Long Chain Fatty Acids Mediate Hepatic Metabolic Flux in Preruminating Dairy Calves Fed Flaxseed Oil, High Oleic Soybean Oil, or Milk Fat.

Nutrition and physiological state affect hepatic metabolism. Our objective was to determine if feeding flaxseed oil (∼50% C18:3n-3 cis), high oleic soybean oil (∼70% C18:1 cis-9), or milk fat (∼50% C16:0) alters hepatic expression of PC, PCK1, and PCK2 and the flow of carbons from propionate and pyruvate into the TCA cycle in preruminating calves. Male Holstein calves (n = 40) were assigned to a diet of skim milk with either: 3% milk fat (MF; n = 8), 3% flaxseed oil (Flax; n = 8), 3% high oleic soybean oil (HOSO; n = 8), 1.5% MF + 1.5% high oleic soybean oil (MF-HOSO; n = 8), or 1.5% MF + 1.5% flaxseed oil (MF-Flax; n = 8) from d 14 to d 21 postnatal. At d 21 postnatal, a liver biopsy was taken for gene expression and metabolic flux analysis. Liver explants were incubated in [U-13C] propionate and [U-13C] pyruvate to trace carbon flux through TCA cycle intermediates or with [U-14C] lactate, [1-14C] palmitic acid, or [2-14C] propionate to quantify substrate oxidation to CO2 and acid soluble products. Compared with other treatments, plasma C18:3n-3 cis was 10 times higher and C18:1 cis-9 was 3 times lower in both flax (Flax and MF-Flax) treatments. PC, PCK1, and PCK2 expression and flux of [U-13C] pyruvate as well as [U-13C] propionate were not different between treatments. PC expression was negatively correlated with the enrichment of citrate M+5 and malate M+3, and PCK2 was negatively correlated with citrate M+5, suggesting that when expression of these enzymes is increased, carbon from pyruvate enters the TCA cycle via PC mediated carboxylation, and then OAA is converted to phosphoenolpyruvate via PCK2. Acid soluble product formation and PC expression were reduced in HOSO (MF-HOSO and HOSO) treatments compared with flax (MF-Flax and Flax), indicating that fatty acids regulate PC expression and carbon flux, but that fatty acid flux control points are not connected to PC, PCK1, or PCK2. In conclusion, fatty acids regulate hepatic expression of PC, PCK1, and PCK2, and carbon flux, but the point of control is distinct.

Distortion in transmission of pathogenic SDHB- and SDHD-mutated alleles from parent to offspring.

Phaeochromocytoma and paraganglioma are highly heritable tumours; half of those associated with a germline mutation are caused by mutations in genes for Krebs's cycle enzymes, including succinate dehydrogenase (SDH). Inheritance of SDH alleles is assumed to be Mendelian (probability of 50% from each parent). The departure from transmission of parental alleles in a ratio of 1:1 is termed transmission ratio distortion (TRD). We sought to assess whether TRD occurs in the transmission of SDHB pathogenic variants (PVs). This study was conducted with 41 families of a discovery cohort from Royal North Shore Hospital, Australia, and 41 families from a validation cohort from St. Bartholomew's Hospital, United Kingdom (UK). Inclusion criteria were a clinically diagnosed SDHB PV and a pedigree available for at least two generations. TRD was assessed in 575 participants with the exact binomial test. The transmission ratio for SDHB PV was 0.59 (P = 0.005) in the discovery cohort, 0.67 (P < 0.001) in the validation cohort, and 0.63 (P < 0.001) in the combined cohort. No parent-of-origin effect was observed. TRD remained significant after adjusting for potential confounders: 0.67 (P < 0.001) excluding families with incomplete family size data; 0.58 (P < 0.001) when probands were excluded. TRD was also evident for SDHD PVs in a cohort of 81 patients from 13 families from the UK. The reason for TRD of SDHB and SDHD PVs is unknown, but we hypothesize a survival advantage selected during early embryogenesis. The existence of TRD for SDHB and SDHD has implications for reproductive counselling, and further research into the heterozygote state.

Impact of Partnered Pharmacist Medication Charting (PPMC) on Medication Discrepancies and Errors: A Pragmatic Evaluation of an Emergency Department-Based Process Redesign.

Medication errors are more prevalent in settings with acutely ill patients and heavy workloads, such as in an emergency department (ED). A pragmatic, controlled study compared partnered pharmacist medication charting (PPMC) (pharmacist-documented best-possible medication history [BPMH] followed by clinical discussion between a pharmacist and medical officer to co-develop a treatment plan and chart medications) with early BPMH (pharmacist-documented BPMH followed by medical officer-led traditional medication charting) and usual care (traditional medication charting approach without a pharmacist-collected BPMH in ED). Medication discrepancies were undocumented differences between medication charts and medication reconciliation. An expert panel assessed the discrepancies' clinical significance, with 'unintentional' discrepancies deemed 'errors'. Fewer patients in the PPMC group had at least one error (3.5%; 95% confidence interval [CI]: 1.1% to 5.8%) than in the early BPMH (49.4%; 95% CI: 42.5% to 56.3%) and usual care group (61.4%; 95% CI: 56.3% to 66.7%). The number of patients who need to be treated with PPMC to prevent at least one high/extreme error was 4.6 (95% CI: 3.4 to 6.9) and 4.0 (95% CI: 3.1 to 5.3) compared to the early BPMH and usual care group, respectively. PPMC within ED, incorporating interdisciplinary discussion, reduced clinically significant errors compared to early BPMH or usual care.

Analysis of Citrus Bioflavonoid Content and Dipeptidyl Peptidase-4 Inhibitory Potential of Commercially Available Supplements.

Citrus bioflavonoids are polyphenolic plant-derived pigments found in high levels in oranges, lemons, grapefruits and other citrus fruits. The three most abundant types of citrus bioflavonoids are hesperidin, naringenin and eriocitrin. Citrus bioflavonoids have long been known to possess powerful free radical-scavenging properties and cardioprotective effects. The study involved the analysis of 10 commercially available citrus bioflavonoid supplements from three different countries: Australia, the United States and Canada. The supplements were tested for their citrus bioflavonoid content which varied from 0.8 to 33.3% w/w. The daily bioflavonoid dose varied from 19 mg to 560 mg. Hesperidin was the major citrus bioflavonoid in nine out of ten supplements. One supplement was found to contain less than 10% of the quantity of rutin claimed to have been added. The DPP-4 inhibitory potential, compared through an estimation of rutin equivalence, ranged from 1.9 mg to 400 mg per day. This data highlights the variability between the supplements in their potential to inhibit DPP-4 for subsequent health benefits.

Surveillance Improves Outcomes for Carriers of SDHB Pathogenic Variants: A Multicenter Study.

CONTEXT: Carriers of succinate dehydrogenase type B (SDHB) pathogenic variants (PVs) are at risk of pheochromocytoma and paraganglioma (PPGL) from a young age. It is widely recommended carriers enter a surveillance program to detect tumors, but there are limited studies addressing outcomes of surveillance protocols for SDHB PV carriers. OBJECTIVE: The purpose of this study was to describe surveillance-detected (s-d) tumors in SDHB PV carriers enrolled in a surveillance program and to compare their outcomes to probands. METHODS: This was a multicenter study of SDHB PV carriers with at least 1 surveillance episode (clinical, biochemical, imaging) in Australian genetics clinics. Data were collected by both retrospective and ongoing prospective follow-up. Median duration of follow-up was 6.0 years. RESULTS: 181 SDHB PV carriers (33 probands and 148 nonprobands) were assessed. Tumors were detected in 20% of nonprobands undergoing surveillance (age range 9-76 years). Estimated 10-year metastasis-free survival was 66% for probands and 84% for nonprobands with s-d tumors (P = .027). S-d tumors were smaller than those in probands (median 27 mm vs 45 mm respectively, P = .001). Tumor size ≥40 mm was associated with progression to metastatic disease (OR 16.9, 95% CI 2.3-187.9, P = .001). Patients with s-d tumors had lower mortality compared to probands: 10-year overall survival was 79% for probands and 100% for nonprobands (P = .029). CONCLUSION: SDHB carriers with s-d tumors had smaller tumors, reduced risk of metastatic disease, and lower mortality than probands. Our results suggest that SDHB PV carriers should undertake surveillance to improve clinical outcomes.

Phytosterol supplements do not inhibit dipeptidyl peptidase-4.

BACKGROUND AND AIMS: Several commercially available phytosterol supplements are promoted for their cholesterol-lowering effects. However, limited information is available about their potential anti-hyperglycaemic effects. This study aimed to evaluate the dipeptidyl peptidase-4 (DPP-4) inhibitory effects of phytosterol supplements in silico and in vitro to determine their potential for anti-diabetic activity. METHODS: Docking studies were carried out in silico to evaluate the potential for interactions between three major phytosterol compounds (stigmasterol, ß-sitosterol, campesterol) and the DPP-4 enzyme, the enzyme that is inhibited by the anti-diabetic gliptins. Gas chromatography-tandem mass spectrometry (GC-MS/MS) was used to analyse three different supplements for phytosterol content. DPP-4 inhibitory activity was tested in vitro for these phytosterol supplements and two major phytosterol standards. RESULTS: In silico calculations predicted free binding energies for DPP-4 with the phytosterols to be: stigmasterol -8.78 kcal/mol; ß-sitosterol -8.70 kcal/mol; campesterol -8.40 kcal/mol. These binding energies indicated a potential for significant DPP-4 inhibition. However, these results were not supported by the in vitro studies. Stigmasterol and ß-sitosterol had an IC50 > 50 mg/ml (maximum tested concentration) and the Thompson's Cholesterol Manager® and Mega Strength Beta Sitosterol® supplements gave an IC50 > 100 mg/ml (maximum tested concentration). Blackmores Cholesterol Health® gave an IC50 value of 40 mg/ml which was attributed to ß-carotene content. CONCLUSIONS: Phytosterol supplements do not appear to offer any anti-diabetic activity potential via pathways that involve the inhibition of DPP-4.

Minimal effects of reduced teaching hours on undergraduate medical student learning outcomes and course evaluations.

Introduction: Various pressures exist for curricular change, including economic forces, burgeoning knowledge, broadening learning outcomes, and improving quality and outcomes of learning experiences. In an Australian 5-year undergraduate medical course, staff were asked to reduce teaching hours by 20% to alleviate perceived overcrowded preclinical curriculum, achieve operating efficiencies and liberate time for students' self-directed learning.Methods: A case study design with mixed methods was used to evaluate outcomes.Results: Teaching hours were reduced by 198 hours (14%) overall, lectures by 153 hours (19%) and other learning activities by 45 hours (7%). Summative assessment scores did not change significantly after the reductions: 0.4% increase, 1.5% decrease and 1.7% increase in Years 1, 2 and 3, respectively. The percentage of students successfully completing their academic year did not change significantly: 94.4% before and 93.3% after the reductions. Student evaluations from eVALUate surveys changed little, except workload was perceived to be more reasonable.Conclusions: Teaching hours, particularly lectures, can be moderately reduced with little impact on student learning outcomes or satisfaction with an undergraduate medical course.

Mild-to-Moderate Gestational Iodine Deficiency Processing Disorder.

This synopsis paper aims to identify if a common pattern of learning and social difficulties can be conceptualized across recent longitudinal studies investigating the influence of mild-to-moderate gestational iodine deficiency (GID) on offspring's optimal cognitive and psycho-social development. The main studies investigated are: The Southampton Women's Study (SWS)-United Kingdom; the Avon Longitudinal Study of Parents and Children (ALSPAC)-United Kingdom; the Gestational Iodine Cohort Longitudinal Study-Tasmania, Australia, and the Danish National Birth Cohort Case-Control Study-Denmark. In contrast to severe GID where there is a global negative impact on neurodevelopment, mild-to-moderate intrauterine iodine deficiency has subtler, but nonetheless important, permanent cognitive and psycho-social consequences on the offspring. This paper links the results from each study and maintains that mild-to-moderate GID is associated with a disorder that is characterized by speed of neural transmitting difficulties that are typically associated with working memory capacity difficulties and attention and response inhibition. The authors maintain that this disorder is better identified as Gestational Iodine Deficiency Processing Disorder (GIDPD), rather than, what to date has often been identified as 'suboptimal development'. The Autistic Spectrum Disorder (ASD), Attention Deficit, Hyperactivity Disorder (ADHD), language and literacy disorders (learning disabilities and dyslexia) are the main manifestations associated with GIDPD. GIDPD is identified on IQ measures, but selectively and mainly on verbal reasoning IQ subtests, with individuals with GIDPD still operating within the 'normal' full-scale IQ range. Greater consideration needs to be given by public health professionals, policy makers and educators about the important and preventable consequences of GID. Specifically, more emphasis should be placed on adequate iodine intake in women prior to pregnancy, as well as during pregnancy and when lactating. Secondly, researchers and others need to further extend, refine and clarify whether GIDPD, as a nosological (medical classification) entity, is a valid disorder and concept for consideration.

Correction: Hynes et al. "Reduced Educational Outcomes Persist into Adolescence Following Mild Iodine Deficiency in Utero, Despite Adequacy in Childhood: 15-Year Follow-Up of the Gestational Iodine Cohort Investigating Auditory Processing Speed and Working Memory" Nutrients 2017, 9 (12), 1354.

The authors wish to make a correction to the published version of their paper [...].

Resection of a functioning intrapericardial paraganglioma associated with succinate dehydrogenase B mutation.

Functional paragangliomas are rare neuroendocrine tumours that secrete catecholamines and are infrequently found in the mediastinum. We report a case of a young male with symptoms of catecholamine excess and a personal and family history of the paraganglioma predisposing succinate dehydrogenase subunit B mutation. The lesion had anatomical intrapericardial juxtaposition to important cardiac anatomy and posed the significant challenge of dissection at surgery. The lesion was successfully resected via sternotomy on cardiopulmonary bypass and confirmed histopathologically as paraganglioma. Intrapericardial paraganglioma is rare and treatment is difficult and time critical considering the proximity of cardiac anatomy as well as malignant potential.

Women Remain at Risk of Iodine Deficiency during Pregnancy: The Importance of Iodine Supplementation before Conception and Throughout Gestation.

In Australia, pregnant women are advised to take an iodine supplement (I-supp) (150 µg/day) to reduce risks to the foetus associated with iodine deficiency (ID). To examine the impact of this recommendation on iodine status, and to identify factors that contribute to adequacy during gestation, supplement use and Urinary Iodine Concentration (UIC) was measured in 255 pregnant women (gestation range 6 to 41 weeks) in Tasmania. The median UIC (MUIC) of 133 µg/L (Inter-quartile range 82⁻233) was indicative of ID, being below the 150⁻249 µg/L range for adequacy during pregnancy. Women taking an iodine-containing-supplement (I-supp) had a significantly higher MUIC (155 µg/L) (n = 171) compared to the combined MUIC (112.5 µg/L) (n = 84) of those who had never (120 µg/L) (n = 61) or were no longer taking an I-supp (90 µg/L) (n = 23) (p = 0.017). Among women reporting I-supp use, the MUIC of those commencing the recommended 150 µg/day prior to conception was significantly higher than those starting supplementation following pregnancy confirmation: 196 (98⁻315) µg/L (n = 45) versus 137.5 (82.5⁻233.5) µg/L (n = 124), p = 0.032. Despite recommendations for iodine supplementation pregnant Tasmanian women remain at risk of ID. Commencing an I-supp of 150 µg/day prior to conception and continuing throughout pregnancy is required to ensure adequacy. Timely advice regarding the importance of adequate iodine nutrition, including supplementation is needed to reduce the risk of irreversible in utero neurocognitive damage to the foetus.

Clinical utility of chromogranin A for the surveillance of succinate dehydrogenase B- and succinate dehydrogenase D-related paraganglioma.

BACKGROUND: Patients with mutations of succinate dehydrogenase B (SDHB) and succinate dehydrogenase D (SDHD) are at high risk of paraganglioma necessitating surveillance. Chromogranin A has been proposed as a biochemical marker of paraganglioma. We sought to determine the diagnostic utility of chromogranin A in a population-based SDHx sample. METHODS: Tasmania is an island state with one tertiary referral centre for endocrine neoplasia. We performed a cross-sectional analysis of all adult SDHB ( n = 52) and SDHD ( n = 10) patients undergoing paraganglioma surveillance between 2011 and 2017. Chromogranin A was referenced against the outcome of paraganglioma surveillance with a minimum of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) and plasma metanephrines (metanephrine and normetanephrine). RESULTS: Chromogranin A correctly predicted the result of paraganglioma surveillance more often in patients with SDHB compared with those with SDHD (77% vs. 22%, P = 0.003). In the SDHB group, chromogranin A demonstrated a sensitivity of 67% and specificity of 79% compared with 22% and 0% in the SDHD group. Chromogranin A identified one of three PET/CT-visualized SDHB-related paragangliomas with normal plasma metanephrines at the expense of nine false-positive results. A normal chromogranin A demonstrated a negative predictive value of 92% for SDHB-related paraganglioma. In patients with SDHB, plasma normetanephrine and metanephrine offered superior specificity (100%, P = 0.01 and 100%, P < 0.01, respectively) with comparable sensitivity (67%, P = 1.0 and 11%, P = 0.06, respectively) to chromogranin A. CONCLUSION: Chromogranin A does not provide additive benefit to standard surveillance for predicting the presence of SDHB- or SDHD-related paraganglioma, but has a useful negative predictive value when normal in patients with SDHB mutation.

D3T acts as a pro-oxidant in a cell culture model of diabetes-induced peripheral neuropathy.

Diabetes mellitus is one of the most common chronic diseases in the United States and peripheral neuropathy (PN) affects at least 50% of diabetic patients. Medications available for patients ameliorate symptoms (pain), but do not protect against cellular damage and come with severe side effects, leading to discontinued use. Our research group uses differentiated SH-SY5Y cells treated with advanced glycation end products (AGE) as a model to mimic diabetic conditions and to study the mechanisms of oxidative stress mediated cell damage and antioxidant protection. N-acetylcysteine (NAC), a common antioxidant supplement, was previously shown by our group to fully protect against AGE-induced damage. We have also shown that 3H-1,2-dithiole-3-thione (D3T), a cruciferous vegetable constituent and potent inducer of nuclear factor (erythroid-derived 2)- like 2 (Nrf2), can significantly increase cellular GSH concentrations and protect against oxidant species-induced cell death. Paradoxically, D3T conferred no protection against AGE-induced cell death or neurite degeneration. In the present study we establish a mechanism for this paradox by showing that D3T in combination with AGE increased oxidant species generation and depleted GSH via inhibition of glutathione reductase (GR) activity and increased expression of the NADPH generating enzyme glucose-6-phosphate dehydrogenase (G6PD). Blocking NADPH generation with the G6PD inhibitor dehydroepiandrosterone was found to protect against AGE-induced oxidant species generation, loss of viability, and neurite degeneration. It further reversed the D3T potentiation effect under AGE-treated conditions. Collectively, these results suggest that strategies aimed at combating oxidative stress that rely on upregulation of the endogenous antioxidant defense system via Nrf2 may backfire and promote further damage in diabetic PN.

Citrus bioflavonoids dipeptidyl peptidase-4 inhibition compared with gliptin antidiabetic medications.

This study compared dipeptidyl peptidase-4 (DPP-4) inhibitory activity of citrus bioflavonoid nutraceuticals compared with three gliptins. Citrus bioflavonoid standards and three commercially available citrus bioflavonoid supplements (Thompson's Super Bioflavonoid Complex®(SB), Ethical Nutrients Bioflavonoids Plus Vitamin C®(EN), and Country Life Citrus Bioflavonoids and Rutin®(CB)) were considered in this study. Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) analysis was undertaken to identify and quantitate the citrus bioflavonoids present in each supplement. The DPP-4 inhibitory activity was determined by fluorometric assay. All of the tested individual citrus flavonoids demonstrated DPP-4 inhibitory activity, with IC50 values ranging from 485 µM (rutin) to 5700 µM (hesperitin and eriodictyol). Similarly, the flavonoid supplements had IC50 values of 16.9 mg/mL (EN), 3.44 mg/mL (SB) and 2.72 mg/mL (CB). These values compare with gliptin IC50 values of 0.684 µM (sitagliptin), 0.707 µM (saxagliptin) and 2.286 µM (vildagliptin). The supplement flavonoid content varied from 11.98% (CB) to 5.26% (EN) and 14.51% (SB) of tablet mass, corresponding to daily flavonoid doses of around 300, 150 and 400 mg, respectively, with CB and SB containing rutin at levels of 7.0% and 7.5% of tablet mass, respectively. While our data demonstrated that citrus bioflavonoid based supplements do possess DPP-4 inhibitory activity, they are several orders of magnitude less potent than gliptins. Further studies using higher concentrations of citrus bioflavonoids, as well as investigations into antioxidant properties which may add additional benefit are warranted.

Reduced Educational Outcomes Persist into Adolescence Following Mild Iodine Deficiency in Utero, Despite Adequacy in Childhood: 15-Year Follow-Up of the Gestational Iodine Cohort Investigating Auditory Processing Speed and Working Memory.

There is increasing evidence that even mild gestational iodine deficiency (GID) results in adverse neurocognitive impacts on offspring. It's unclear, however, if these persist long-term and whether they can be ameliorated by iodine sufficiency in childhood. We followed a unique cohort (Gestational Iodine Cohort, n = 266) where gestation occurred during a period of mild population iodine deficiency, with children subsequently growing-up in an iodine replete environment. We investigated whether associations between mild GID and reductions in literacy outcomes, observed at age 9-years, persisted into adolescence. Comparisons were made between offspring of mothers with gestational urinary iodine concentrations (UICs) ≥ 150 µg/L and < 150 µg/L. Educational outcomes were measured using Australian National Assessment Program-Literacy and Numeracy (NAPLAN) tests. Children whose mothers had UICs < 150 µg/L exhibited persistent reductions in spelling from Year 3 (10%, -41.4 points (95% Confidence Interval -65.1 to -17.6, p = 0.001)) to Year 9 (5.6%, -31.6 (-57.0 to -6.2, p = 0.015)) compared to children whose mothers had UICs ≥ 150 µg/L. Associations remained after adjustment for biological factors, socioeconomic status and adolescent UIC. Results support the hypothesis that mild GID may impact working memory and auditory processing speed. The findings have important public health implications for management of iodine nutrition in pregnancy.

Inhibition of pyruvate carboxylase by 1α,25-dihydroxyvitamin D promotes oxidative stress in early breast cancer progression.

Maintaining reductive-oxidative (redox) balance is an essential feature in breast cancer cell survival, with cellular metabolism playing an integral role in maintaining redox balance through its supply of reduced NADPH. In the present studies, the effect of 1,25-dihydroxyvitamin D (1,25(OH)2D) on redox balance was investigated in early stages of breast cancer. Treatment with 1,25(OH)2D promoted oxidative stress in MCF10A-ras and MCF10A-ErbB2 breast epithelial cells, as measured by the decreased ratios of NADPH/NADP+ and reduced to oxidized glutathione (GSH/GSSG). The mRNA and protein expression of the enzyme pyruvate carboxylase (PC) was downregulated with 1,25(OH)2D treatment, suggesting a potential mechanism. Genetic depletion of PC in MCF10A-ras cells resulted in a decreased ratio of NADPH/NADP+ and GSH/GSSG, with 1,25(OH)2D treatment having no further effect. Mutation analysis confirmed the presence and functionality of a vitamin D response element in the PC gene promoter region. Collectively, these results provide evidence that 1,25(OH)2D promotes oxidative stress in early breast cancer progression through transcriptional downregulation of PC.

Utility of FDG-PET Imaging for Risk Stratification of Pancreatic Neuroendocrine Tumors in MEN1.

Context: Patients with multiple endocrine neoplasia type 1 (MEN1) are at high risk of malignant pancreatic neuroendocrine tumors (pNETs). Structural imaging is typically used to screen for pNETs but is suboptimal for stratifying malignant potential. Objective: To determine the utility of fluorodeoxyglucose (18F) positron emission tomography/computed tomography (18F-FDG PET/CT) for predicting the malignant potential of pNETs in MEN1. Design: Retrospective observational study. Setting: Tertiary referral hospital. Patients: Forty-nine adult patients with MEN1 carrying a common MEN1 mutation who underwent 18F-FDG PET/CT for MEN1 surveillance between 1 January 2010 and 30 September 2016. Interventions: Structural and functional imaging (magnetic resonance imaging, CT, ultrasonography, and 18F-FDG PET/CT) and surgical histopathology. Main Outcome Measures: pNET size, behavior, and histopathology. Results: Twenty-five (51.0%) of 49 patients studied had pancreatic lesions on structural imaging. Five (25%) of these had 18F-FDG-PET-avid lesions. In addition, two had solitary FDG-avid liver lesions, and one a pancreatic focus without structural correlate. Eight patients with pNETs underwent surgery (three FDG-avid lesions and five nonavid pNETs). The Ki-67 index was ≥5% in FDG-avid pNETs and <2% in nonavid pNETs. Overall, six of the eight (75%) patients with FDG-avid hepatopancreatic lesions harbored aggressive or metastatic NETs compared with one of 41 patients (2.4%) without hepatopancreatic FDG avidity [P < 0.001; sensitivity; 85.7% (95% confidence interval [CI], 48.7% to 99.3%); specificity, 95.2% (95% CI, 84.2% to 99.2%)]. Conclusion: 18F-FDG PET/CT is an effective screening modality in MEN1 for identifying pNETs of increased malignant potential. Surgical resection is recommended for FDG-avid pNETs.

1α,25-dihydroxyvitamin D inhibits de novo fatty acid synthesis and lipid accumulation in metastatic breast cancer cells through down-regulation of pyruvate carboxylase.

Both increased de novo fatty acid synthesis and higher neutral lipid accumulation are a common phenotype observed in aggressive breast cancer cells, making lipid metabolism a promising target for breast cancer prevention. In the present studies, we demonstrate a novel effect of the active metabolite of vitamin D, 1α,25-dihydroxyvitamin D (1,25(OH)2D) on lipid metabolism in malignant breast epithelial cells. Treatment of MCF10CA1a breast epithelial cells with 1,25(OH)2D (10 nM) for 5 and 7 days decreased the level of triacylglycerol, the most abundant form of neutral lipids, by 20%(±3.9) and 50%(±5.9), respectively. In addition, 1,25(OH)2D treatment for 5 days decreased palmitate synthesis from glucose, the major fatty acid synthesized de novo (48%±5.5 relative to vehicle). We have further identified the anaplerotic enzyme pyruvate carboxylase (PC) as a target of 1,25(OH)2D-mediated regulation and hypothesized that 1,25(OH)2D regulates breast cancer cell lipid metabolism through inhibition of PC. PC mRNA expression was down-regulated with 1,25(OH)2D treatment at 2 (73%±6 relative to vehicle) and 5 (56%±8 relative to vehicle) days. Decrease in mRNA abundance corresponded with a decrease in PC protein expression at 5 days of treatment (54%±12 relative to vehicle). Constitutive overexpression of PC in MCF10CA1a cells using a pCMV6-PC plasmid inhibited the effect of 1,25(OH)2D on both TAG accumulation and de novo palmitate synthesis from glucose. Together, these studies demonstrate a novel mechanism through which 1,25(OH)2D regulates lipid metabolism in malignant breast epithelial cells.