TPS4146 Background: Pancreatic cancer (PC) has one of the lowest 5-year survival rates. Gemcitabine (G)-based chemotherapy is standard-of-care first-line systemic therapy. Fluorine-18 radiolabelled 3-deoxy-3-fluorothymidine (FLT), a thymidine analogue, is a substrate for thymidine kinase 1 (TK1), which is highly expressed in proliferating cells in late G1/S phase. FLT uptake (imaged and quantified by positron emission tomography (PET)) correlates with pathology-based proliferation markers and with decreases with therapy in a number of cancers. G, a nucleoside analogue, decreases proliferation by inhibiting DNA synthesis, primarily acting on S and G1/S phase thus decreasing tumour FLT uptake. Human equilibrative nucleoside transporter (hENT1) transports G and FLT into cells, making hENT1 activity a key determinant of both FLT uptake and G efficacy. Methods: Two parallel proof-of-concept studies are designed to explore the feasibility of assessing proliferation, nucleoside transport, magnitude of treatment-related FLT uptake changes and understanding the pathophysiological basis of FLT-PET imaging in patients (pts) with (1) localized or (2) advanced PC. Up to 24 PC pts with ECOG PS 0-2, able to undergo imaging and with at least one potentially evaluable lesion larger than 2cm on CT/MRI are eligible. Pts with localized disease (study 1) will have dynamic FLT-PET pre-operatively preceded by a radiolabelled H 2 O PET scan to assess tumour perfusion. These pts will also undergo 2-deoxy-2-fluoro-D-glucose (FDG)-PET and diffusion-weighted MR scans. For pts with metastatic disease (study 2), dynamic FLT-PET will be performed before and after G-based chemotherapy. FLT uptake expressed as a standardized uptake value (SUV), will be determined. Tumour pathological markers from the surgical samples and imaging parameters will be correlated; hENT1 status will be assessed (by immunohistochemistry) after surgery (study 1) and before treatment (study 2). Reproducibility FLT-PET studies will be performed in a cohort of subjects to assess the variability in uptake quantification.
Objective Posttraumatic stress disorder (PTSD) is associated with indicators of poor physical health and sleep disturbance. This study investigated the relationship between PTSD and metabolic risk factors and examined the role of sleep duration in medically healthy and medication-free adults. Methods Participants with PTSD (n = 44, mean age = 30.6 years) and control participants free of lifetime psychiatric history (n = 50, mean age = 30.3 years) recorded sleep using sleep diary for 10 nights and actigraphy for 7 nights. We assessed metabolic risk factors including fasting triglycerides, total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein cholesterol, as well as abdominal fat using dual-energy x-ray absorptiometry. Results PTSD was associated with shorter sleep duration (based on self-report, not actigraphy) and higher metabolic risks (controlling for body fat percentage), including increased triglycerides (p = .03), total cholesterol (p < .001), LDL cholesterol (p = .006), very low density lipoprotein cholesterol (p = .002), and cholesterol/high-density lipoprotein ratio (p = .024). In addition, sleep duration was associated with metabolic risks in PTSD (significant correlations ranged from r = −0.20 to r = −0.40) but did not fully account for the association between PTSD and metabolic measures. Conclusions Metabolic risk factors are associated with PTSD even in early adulthood, which highlights the need for early intervention. Future longitudinal research should assess whether sleep disturbance in PTSD is a mechanism that contributes to heightened metabolic risk to elucidate the pathway from PTSD to higher rates of medical disorders such as obesity, diabetes, and heart disease.
Autoimmune pancreatitis (AIP) is a rare form of chronic pancreatitis, with as yet undetermined incidence and prevalence in the general population.Our understanding of it continues to evolve.In the last few years, 2 separate subtypes have been identified: type 1 AIP has been recognised as the pancreatic manifestation of a multiorgan disease, named immunoglobulin G4 (IgG4)related disease while type 2 AIP is a pancreas specific disorder not associated with IgG4.International criteria for the diagnosis of AIP have been defined: the HISORt criteria from the Mayo clinic, the Japan consensus criteria and, most recently, the international association of pancreatology "International Consensus Diagnostic Criteria".Despite this, in clinical practice it can still be very difficult to confirm the diagnosis and differenti-ate AIP from a pancreatic cancer.There are no large studies into the long-term prognosis and management of relapses of AIP, and there is even less information at present regarding the Type 2 AIP subtype.Further studies are necessary to clarify the pathogenesis, treatment and long-term outcomes of this disease.Critically for clinicians, making the correct diagnosis and differentiating the disease from pancreatic cancer is of the utmost importance and the greatest challenge.
Consumption of high-fructose diets promotes hepatic fatty acid synthesis (de novo lipogenesis [DNL]) and an atherogenic lipid profile. It is unclear whether these effects occur independent of positive energy balance and weight gain.We compared the effects of a high-fructose, (25% of energy content) weight-maintaining diet to those of an isocaloric diet with the same macronutrient distribution but in which complex carbohydrate (CCHO) was substituted for fructose.Eight healthy men were studied as inpatients for consecutive 9-day periods. Stable isotope tracers were used to measure fractional hepatic DNL and endogenous glucose production (EGP) and its suppression during a euglycemic-hyperinsulinemic clamp. Liver fat was measured by magnetic resonance spectroscopy.Weight remained stable. Regardless of the order in which the diets were fed, the high-fructose diet was associated with both higher DNL (average, 18.6 ± 1.4% vs 11.0 ± 1.4% for CCHO; P = .001) and higher liver fat (median, +137% of CCHO; P = .016) in all participants. Fasting EGP and insulin-mediated glucose disposal did not differ significantly, but EGP during hyperinsulinemia was greater (0.60 ± 0.07 vs 0.46 ± 0.06 mg/kg/min; P = .013) with the high-fructose diet, suggesting blunted suppression of EGP.Short-term high-fructose intake was associated with increased DNL and liver fat in healthy men fed weight-maintaining diets.
Background: Some HIV protease inhibitors (PIs) have been shown to induce insulin resistance in vitro but the degree to which specific PIs affect insulin sensitivity in humans is less well understood. Methods: In two separate double-blind, randomized, cross-over studies, we assessed the effects of a single dose of ritonavir (800 mg) and amprenavir (1200 mg) on insulin sensitivity (euglycemic hyperglycemic clamp) in healthy normal volunteers. Results: Ritonavir decreased insulin sensitivity (−15%; P = 0.008 versus placebo) and non-oxidative glucose disposal (−30%; P = 0.0004), whereas neither were affected by amprenavir administration. Conclusion: Compared to previously performed studies of identical design using single doses of indinavir and lopinavir/ritonavir, a hierarchy of insulin resistance was observed with the greatest effect seen with indinavir followed by ritonavir and lopinavir/ritonavir, with little effect of amprenavir.
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