Radiolabelled Tracers Research Articles

Use of PET/MRI for identification and characterisation of liver lesions

Magnetic resonance imaging (MRI) has long been considered the gold standard for evaluation of hepatic lesions. There has, however, been much recent interest in functional analysis of malignant lesions, and conventional imaging tests are no longer able to answer all the clinical questions. In the current era, anatomical characterisation, e.g. regarding size and density, is no longer deemed adequate. Combined imaging with PET/CT provides clarity and insight but at times can be challenging, especially in certain parts of the body such as the liver, pelvis and brain, where test sensitivity is compromised. PET/MRI, a hybrid imaging technology, can be used to improve upon the soft-tissue contrast offered by MRI and the biochemical and metabolic information provided by PET, with overall improvement in test sensitivity and hence increased diagnostic accuracy and improved tissue characterisation. Furthermore, various radiolabelled PET tracers can be used to improve the accuracy of staging, determination of the extent of disease, evaluation of treatment response, prognostic assessment and differentiation between post-therapeutic changes and tumour recurrence. In this article, we review the advantages of PET/MRI over conventional imaging in identifying and characterising liver lesions.

Developments in sentinel lymph node biopsy for penile cancer

Sentinel lymph node biopsy is used for tumour staging of many cancers. In new research, a fluorescent, radiolabelled tracer gave equivalent radiographic localization and improved visualization of sentinel nodes in penile cancer, compared with current standard tracers, but technical and financial considerations could influence its widespread use.

INMiND: getting to the bottom of neuroinflammation

INMiND: getting to the bottom of neuroinflammation

Evaluation of transcranial sonographic findings and MIBG cardiac scintigraphy in the diagnosis of idiopathic Parkinson's disease

The diagnosis of idiopathic Parkinson's disease (IPD) is based on clinical criteria. In the last two decades several neuroimaging methods using transcranial sonography (TCS) or radiolabelled tracers such as the myocardial MIBG scintigraphy were applied to support diagnosis of IPD. They have been used independently of each other and their interrelation is not yet clear. In the present study we analyzed the relation between findings of TCS, MIBG scintigraphy, and clinical presentation in 42 patients with IPD who were clinically diagnosed and underwent clinical follow-up over ≥3 years in order to confirm IPD diagnosis throughout the clinical course. The extent of substantia nigra hyperechogenicity (SN+) contralateral to the clinically more affected body side (SNcontra) was compared to myocardial 123I-MIBG uptake. SNcontra did not correlate with the myocardial MIBG uptake (r = −0.10; p = 0.52). Both myocardial MIBG uptake and TCS did not correlate significantly with Hoehn and Yahr stage (r = −0.03; p = 0.87 and r = −0.10; p = 0.54, respectively). Sensitivity of TCS in the diagnosis of IPD was 79%, of MIBG scintigraphy 81%. The combination of both measurements reached a sensitivity of 95%. TCS and MIBG scintigraphy may disclose complementary aspects of IPD. The combined use of both neuroimaging methods might improve the diagnostic sensitivity regarding IPD.

Direct intranigral administration of an ubiquitin proteasome system inhibitor in rat: Behavior, positron emission tomography, immunohistochemistry

Several independent lines of research suggest that disruption of the ubiquitin proteasome system (UPS) may play a role in the pathophysiology of Parkinson's disease. Direct intracerebral injection of UPS inhibitors (e.g. lactacystin) in animals has consistently produced important features of the disease. In this study, a range of lactacystin doses (0.5, 1, 2, 10 and 20μg) were injected into the right substantia nigra in rats to determine the ideal dose required to produce a robust and specific lesion of the dopamine nigro-striatal system and motor deficits. Motor behavior, assessed with the tapered ledged beam task, was severely affected in animals that received high doses (10 and 20μg) but only mild, impairments were observed in animals that received low doses (0.5, 1, and 2μg). Positron emission tomography was performed with a dedicated small animal scanner on the rats following the injection of the radio-labeled tracer (±)[11C]dihydrotetrabenazine (DTBZ) which labels vesicular monoamine transporter type 2. Severe loss of [11C]DTBZ binding in the ipsilateral striatum was observed in the higher dose groups and mild loss was observed in the low dose groups. Stereological cell counting of tyrosine hydroxylase immunoreactive cells in the substantia nigra and the ventral tegmental area indicated a dose dependent loss of dopaminergic neurons. Significant correlations were found between the behavioral motor deficits, striatal [11C]DTBZ binding and cell counts of tyrosine hydroxylase immunoreactive cells. Taken together these results indicate that intranigral injection of lactacystin produces dose dependent effects on the dopamine nigro-striatal system and a dose of 10μg will produce a consistent severe lesion.

A new role for plasma membrane phosphatidylinositol 4‐phosphate (PI4P)?

Many crucial functions of the plasma membrane (PM) rely on the minor inner leaflet lipid, phosphatidylinositol 4,5‐bisphosphate [PI(4,5)P2]. The major intermediate in PI(4,5)P2 synthesis, PI4P, seems paradoxically to be superfluous for maintenance or function of PI(4,5)P2. Inhibiting the enzyme that generates PM PI4P, PI 4‐kinase (PI4K) type III α (PI4KA), leads to depletion of PI(4,5)P2 levels only when phospholipase C (PLC) is activated, suggesting that other PI4K activities synthesize PI(4,5)P2 in resting cells. Here, we set out to test this hypothesis. Using a combination of live cell imaging with fluorescent PI4P and PI(4,5)P2 biosensors, we show that type II or type III β PI4K inhibitors lead to reductions in endosomal and Golgi‐localized PI4P pools, whereas only an inhibitor of PI4KA produces a reduction in PM PI4P. However, no combination of these agents led to substantial depletion of PM PI(4,5)P2. Use of radiolabelled tracers demonstrated that PI4KA inhibitor caused reduced absolute levels of PI4P with little change in PI(4,5)P2, despite a dramatic reduction in acute PI4P and PI(4,5)P2 synthesis. Therefore, PI(4,5)P2 levels are maintained when PI4KA is blocked not because there is an alternative route of synthesis, but because PI(4,5)P2 turnover simply stops. Consistently, in cells depleted of PM PI4P by a PI4KA inhibitor, forced degradation of PI(4,5)P2 with a 5‐phosphatase yields a pool of PI4P, which rapidly runs down due to the absence of PI4KA activity to maintain it. These results suggest a novel function for PM PI4P, which is as a metabolic “buffer” whose levels and turnover can be rapidly sensed and adjusted in order to maintain the functionally crucial PI(4,5)P2 pool. This work was supported by the intramural research program of the Eunice Kennedy Shriver National Institute for Child Health and Human Development, NIH.

A Novel Double-Tracer Technique to Characterize Absorption, Distribution, Metabolism and Excretion (ADME) of [14C]Tofogliflozin After Oral Administration and Concomitant Intravenous Microdose Administration of [13C]Tofogliflozin in Humans

Human mass balance studies and the assessment of absolute oral bioavailability (F) are usually assessed in separate studies. Intravenous microdose administration of an isotope tracer concomitant to an unlabeled oral dose is an emerging technique to assess F. We report a novel double-tracer approach implemented for tofogliflozin combining oral administration of a radiolabel tracer with concomitant intravenous administration of a stable isotope tracer. Tofogliflozin is a potent and selective sodium/glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes mellitus currently in clinical development. The objectives of the present study were to assess the systemic exposure of major circulating metabolites, excretion balance, F and contribution of renal clearance (CLR) to total clearance (CL) of tofogliflozin in healthy subjects within one study applying a novel double-tracer technique. Six healthy male subjects received 20 mg [(12)C/(14)C]tofogliflozin (3.73 MBq) orally and a concomitant microdose of 0.1 mg [(13)C]tofogliflozin intravenously. Pharmacokinetics of tofogliflozin were determined for the oral and intravenous route; the pharmacokinetics of the metabolites M1 and M5 were determined for the oral route. Quantification of [(12)C]tofogliflozin in plasma and urine and [(13)C]tofogliflozin in plasma was performed by selective LC-MS/MS methods. For the pre-selected metabolites of tofogliflozin, M1 and M5, a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) was applied to plasma and urine samples. Total radioactivity was assessed in plasma, urine and feces. Pharmacokinetic analysis was conducted by non-compartmental methods. The pharmacokinetics of tofogliflozin in healthy subjects were characterized by an F of 97.5 ± 12.3 %, CL of 10.0 ± 1.3 l/h and volume of distribution at steady-state (V(ss)) of 50.6 ± 6.7 l. The main route of elimination of total drug-related material was by excretion into urine (77.0 ± 4.1 % of the dose). The observed CL(R) of 25.7 ± 5.0 ml/min was higher than the product of the estimated glomerular filtration rate (eGFR) and fraction unbound in plasma (f(u)) (eGFR × f(u) 15 ml/min), indicating the presence of net active tubular secretion in the renal elimination of tofogliflozin. However, CLR contributed only 15.5 % to the CL of tofogliflozin, suggesting that reductions in CLR by renal impairment won't significantly affect systemic exposure to tofogliflozin. Tofogliflozin and its metabolite M1 were the only major circulating entities accounting for 46 ± 8.6 and 50 ± 8.2 %, respectively, of total circulating drug-related material, while the metabolite M5 was a minor circulating metabolite accounting for 3.0 ± 0.3 % of total circulating drug-related material. Both the M1 and M5 metabolites were excreted into urine and the major metabolite M1 did not exhibit active tubular secretion. These results demonstrate the utility of the double-tracer approach to provide essential pharmacokinetic data and excretion data for drug-related material in one study at the same dosing occasion. The data obtained allowed the characterization of absorption, distribution, metabolism and excretion of tofogliflozin. Tofogliflozin exhibited highly favorable pharmacokinetic properties as demonstrated by its high F, low CL and a low V(ss. The presence of only one major circulating metabolite of tofogliflozin was unambiguously demonstrated. As a drug targeting the kidney, luminal exposure of the kidney is achieved by renal filtration and active tubular secretion.

In vitro binding of a radio‐labeled positive allosteric modulator for metabotropic glutamate receptor subtype 5

The positive allosteric modulator (PAM) binding site for metabotropic glutamate receptor subtype 5 (mGlu(5)) lacks a readily available radio-labeled tracer fordetailed structure-activity studies. This communication describes a selective mGlu(5) compound, 7-methyl-2-(4-(pyridin-2-yloxy)benzyl)-5-(pyridin-3-yl)isoindolin-1-one (PBPyl) that binds with high affinity to human mGlu(5) and exhibits functional PAM activity. Analysis of PBPyl by FLIPR revealed an EC(50) of 87 nM with an 89% effect in transfected HEK293 cells and an EC(50) of 81 nM with a 42% effect in rat primary neurons. PBPyl exhibited 5-fold higher functional selectivity for mGlu(5) in a full mGlu receptor panel. Unlabeled PBPyl was tested for specific binding using a liquid chromatography mass spectrometry (LC/MS/MS)-based filtration binding assay and exhibited 40% specific binding in recombinant membranes, a value higher than any candidate compound tested. In competition binding studies with [(3)H]MPEP, the mGlu(5) receptor negative allosteric modulator (NAM), PBPyl exhibited a k(i) value of 34 nM. PBPyl also displaced [(3)H]ABP688, a mGluR(5) receptor NAM, in tissue sections from mouse and rat brain using autoradiography. Areas of specific binding included the frontal cortex, striatum and nucleus accumbens. PBPyl was radiolabeled to a specific activity of 15 Ci/mmol and tested for specific binding in a filter plate format. In recombinant mGlu(5b) membranes, [(3)H] PBPyl exhibited saturable binding with a K(d) value of 18.6 nM. In competition binding experiments, [(3)H] PBPyl was displaced by high affinity mGlu(5) positive and negative modulators. Further tests showed that PBPyl displays less than optimal characteristics as an in vivo tool, including a high volume of distribution and ClogP, making it more suitable as an in vitro compound. However, as a first report of direct binding of an mGlu(5) receptor PAM, this study offers value toward the development of novel PET imaging agents for this important therapeutic target.

Detection, Quantification, and Microlocalisation of Targets of Pesticides Using Microchannel Plate Autoradiographic Imagers

Organophosphorus (OP) compounds are a diverse chemical group that includes nerve agents and pesticides. They share a common chemical signature that facilitates their binding and adduction of acetylcholinesterase (AChE) within nerve synapses to induce cholinergic toxicity. However, this group diversity results in non-uniform binding and inactivation of other secondary protein targets, some of which may be adducted and protein activity influenced, even when only a relatively minor portion of tissue AChE is inhibited. The determination of individual OP protein binding targets has been hampered by the sensitivity of methods of detection and quantification of protein-pesticide adducts. We have overcome this limitation by the employment of a microchannel plate (MCP) autoradiographic detector to monitor a radiolabelled OP tracer compound. We preincubated rat thymus tissue in vitro with the OP pesticides, azamethiphos-oxon, chlorfenvinphos-oxon, chlorpyrifos-oxon, diazinon-oxon, and malaoxon, and then subsequently radiolabelled the free OP binding sites remaining with 3H-diisopropylfluorophosphate (3H-DFP). Proteins adducted by OP pesticides were detected as a reduction in 3H-DFP radiolabelling after protein separation by one dimensional polyacrylamide gel electrophoresis and quantitative digital autoradiography using the MCP imager. Thymus tissue proteins of molecular weights ~28 kDa, 59 kDa, 66 kDa, and 82 kDa displayed responsiveness to adduction by this panel of pesticides. The 59 kDa protein target (previously putatively identified as carboxylesterase I) was only significantly adducted by chlorfenvinphos-oxon (p < 0.001), chlorpyrifos-oxon (p < 0.0001), and diazinon-oxon (p < 0.01), the 66 kDa protein target (previously identified as serum albumin) similarly only adducted by the same three pesticides (p < 0.0001), (p < 0.001), and (p < 0.01), and the 82 kDa protein target (previously identified as acyl peptide hydrolase) only adducted by chlorpyrifos-oxon (p < 0.0001) and diazinon-oxon (p < 0.001), when the average values of tissue AChE inhibition were 30%, 35%, and 32% respectively. The ~28 kDa protein target was shown to be heterogeneous in nature and was resolved to reveal nineteen 3H-DFP radiolabelled protein spots by two dimensional polyacrylamide gel electrophoresis and MCP autoradiography. Some of these 3H-DFP proteins spots were responsive to adduction by preincubation with chlorfenvinphos-oxon. In addition, we exploited the useful spatial resolution of the MCP imager (~70 μm) to determine pesticide micolocalisation in vivo, after animal dosing and autoradiography of brain tissue sections. Collectively, MCP autoradiographic imaging provided a means to detect targets of OP pesticides, quantify their sensitivity of adduction relative to tissue AChE inhibition, and highlighted that these common pesticides exhibit specific binding character to protein targets, and therefore their toxicity will need to be evaluated on an individual compound basis. In addition, MCP autoradiography afforded a useful method of visualisation of the localisation of a small radiolabelled tracer within brain tissue.

Transbilayer phospholipids molecular imaging

Nuclear medicine has become a key part of molecular imaging. In the present review article, we focus on the transbilayer phospholipids as exquisite targets for radiolabelled probes in molecular imaging. Asymmetry of phospholipid distribution is a characteristic of mammalian cell membranes. Phosphatidylcholine and sphyngomyelin cholinophospholipids are primarily located within the external leaflet of the cell membrane. Phosphatidylserine and phosphatidylethanolamine aminophospholipids, and also phosphatidylinositol are primarily located within the internal leaflet of the cell membrane. New radiolabelled tracers have been designed in preclinical and clinical research for PET-CT and SPECT-CT molecular imaging of transbilayer phospholipids.

A Critical Review of Neuroimaging Applications in Sports Concussion

While abnormalities related to concussion are typically not identified on traditional clinical neuroimaging (i.e., computed tomography [CT] or magnetic resonance imaging [MRI]), more sophisticated neuroimaging techniques have the potential to reveal the complex neurometabolic processes related to concussion and its recovery. Clinically, these techniques may one day provide useful information to guide clinicians in the management and treatment of sports concussion. This article critically reviews the current state of the literature regarding neuroimaging and sports concussion, identifies challenges in the application of these techniques, and identifies areas for future research.

11C]Meta-Hydroxyephedrine PET/CT

Aim of the present review is to report the use of Positron Emission Tomography (PET) with [11C]- metahydroxyephedrine ([11C]mHED) in different clinical conditions, including heart failure, coronary artery disease, arrhythmogenic disorders, diabetes mellitus, idiopathic Parkinsons disease and adrenal tumors. [11C]mHED is a radio-labeled neurotransmitter PET tracer used to evaluate global and regional sympathetic presynaptic innervation in vivo, and firstly carried out in cardiac tissue in the 1990s. After the radiosynthesis and the injection of 740MBq of [11C]mHED with 2±0.5 Ci/μmole specific activity, the tracer is avidly retained in myocardium within 10 minutes and remains entrapped for at least 60 minutes. The transplanted heart is a good model to evaluate specificity of tracers for presynaptic innervation whose involvement in heart failure has been characterized in several studies using PET and [11C]mHED. In addition to transplanted heart, PET and [11C]mHED prognostic value has been also assessed in Diabetes Mellitus cardiac neuropathy and in neurological disorders related to Idiopathic Parkinsons disease. Neuronal imaging by PET may be also useful in determining the risk of sudden death in patients with viable but denervated myocardium after an infarction. In addition to the evaluation of neuronal cardiac disorders, PET with [11C]mHED has been proposed in oncological studies for the detection of adrenal tumors.

Modelling acute renal failure using blood and breath biomarkers in rats

This paper compares three methods for estimating renal function, as tested in rats. Acute renal failure (ARF) was induced via a 60-min bilateral renal artery clamp in 8 Sprague–Dawley rats and renal function was monitored for 1 week post-surgery. A two-compartment model was developed for estimating glomerular filtration via a bolus injection of a radio-labelled inulin tracer, and was compared with an estimated creatinine clearance method, modified using the Cockcroft–Gault equation for rats. These two methods were compared with selected ion flow tube-mass spectrometry (SIFT-MS) monitoring of breath analytes. Determination of renal function via SIFT-MS is desirable since results are available non-invasively and in real time. Relative decreases in renal function show very good correlation between all 3 methods ( R 2 = 0.84, 0.91 and 0.72 for breath-inulin, inulin-creatinine, and breath-creatinine correlations, respectively), and indicate good promise for fast, non-invasive determination of renal function via breath testing.

Forme pseudo-tuberculeuse d’un carcinome épidermoïde du poumon exploré par TEP/TDM

In Oncology, PET/CT images interpretation can prove tricky due to the lack of specific radiolabelled tracers. We present a tobacco addict 58 years old man with lung squamous cell carcinoma mimicking evolutive tuberculosis on radiological imaging. In this patient, a negative sputum analysis of mycobaterium tuberculosis and scanty radiologic data triggered a PET/CT exam. Eventually, biopsy conveyed the proper diagnosis of lung squamous cell carcinoma. Ordering a PET/CT examen must take into account good analysis of radiologic imaging and endoscopic data susceptible to bring essential information in lung tumours related clinical conditions; allowing to streamline the diagnostic work-up.

Molecular imaging of angiogenesis with SPECT

Single-photon emission computed tomography (SPECT) and position emission tomography (PET) are the two main imaging modalities in nuclear medicine. SPECT imaging is more widely available than PET imaging and the radionuclides used for SPECT are easier to prepare and usually have a longer half-life than those used for PET. In addition, SPECT is a less expensive technique than PET. Commonly used gamma emitters are: 99mTc (Emax 141 keV, T 1/2 6.02 h), 123I (Emax 529 keV, T 1/2 13.0 h) and 111In (Emax 245 keV, T 1/2 67.2 h). Compared to clinical SPECT, PET has a higher spatial resolution and the possibility to more accurately estimate the in vivo concentration of a tracer. In preclinical imaging, the situation is quite different. The resolution of microSPECT cameras (<0.5 mm) is higher than that of microPET cameras (>1.5 mm). In this report, studies on new radiolabelled tracers for SPECT imaging of angiogenesis in tumours are reviewed.

11C-Methionine PET/CT for multiple myeloma

A 57-year-old woman with 6-year history of IgA-k myeloma experienced an increase of serum IgA level from 331 to 683 mg/dl during maintenance therapy with thalidomide after autologous peripheral blood stem cell transplantation followed by allogeneic mini-transplantation. Bone marrow aspiration revealed no sign of relapse of the myeloma. We conducted positron emission tomography/computed tomography (PET/CT) scans using C-methionine (MET) and F-fluorodeoxyglucose (FDG). In MET-PET/CT, there were multiple abnormal hypermetabolic lesions, while FDG uptake in these lesions was faint (Fig. 1). After four courses of bortezomib therapy, MET-PET/CT revealed no abnormal uptake of MET, with decreased serum IgA level (25.3 mg/dl), indicating that MET uptake was correlated with the clinical course, as denoted by IgA level. C-Methionine is a radiolabelled PET tracer that is clinically used for brain tumor. An earlier study reported that MET-PET depicted active myeloma clearly, which might reflect the increased metabolism of amino acids in myeloma cells for producing abundant immunoglobulin [1]. In the present case, MET-PET/CT was very useful for determining the precise localization of the myelomatous lesions and evaluating therapeutic effects. Although FDGPET/CT is reported to have higher sensitivity for localized myelomatous lesions than other imaging modalities, our case suggests the possibility that MET-PET/CT detects myelomatous lesions more clearly than FDG-PET/CT. Considering that in myeloma patients higher FDG uptake or a larger number of FDG-avid lesions is reported to be associated with inferior overall survival and event-free survival, the lower FDG uptake in this patient is possibly related to the slowly progressive nature of her myeloma. In addition, in 30% of myeloma patients, FDG-PET/CT reportedly failed to show the abnormal findings in the spine and pelvis; this may account for the lower FDG uptake in these lesions. Although many imaging modalities, including FDGPET/CT are now widely available, the findings of the present case suggest that MET-PET/CT can provide valuable information for patients with myeloma and has a potential to become an important imaging test. However, further investigation to compare the MET-PET/CT with FDG-PET/CT or other imaging modalities are needed to confirm the diagnostic efficiency and the clinical feasibility of MET-PET/CT for multiple myeloma.

Fatty acids alter glycerolipid metabolism and induce lipid droplet formation, syncytialisation and cytokine production in human trophoblasts with minimal glucose effect or interaction

The diabetic pregnancy is characterized by maternal hyperglycaemia and dyslipidaemia, such that placental trophoblast cells are exposed to both. The objective was to determine the effects of hyperglycaemia, elevated non-esterified fatty acids (NEFA) and their interactions on trophoblast cell metabolism and function. Trophoblasts were isolated from normal term human placentas and established in culture for 16 h prior to experiments. Glucose utilisation, fatty acid oxidation and fatty acid esterification were determined using radiolabelled metabolic tracer methodology at various glucose and NEFA concentrations. Trophoblast lipid droplet formation including adipophilin mRNA expression, viability, apoptosis, syncytialisation, secretion of hormones and pro-inflammatory cytokines were also assessed. Glucose utilisation via glycolysis was near maximal at the low physiological glucose concentration of 4 mM; whereas NEFA esterification into triacylglycerol and diacylglycerol increased linearly with increasing NEFA concentrations without evidence of plateau. Culture of trophoblasts in 0.25 mM NEFA for 24 h upregulated fatty acid esterification processes, inhibited fatty acid oxidation, inhibited glycerol release (a marker of lipolysis) and promoted adipophilin and lipid droplet formation, all consistent with upregulation of fatty acid storage and buffering capacity. NEFA also promoted trophoblast syncytialisation and TNFα, IL-1β, IL-6 and IL-10 production without effects on cell viability, apoptosis or hormone secretion. Hyperglycaemia caused intracellular glycogen accumulation and reduced lipid droplet formation, but had no other effects on trophoblast metabolism or function. NEFA have effects on trophoblast metabolism and function, mostly independent of glucose, that may have protective as well as pathophysiological roles in pregnancies complicated by diabetes and/or obesity.

Role of PET and PET/CT in Anticancer Drug Therapy Response Evaluation

Anti-cancer drug development is a major area of research. New imaging techniques provide a novel method for anti-cancer drug development and monitoring response to therapy by targeting functional metabolic activity at cellular level. The current assessment of the response to therapy in solid tumors based on measurement of the changes in tumor size have many limitations. Positron emission tomography (PET) has been used to measure changes in drug induced metabolism, cellular proliferation and tissue perfusion. Also, changes induced by immuno-modulating drugs such as apoptosis, telomere activity, growth factor levels and many more can be studied using specific radiolabelled PET tracers. Initially PET was used alone without any computed tomography (CT) or magnetic resonance imaging (MRI) hybridization. Since there are few limitations associated with PET alone, a novel combined PET/CT system has recently been built that improves the ability to correctly localize and interpret radiotracer uptake. Hybrid PET/CT scanners provide both the anatomical and functional aspects of the tissue. PET and PET/CT have been found to be very useful in various cancers. In the present study we have investigated role of PET/CT as a predictor of early response to chemotherapy in locally advanced breast cancer patients, lymphoma, pediatric cancer, lung cancer, etc. We have performed more than 14000 PET/CT at our institute. We have found that fluorine-18 fluoro-deoxy-glucose ( 18 F-FDG) PET/CT plays important role in early assessment of treatment response in various cancer patients. A positive PET/CT scans after the completion of therapy is a strong predictor of residual disease, whereas, a negative study is associated with complete remission in these patients.

Carbon-nitrogen interactions regulate climate-carbon cycle feedbacks: results from an atmosphere-ocean general circulation model

Abstract. Inclusion of fundamental ecological interactions between carbon and nitrogen cycles in the land component of an atmosphere-ocean general circulation model (AOGCM) leads to decreased carbon uptake associated with CO2 fertilization, and increased carbon uptake associated with warming of the climate system. The balance of these two opposing effects is to reduce the fraction of anthropogenic CO2 predicted to be sequestered in land ecosystems. The primary mechanism responsible for increased land carbon storage under radiatively forced climate change is shown to be fertilization of plant growth by increased mineralization of nitrogen directly associated with increased decomposition of soil organic matter under a warming climate, which in this particular model results in a negative gain for the climate-carbon feedback. Estimates for the land and ocean sink fractions of recent anthropogenic emissions are individually within the range of observational estimates, but the combined land plus ocean sink fractions produce an airborne fraction which is too high compared to observations. This bias is likely due in part to an underestimation of the ocean sink fraction. Our results show a significant growth in the airborne fraction of anthropogenic CO2 emissions over the coming century, attributable in part to a steady decline in the ocean sink fraction. Comparison to experimental studies on the fate of radio-labeled nitrogen tracers in temperate forests indicates that the model representation of competition between plants and microbes for new mineral nitrogen resources is reasonable. Our results suggest a weaker dependence of net land carbon flux on soil moisture changes in tropical regions, and a stronger positive growth response to warming in those regions, than predicted by a similar AOGCM implemented without land carbon-nitrogen interactions. We expect that the between-model uncertainty in predictions of future atmospheric CO2 concentration and associated anthropogenic climate change will be reduced as additional climate models introduce carbon-nitrogen cycle interactions in their land components.

Leptin prevents the metabolic effects of adiponectin in L6 myotubes

Adiponectin and leptin are negatively and positively correlated with human obesity respectively, and have both been shown to regulate energy metabolism in skeletal muscle. However, little is known about their signalling and functional crosstalk. Here we investigated the effects of leptin on metabolic actions of (1) globular adiponectin (gAd) and (2) full-length adiponectin (fAd) in L6 cells. Glucose uptake was measured upon gAd and fAd treatment after incubation with different doses (0.3, 0.6, 3, 6, 60 nmol/l) of leptin for 6, 12 and 24 h. We also measured adiponectin receptor (ADIPOR) expression and stimulation of downstream signalling by gAd and fAd using co-immunoprecipitation and western blotting following leptin pretreatment, as well as analysis of fatty acid uptake and oxidation using radiolabelled tracers. Leptin attenuated the stimulation of glucose uptake by gAd and fAd in a dose- and time-dependent manner, a finding correlated with decreased levels of ADIPOR1 and ADIPOR2. gAd and fAd increased palmitate uptake via activation of AMP protein kinase (T172), enhanced expression of the fatty acid transporter CD36, phosphorylated acetyl-CoA carboxylase (S79) and enhanced palmitate oxidation, all of which were attenuated by leptin pretreatment. Adiponectin can also enhance insulin sensitivity via direct signalling crosstalk; here we show that enhanced insulin-stimulated IRS-1 (Y612) and Akt (T308) phosphorylation in response to fAd was attenuated by leptin. APPL1 was recently identified as a critical mediator of adiponectin action in skeletal muscle. We demonstrated that leptin attenuated binding of APPL1 to LKB1, a downstream target leading to AMPK phosphorylation. The direct metabolic and insulin-sensitising effects of adiponectin were attenuated in the presence of leptin.