and failed to improve Akt phosphorylation in liver and muscle of HF-fed mice, PF-4708671 treatment improved glucose tolerance and increased Akt phosphorylation in metabolic tissues of these obese mice. Chronic S6K1 inhibition by PF-4708671 improves glucose homeostasis in obese mice through enhanced Akt activation in liver and muscle. Our results suggest that specific S6K1 blockade is a valid pharmacological approach to improve glucose disposal in obese diabetic individuals.

Microvascular invasion in hepatocellular carcinoma.

Microvascular invasion is a crucial histopathologic prognostic factor for hepatocellular carcinoma. We reviewed the literature and aimed to draw attention to clinicopathologic and imaging findings that may predict the presence of microvascular invasion in hepatocellular carcinoma. Imaging findings suggesting microvascular invasion are disruption of capsule, irregular tumor margin, peritumoral enhancement, multifocal tumor, increased tumor size, and increased glucose metabolism on positron emission tomography-computed tomography. In the presence of typical findings, microvascular invasion may be predicted.

Abstract A39: Identification and biostatistical analysis of conserved metabolic profiles in breast tumors from transgenic mouse models

Abstract Novel breast biomarkers with prognostic and therapeutic value include metabolites that are differentially expressed in breast tumors. The goal of this study is to identify global metabolic profiles of breast tumors derived from multiple established transgenic mouse models to gain insight into breast cancers of differing origin. We compared breast tumor samples to normal tissue and between cancer models from transgenic mouse breast cancer models overexpressing the following oncogenes: PyMT, PyMT-DB, Wnt1, Neu, and C3-TAg transgenic mice. Our breast tissue samples were analyzed on GC-MS and LC-MS/MS platforms, and analysis included 374 biochemical compounds of known identity. Comparison of global metabolic profiles between the different mouse breast cancer and normal tissue revealed many metabolic differences between genetic models. The vast majority of metabolomic profiles demonstrated differential levels of biochemicals between normal and tumor tissues consistent with changes in metabolism that support rapid growth. Breast tumors had increased glucose metabolism, amino acid metabolism, catabolism, and levels of the TCA cycle intermediates, consistent with increased energy production and anaplerotic contributions from amino acid catabolism. We also saw increased phospholipid metabolism, cholesterol uptake, and nucleotide metabolites. Combined with published gene expression data for these mouse models, we were able to conduct biostatistical analysis to search for correlation between gene expression and metabolite levels. We identified novel key metabolites and genes that correlate with the most other metabolites/genes; the list of these “hub” metabolites/genes could prove to be novel sites of regulation for breast cancer progression. We identified novel metabolic profiles of breast cancer that will be foundational in identifying metabolites with clinical prognostic value. Currently we are using both 3D culture and preclinical animal models to examine the role of the differentially expressed metabolites in breast cancer progression and treatment. Citation Format: Chen Dai, Laurie Littlepage, Jun Li. Identification and biostatistical analysis of conserved metabolic profiles in breast tumors from transgenic mouse models. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr A39.

PET Evidence of the Effect of Donepezil on Cognitive Performance in an Animal Model of Chemobrain.

A considerable number of patients with breast cancer complain of cognitive impairment after chemotherapy. In this study, we showed that donepezil enhanced memory function and increased brain glucose metabolism in a rat model of cognitive impairment after chemotherapy using behavioral analysis and positron emission tomography (PET). We found that chemotherapy affected spatial learning ability, reference memory, and working memory and that donepezil improved these cognitive impairments. According to PET analysis, chemotherapy reduced glucose metabolism in the medial prefrontal cortex and hippocampus, and donepezil increased glucose metabolism in the bilateral frontal lobe, parietal lobe, and hippocampus. Reduced glucose metabolism was more prominent after treatment with doxorubicin than cyclophosphamide. Our results demonstrated the neural mechanisms for cognitive impairment after chemotherapy and show that cognition was improved after donepezil intervention using both behavioral and imaging methods. Our results suggested that donepezil can be employed clinically for the treatment of cognitive deficits after chemotherapy.

A Molecular and Whole Body Insight of the Mechanisms Surrounding Glucose Disposal and Insulin Resistance with Hypoxic Treatment in Skeletal Muscle.

Although the mechanisms are largely unidentified, the chronic or intermittent hypoxic patterns occurring with respiratory diseases, such as chronic pulmonary disease or obstructive sleep apnea (OSA) and obesity, are commonly associated with glucose intolerance. Indeed, hypoxia has been widely implicated in the development of insulin resistance either via the direct action on insulin receptor substrate (IRS) and protein kinase B (PKB/Akt) or indirectly through adipose tissue expansion and systemic inflammation. Yet hypoxia is also known to encourage glucose transport using insulin-dependent mechanisms, largely reliant on the metabolic master switch, 5′ AMP-activated protein kinase (AMPK). In addition, hypoxic exposure has been shown to improve glucose control in type 2 diabetics. The literature surrounding hypoxia-induced changes to glycemic control appears to be confusing and conflicting. How is it that the same stress can seemingly cause insulin resistance while increasing glucose uptake? There is little doubt that acute hypoxia increases glucose metabolism in skeletal muscle and does so using the same pathway as muscle contraction. The purpose of this review paper is to provide an insight into the mechanisms underpinning the observed effects and to open up discussions around the conflicting data surrounding hypoxia and glucose control.

Abstract A60: Inhibition of growth of bladder cancer cells by compounds that affect glucose metabolism

Abstract The tendency of cancer cells to have enhanced rates of glycolysis presents a target for combination therapy with agents that affect glucose metabolism. We have explored the action of three compounds on a panel of eight human bladder cancer cell lines showing a spectrum of growth rates. The compounds were an inhibitor of PFKFB3, namely 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO), an inhibitor of pyruvate dehydrogenase kinase, dichloroacetate, and, paradoxically, phenformin. The biguanide phenformin increases glucose metabolism in some cancer cell lines but it can also be growth inhibitory. Effects on glucose metabolism and lactic acid production were monitored respectively by an enzyme-linked colorimetric assay for glucose in the medium and changes in the pH of the medium reflected by the absorbance of phenol red at 560 nm. Changes in these parameters were most marked for the rapidly growing T24 and UM-UC-3 bladder cancer cells and generally showed parallel changes with control and treated cells. We had previously established growth inhibitory effects of 10µM 3PO on the eight bladder cancer cell lines monitored by staining with sulforhodamine B. Inhibitory effects of 2.5 mM dichloracetate have been observed with additive inhibitory effects when cells were treated with combinations of 3PO and dichloracetate. Effects of phenformin as a single agent were studied at 10, 25 and 50µM. Concentration-related increases in medium acidification and glucose uptake were most consistently seen with T24 cells. The effects with 50µM phenformin could be blocked by coincubation with 2.5 mM dichloracetate. On the other hand, additive inhibitory effects on growth may be observed with combinations of phenformin and dichloroacetate. Sensitivity to the actions of phenformin could not be simply related to growth rate. The T24 and UM-UC-3 cells have similar growth rates and had similar inhibitory effects on growth when treated with phenformin. However, medium acidification and glucose uptake were less affected in the UM-UC-3 cells. Although there are conditions in which phenformin appears to increase the Warburg effect as it relates to glucose metabolism, there can be additive growth inhibitory effects when bladder cancer cells are treated with phenformin in combination with agents that inhibit glucose metabolism. Citation Format: Michael A. Lea, Mansour Altayyar, Charles desBordes. Inhibition of growth of bladder cancer cells by compounds that affect glucose metabolism. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr A60.

Neuroprotective Effects of Electroacupuncture on an Animal Model of Bilateral Common Carotid Artery Occlusion.

Mild cognitive impairment (MCI) is considered as an intermediate zone between normal aging and dementia. The most prominent feature of MCI is an isolated mild decline in memory, whereas other cognitive functions remain intact. The symptoms of vascular cognitive impairment (VCI) range from MCI to dementia, and an animal model of VCI has been established in a gerbil by transient bilateral common carotid artery occlusion (BCCAO). In the current study, we set out to investigate whether electroacupuncture (EA) could improve memory in gerbils with BCCAO-induced MCI. Animals were randomly divided into two groups: sham-operated group (n = 17) and a model group that was subdivided into BCCAO, n = 17, and EA-treated BCCAO, n = 28. Gerbils were treated with EA at KI3 or GV20 four times every other day using a set of electrical stimulus pulses (1mA, 2Hz) that were applied for 20min. For investigation of cognitive function, we performed a Y-maze test and Western blotting to identify the expression of neuroinflammatory proteins. EA treatment at KI3 ("Taegye" acupoint) improved cognitive function and reduced the expression of neuroinflammatory proteins including ionized calcium-binding adaptor molecule 1, toll-like receptor 4, tumor necrosis factor alpha, and phospho-extracellular signal-regulated kinase in the hippocampus of gerbils that had undergone BCCAO. Furthermore, using micro-positron emission tomography/computed tomography, we demonstrated that EA treatment increased glucose metabolism in the hippocampus of these animals. The present study highlights the neuroprotective effect of EA treatment against BCCAO-induced memory dysfunction, neuroinflammation, and glucose metabolism. Our findings suggest that EA, which has previously been used in complementary and alternative medicine, might also be considered as a therapy that can improve memory and reduce neuroinflammation associated with dementia.

Primary intratesticular rhabdomyosarcoma: A case report and literature review.

Rhabdomyosarcoma (RMS) that primarily occurs in the testes is particularly rare, with only retrospective studies and sporadic cases reported in the literature. The present study describes the case of a large, primary intratesticular RMS (ITRMS) that was treated with a radical inguinal orchiectomy (RIO) and a regimen of chemotherapy. The study also presents a review of the literature regarding primary ITRMSs, aiming to elucidate the clinical characteristics and optimal treatment of the disease. A 14-year-old male presented with a 1-year history of a slow-growing, painless, left scrotal mass. Magnetic resonance imaging identified a mass in the left scrotum with mixed signal intensity; no abnormal signals were identified in the right testicle and retroperitoneal lymph node. An X-ray of the chest demonstrated no evidence of metastasis. Subsequent to this, a left RIO was performed. Histopathological and immunohistochemical examination confirmed the final diagnosis of embryonal ITRMS. At 21 days post-surgery, an 18F-fluorodeoxyglucose-positron emission tomography-computed tomography (FDG-PET-CT) scan identified widespread metastatic lesions in the lungs, local lymph nodes and bones, presenting as increased glucose metabolism nodules. Subsequently, the patient received six sequential cycles of adjunct chemotherapy. The patient is alive with disease in October 2015. The case described is noteworthy as it is an example of ITRMS, in which the patient received successful treatment. However, multidisciplinary treatment may further improve the outcome of the disease.

Abstract 17970: Atrial Fibrillation is Associated With Increased Atrial Metabolic Activity on FDG/PET Imaging in Patients With Ischemic Cardiomyopathy

Introduction: Atrial Fibrillation (AF) is a common arrhythmia but its pathogenesis remains incompletely understood. Alterations in metabolism may play a role. 18F-fluorodeoxyglucose (FDG) PET reflects glucose uptake in metabolically active tissue but studies evaluating the relationship between atrial FDG uptake and atrial fibrillation are limited. Hypothesis: We hypothesized that patients with ischemic cardiomyopathy who have had AF have increased atrial wall FDG uptake compared to patients without AF (no-AF). Methods: Atrial uptake was assessed visually and quantitatively on FDG-PET/CT images in 42 patients (24 AF, 18 no-AF). The maximum and mean FDG Standard Uptake Value (SUV) in the left atrium (LA), right atrium (RA) and mean blood pool activity were measured (see figure). The Tissue:Blood ratio (TBR) was calculated using the maximum atrial wall SUV (TBRmax) and mean SUV (TBRmean). Results: Median age was 72 years; (78% male). Mean LVEF was similar between AF vs. No-AF patients (24+/-10% vs. 26+/-11%, p=0.57). The RA was visualized in 88% of AF and 44% of no-AF patients (p=0.002). The LA was visualized in 88% of AF and 72% of no-AF patients (p=0.22). See table for TBR results. TBRmax and TBRmean were significantly increased in the RA wall of patients with AF vs. no-AF. There was a trend for increased FDG in the LA wall of AF patients. Conclusion: Among patients with ischemic cardiomyopathy, significantly greater FDG uptake was noted in the RA of patients with AF vs. No-AF (with a trend for LA uptake). These findings suggest increased glucose metabolism in the atria in patients with AF. Further study is warranted to determine the clinical and biological significance of these findings.

Evaluation of 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography in rat models with hepatocellular carcinoma with liver cirrhosis.

Liver cirrhosis is a predominant risk factor for hepatocellular carcinoma (HCC). However, the exact mechanism of the progression from cirrhosis to cancer remains unclear. The uptake of 2-[(18)F]-fluoro-2-deoxy-D-glucose ((18)F-FDG) is widely used as a marker of increased glucose metabolism to monitor the progression of cancer with positron emission tomography (PET)/computed tomography (CT). Here we investigated the feasibility of using (18)F-FDG PET/CT in the diethylnitrosamine (DEN) mediated experimental hepatocellular carcinoma model. Rats received weekly intraperitoneal injections of DEN for 16 weeks for induction of HCC. We recorded starting from 0 days or 0 weeks after the last DEN injection. The weight and survival rate of rats were then measured. Also, an (18)F-FDG PET scan and serum analysis were performed at minus 2, 0, plus 2, and plus 4 weeks after the last DEN injection. The body weight of rats was maintained between 350 g and 370 g during 14 and 20 weeks, and the rats were euthanized at 35 days after the last DEN injection. The serum levels of alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphate (ALP) were significantly higher at zero weeks after the last DEN injection. The (18)F-FDG uptake for the quantitative evaluation of HCC was done by measuring the region of interest (ROI). At minus two weeks after the last DEN injection, the ROI of rats had significantly increased compared to the normal group, in a time-dependent manner. These results suggest that FDG uptake serves as a good screening test to evaluate the feasibility of DEN-induced HCC.