A recurrent nova super-remnant in the Andromeda galaxy.

The accretion of hydrogen onto a white dwarf star ignites a classical nova eruption1,2-a thermonuclear runaway in the accumulated envelope of gas, leading to luminosities up to a million times that of the Sun and a high-velocity mass ejection that produces a remnant shell (mainly consisting of insterstellar medium). Close to the upper mass limit of a white dwarf3 (1.4 solar masses), rapid accretion of hydrogen (about 10-7 solar masses per year) from a stellar companion leads to frequent eruptions on timescales of years4,5 to decades6. Such binary systems are known as recurrent novae. The ejecta of recurrent novae, initially moving at velocities of up to 10,000 kilometres per second7, must 'sweep up' the surrounding interstellar medium, creating cavities in space around the nova binary. No remnant larger than one parsec across from any single classical or recurrent nova eruption is known8-10, but thousands of successive recurrent nova eruptions should be capable of generating shells hundreds of parsecs across. Here we report that the most frequently recurring nova, M31N 2008-12a in the Andromeda galaxy (Messier 31 or NGC 224), which erupts annually11, is indeed surrounded by such a super-remnant with a projected size of at least 134 by 90 parsecs. Larger than almost all known remnants of even supernova explosions12, the existence of this shell demonstrates that the nova M31N 2008-12a has erupted with high frequency for millions of years.

The leakage of sewer systems and the impact on the 'black and odorous water bodies' and WWTPs in China.

China has achieved significant progress on wastewater treatment and aquatic environmental protection. However, leakage (in- and exfiltration) of sewer systems is still an issue. By using the statistical data of water and wastewater in 2016 in China, and the person loads (PLs) of water and wastewater in Singapore, the leakage fractions of hydraulic flow, organic carbon (COD), nitrogen (N) and phosphorus (P) mass loading, and in-sewer COD biological removal in the sewer systems of China (except Hong Kong, Macau and Taiwan), Shanghai, Guangzhou and Beijing were reported for the first time. The fractions of hydraulic flow infiltration (13%, Shanghai and Guangzhou) and exfiltration (39%, China) were calculated. Except Beijing, whose sewer networks are under appropriate management with small leakage fractions, the exfiltration fractions of COD (including in-sewer biological COD removal) ranged from 41% (Shanghai) to 66% (China) and averaged 55%; N ranged from 18% (Shanghai) to 48% (China) and averaged 33%; and P ranged from 23% (Shanghai and Guangzhou) to 44% (China) and averaged 30%. The exfiltrated sewage, COD, N and P not only wastes resources, but also contaminates the aquatic environment (especially groundwater) and contributes to 'black and odorous water bodies'. In- and exfiltration in the sewer network leads to low influent COD concentration, C/N ratio and high inorganic solids and inert particulate COD concentrations of many municipal wastewater treatment plants (WWTPs) causing high cost for nutrient removal, poor resource recovery, additional reactor/settler volume requirement and other operational problems. Therefore, tackling sewer leakage is of primary importance to today's environment in China. Recommendations for the inspection of sewer systems and the rehabilitation of damaged sewers as well as the development of design and operation guidelines of municipal WWTPs tailored to the specific local sewage characteristics and other conditions are proposed.

Profile of diabetes in men aged 79-97 years: the Western Australian Health in Men Study.

AIMS: To investigate behavioural, physical and biochemical characteristics associated with diabetes in the oldest age group of elderly men. METHODS: We conducted a cross-sectional analysis of community-dwelling men aged 79-97 years from Perth, Western Australia. Lifestyle behaviours, self-rated health, physical function, and fasting glucose and HbA1c levels were assessed. RESULTS: Of 1426 men, 315 had diabetes (22%). Men with diabetes were of similar age to men without (84.9 vs 84.5 years; P = 0.14). Only 26.5% of men with diabetes self-rated their health as excellent or very good, compared with 40.6% of men without diabetes (P < 0.001). Diabetes was associated with less involvement with recreational walking (32.7 vs 41.0%; P < 0.01) and leisure activities (19.0 vs 26.5%; P < 0.01). Men with diabetes had poorer physical function on multiple measures, including longer times for the Timed Up-and-Go test (15.0 ± 6.9 s vs 13.4 ± 5.3 s; P < 0.001) and weaker knee extension (20.2 vs 21.9 kg; P < 0.001). In multivariate analyses, diabetes was associated with an increased prevalence of myocardial infarction (odds ratio 1.80, 95% CI 1.25-2.60; P < 0.001) and falls resulting in injury (odds ratio 1.55, 95% CI 1.06-2.26; P = 0.02). Average HbA1c was 49 ± 8 mmol/mol (6.6 ± 0.8%) in men with diabetes, with 90.6% of these men on diet or oral hypoglycaemic therapy. CONCLUSIONS: In older men, diabetes is associated with poorer self-perceived health, reduced healthy lifestyle behaviours and physical function, heart disease and injurious falls. The majority of these men with diabetes had good glycaemic control. Encouraging healthy lifestyle behaviours and improving physical function should be evaluated as interventions to improve quality-of-life and health outcomes.

A myosin activator improves actin assembly and sarcomere function of human-induced pluripotent stem cell-derived cardiomyocytes with a troponin T point mutation.

We have investigated cardiac myocytes derived from human-induced pluripotent stem cells (iPSC-CMs) from two normal control and two family members expressing a mutant cardiac troponin T (cTnT-R173W) linked to dilated cardiomyopathy (DCM). cTnT is a regulatory protein of the sarcomeric thin filament. The loss of this basic charge, which is strategically located to control tension, has consequences leading to progressive DCM. iPSC-CMs serve as a valuable platform for understanding clinically relevant mutations in sarcomeric proteins; however, there are important questions to be addressed with regard to myocyte adaptation that we model here by plating iPSC-CMs on softer substrates (100 kPa) to create a more physiologic environment during recovery and maturation of iPSC-CMs after thawing from cryopreservation. During the first week of culture of the iPSC-CMs, we have determined structural and functional characteristics as well as actin assembly dynamics. Shortening, actin content, and actin assembly dynamics were depressed in CMs from the severely affected mutant at 1 wk of culture, but by 2 wk differences were less apparent. Sarcomeric troponin and myosin isoform composition were fetal/neonatal. Furthermore, the troponin complex, reconstituted with wild-type cTnT or recombinant cTnT-R173W, depressed the entry of cross-bridges into the force-generating state, which can be reversed by the myosin activator omecamtiv mecarbil. Therapeutic doses of this drug increased both contractility and the content of F-actin in the mutant iPSC-CMs. Collectively, our data suggest the use of a myosin activation reagent to restore function within patient-specific iPSC-CMs may aid in understanding and treating this familial DCM.

Surgical management of pituitary metastases.

BACKGROUND: Pituitary metastases are rare and commonly described in case reports or small case series. Due to its rarity this entity is not subject to standardized treatment guidelines, there is debate about typical initial symptoms that may lead to finding the correct diagnosis and information about the clinical course is also sparse. METHODS: We have conducted a retrospective analysis of patients with pituitary metastases who were surgically treated via a transsphenoidal procedure at our institution between 2006 and 2014. Underlying primary disease, clinical and surgical course as well as adjuvant radiotherapy and follow-up data are presented. RESULTS: 14 patients met the inclusion criteria (8 female, 6 male). Mean age was 61.5 years. Most patients became symptomatic with visual symptoms--both visual deterioration and/or diplopia (n = 13)--and anterior lobe insufficiency (n = 8). Surprisingly diabetes insipidus was only seen in three patients. All patients underwent transsphenoidal surgery initially, four patients had to undergo surgery for residual tumor or recurrence, two of them via a transcranial route. Breast cancer was the most common entity (n = 6), followed by prostate cancer (n = 3), nsclc (n = 2) and melanoma, thyroid cancer and renal cancer in one case each. Postoperative MRI showed gross total resection in four cases and residual disease in eight cases (subtotal resection, partial resection and biopsy), two patients files were incomplete regarding MRI-results. All patients underwent adjuvant radiotherapy. Survival after the initial diagnosis of cancer was 36 and 16 months after diagnosis of pituitary metastases. CONCLUSION: Our results indicate that transsphenoidal surgery is a safe method to resect pituitary metastases and that the extend of resection does not have an influence on survival time. Our results also indicate that diabetes insipidus may not be the most common initial symptom of pituitary metastases and lack thereof should not lead to making a wrong diagnosis and delaying appropriate therapy.

Examining the biodegradation of endocrine disrupting bisphenol A and nonylphenol in WWTPs.

The aim of this work was to examine biodegradation of the endocrine disrupting chemicals bisphenol A (BPA) and nonylphenol (NP) in activated sludge. Experiments were performed in a pilot wastewater treatment plant (WWTP) in Copenhagen, Denmark. During standard operation the BPA concentration was halved whereas the NP concentration was unchanged. Step-addition experiments showed that biomass adaptation to increased BPA and NP concentrations took 10 to more than 40 days depending on temperature, hydraulic retention time, and pre-exposure of the biomass. Mass-balance experiments showed that above 99% of the dosed BPA and 90% of the dosed NP is removed by biodegradation at steady-state. Batch experiments showed that BPA biodegradation occur solely under aerobic conditions. The work is believed to add vital knowledge to our understanding of parameters and processes governing biodegradation of EDCs in WWTPs.

Development of a quantitative forecasting system for Septoria tritici based on a long-term monitoring.

Septoria tritici is the most important diseases in winter wheat in Schleswig-Holstein (northern Germany) and in many other regions over the world. But the disease severity as well as the timing of the epidemic progression varies between locations and seasons and so he influence on yield parameters like absolute yield or yield loss. To optimize the disease management a quantitative knowledge of the factors affecting the disease progression is necessary. Weather is the driving force of the disease progression, the weather from sowing until stem elongation influence mostly the disease severity on the lower leaves whereas the weather during the vegetation period determines the epidemic disease patterns of the upper yield relevant leaves (F-3 to flag leaf). The epidemic disease progression occurs in several pushes, also recognized as "sudden outbreaks", where such an increase is initiated by a weather scenario called infection cycle. The object of this study is the identification of the most important factors of each part of the disease progression and their interaction. So that weather scenarios as well as cropping parameters can be evaluated and recommendations for the disease management can be made.

Deregulated cyclin E promotes p53 loss of heterozygosity and tumorigenesis in the mouse mammary gland.

Deregulation of cyclin E expression and/or high levels have been reported in a variety of tumors and have been used as indicators of poor prognosis. Although the role that cyclin E plays in tumorigenesis remains unclear, there is evidence that it confers genomic instability when deregulated in cultured cells. Here we show that deregulated expression of a hyperstable allele of cyclin E in mice heterozygous for p53 synergistically increases mammary tumorigenesis more than that in mice carrying either of these markers individually. Most tumors and tumor-derived cell lines demonstrated loss of p53 heterozygosity. Furthermore, this tumor susceptibility is related to the number of times the transgene is induced indicating that it is directly attributable to the expression of the cyclin E transgene. An indirect assay indicates that loss of p53 function is an early event occurring in the mammary epithelia of midlactation mammary glands in which cyclin E is deregulated long before evidence of malignancy. These data support the hypothesis that deregulated expression of cyclin E stimulates p53 loss of heterozygosity by promoting genomic instability and provides specific evidence for this in vivo. Cyclin E deregulation and p53 loss are characteristics often observed in human breast carcinoma.

Dosage suppressors of pds1 implicate ubiquitin-associated domains in checkpoint control.

In budding yeast, anaphase initiation is controlled by ubiquitin-dependent degradation of Pds1p. Analysis of pds1 mutants implicated Pds1p in the DNA damage, spindle assembly, and S-phase checkpoints. Though some components of these pathways are known, others remain to be identified. Moreover, the essential function of Pds1p, independent of its role in checkpoint control, has not been elucidated. To identify loci that genetically interact with PDS1, we screened for dosage suppressors of a temperature-sensitive pds1 allele, pds1-128, defective for checkpoint control at the permissive temperature and essential for viability at 37 degrees C. Genetic and functional interactions of two suppressors are described. RAD23 and DDI1 suppress the temperature and hydroxyurea, but not radiation or nocodazole, sensitivity of pds1-128. rad23 and ddi1 mutants are partially defective in S-phase checkpoint control but are proficient in DNA damage and spindle assembly checkpoints. Therefore, Rad23p and Ddi1p participate in a subset of Pds1p-dependent cell cycle controls. Both Rad23p and Ddi1p contain ubiquitin-associated (UBA) domains which are required for dosage suppression of pds1-128. UBA domains are found in several proteins involved in ubiquitin-dependent proteolysis, though no function has been assigned to them. Deletion of the UBA domains of Rad23p and Ddi1p renders cells defective in S-phase checkpoint control, implicating UBA domains in checkpoint signaling. Since Pds1p destruction, and thus checkpoint regulation of mitosis, depends on ubiquitin-dependent proteolysis, we propose that the UBA domains functionally interact with the ubiquitin system to control Pds1p degradation in response to checkpoint activation.

Modelling as a tool when interpreting biodegradation of micro pollutants in activated sludge systems.

The aims of the present work were to improve the biodegradation of the endocrine disrupting micro pollutant, bisphenol A (BPA), used as model compound in an activated sludge system and to underline the importance of modelling the system. Previous results have shown that BPA mainly is degraded under aerobic conditions. Therefore the aerobic phase time in the BioDenitro process of the activated sludge system was increased from 50% to 70%. The hypothesis was that this would improve the biodegradation of BPA. Both the influent and the effluent concentrations of BPA in the experiment dropped significantly after increasing the aerobic time. From simulations with a growth-based biological/physical/chemical process model it was concluded that although the simulated effluent concentration of BPA was independent of the influent concentration at steady-state, the observed drop in effluent concentrations probably was caused by either a larger specific biomass to influent BPA ratio, improved biodegradation related to the increased aerobic phase time, or a combination of the two. Thereby it was not possibly to determine if the increase in aerobic phase time improved the biodegradation of BPA. The work underlines the importance of combining experimental results with modelling when interpreting results from biodegradation experiments with fluctuating influent concentrations of micro pollutants.

[Comparison of diagnostic accuracy of (18)F-FDG PET, (123)I-IMT- and (99m)Tc-MIBI SPECT: evaluation of tumour progression in irradiated low grade astrocytomas]. / Vergleich der diagnostischen Genauigkeit von (18)F-FDG PET, (123)I-IMT- und (99m)Tc-MIBI SPECT zur Ermittlung des Progressionsstatus bestrahlter niedriggradiger Astrozytome.

AIM: To evaluates the diagnostic accuracy of the SPECT-tracers 3-(123)I-alpha-methyl-L-tyrosine (IMT) and (99m)Tc(I)- hexakis(2-methoxyisobutylisonitrile) (MIBI) as well as the PET-tracer 2-(18)F-2-deoxyglucose (FDG) for detecting tumour progression in irradiated low grade astrocytomas (LGA). PATIENTS, METHODS: We examined 91 patients (56 males; 35 females; 44.7 +/- 11.5 years), initially suffering from histologically proven LGAs (mean WHO grade II) and treated by stereotactic radiotherapy (59.0 +/- 4.6 Gy). On average 21.9 +/- 11.2 months after radiotherapy, patients presented new Gd-DTPA enhancing lesions on MRI, which did not allow a differentiation between progressive tumour (PT) and non-PT (nPT) at this point of time. PET scans (n = 82) were acquired 45 min after injection of 208 +/- 32 MBq FDG. SPECT scans started 10 min after injection of 269 +/- 73 MBq IMT (n = 68) and 15 min after injection of 706 +/- 63 MBq MIBI (n = 34). Lesions were classified as PT and nPT based on prospective follow-up (clinically, MRI) for 17.2 +/- 9.9 months after PET/SPECT. Lesion-to-normal ratios (L/N) were calculated using contra lateraly mirrored reference regions for the SPECT examinations and reference regions in the contra lateral grey (GM) and white matter (WM) for FDG PET. Ratios were evaluated by Receiver Operating Characteristic (ROC) analysis. RESULTS: In the patient groups nPT and PT, L/N ratios for FDG (GS) were 0.6 +/- 0.3 vs. 1.2 +/- 0.5 (p = 0.003), for FDG (WS) 1.2 +/- 0.4 vs. 2.6 +/- 0.4 (p < 0.001), for IMT 1.1 +/- 0.1 vs. 1.8 +/- 0.4 (p < 0.001) and for MIBI 1.6 +/- 0.7 vs. 2.6 +/- 2.2 (p = 0.554). Areas under the non-parametric ROC-curves were: 0.738 +/- 0.059 for FDG (GS), 0.790 +/- 0.057 for FDG (WS), 0.937 +/- 0.037 for IMT and 0.564 +/- 0.105 for MIBI. CONCLUSION: MIBI-SPECT examinations resulted in a low accuracy and especially in a poor sensitivity even at modest specificity values. A satisfying diagnostic accuracy was reached with FDG PET. Using WM as reference region for FDG PET, a slightly higher AUC as compared to GM was calculated. IMT yielded the best ROC characteristics and the highest diagnostic accuracy for differentiating between PT and nPT in irradiated LGA.

Integrated modelling of two xenobiotic organic compounds.

This paper presents a dynamic mathematical model that describes the fate and transport of two selected xenobiotic organic compounds (XOCs) in a simplified representation of an integrated urban wastewater system. A simulation study, where the xenobiotics bisphenol A and pyrene are used as reference compounds, is carried out. Sorption and specific biological degradation processes are integrated with standardised water process models to model the fate of both compounds. Simulated mass flows of the two compounds during one dry weather day and one wet weather day are compared for realistic influent flow rate and concentration profiles. The wet weather day induces resuspension of stored sediments, which increases the pollutant load on the downstream system. The potential of the model to elucidate important phenomena related to origin and fate of the model compounds is demonstrated.

Immunoscintigraphy with positron emission tomography: gallium-68 chelate imaging of breast cancer pretargeted with bispecific anti-MUC1/anti-Ga chelate antibodies.

Pretargeting techniques that are based on the sequential administrations of bispecific antitumor/antimetal chelate antibodies (BS-MAbs), a blocker to saturate the anti-chelate binding sites of the BS-MAb still present in the circulation, and the radiolabeled chelate are suitable to increase tumor-to-normal tissue contrasts and enable positron emission tomography (PET) as an imaging method. As demonstrated in the nude mouse model, a combination of pretargeted immunoscintigraphy and PET markedly improved the detection of tumor xenografts. With the presented preliminary clinical trial, we attempted to assess the efficacy of pretargeting and PET for breast cancer localization in patients. The BS-MAb used for pretargeting was synthesized from the F(ab')(2) fragments of the anti-MUC1 MAb 12H12, which reacts with the vast majority of breast tumors, and the F(ab') fragments of an anti-gallium (Ga) chelate MAb via a mixed functional chemical linker. For labeling of the Ga-chelate, we used the short-lived positron emitter Ga-68 (t(1/2), 68 min; beta(+), 88%). The dose and time schedule of pretargeting was deduced from previous animal experiments. Ten patients with biopsy-proven, primary breast carcinoma were infused with 10 mg of the BS-MAB: Eighteen h later, they received i.v. injections of 10.7 mg of a blocker and, 15 min later, 9.6 microg of the Ga chelate labeled with 230-300 MBq of (68)GA: PET imaging was started 60-90 min after injection of the (68)Ga chelate. Average tumor-to-blood and tumor:normal breast tissue ratios were 0.9 and 3.0 at 1 h postinjection. Tumor uptake amounted to approximately 0.003% iD/g corresponding to a standard uptake value of approximately 2. Blood clearance of the (68)Ga chelate showed a t(1/2) beta of approximately 100 min. Fourteen of 17 known lesions, averaging 25 +/- 16 mm in size, were clearly visualized as foci of increased activity with PET. No false-positive but three false-negative readings were obtained. An enhanced, bilateral activity uptake in the whole breast parenchyma, found in 4 of the 10 patients, compromised the recognition of these tumor sites. Although the shedding of the MUC1 antigen and the comparatively low tumor affinity of the BS-MAb, common to all anti-mucin MAbs, proved not to be optimal for increasing tumor:tissue ratios with a pretargeting technique, PET imaging offered better sensitivity for the detection of breast cancer at low tumor contrasts than conventional immunoscintigraphy. This could be demonstrated by the clear visualization of tumor sites 10 mm in size, which contrasted only by a factor of 2 from surrounding normal breast tissue.

UBA domains mediate protein-protein interactions between two DNA damage-inducible proteins.

The Saccharomyces cerevisiae genes RAD23 and DDI1 were identified in a screen for multicopy suppressors of the temperature-sensitivity of a mutant allele of S. cerevisiae PDS1. Pds1 is a regulator of anaphase that needs to accumulate and then be degraded by the ubiquitin-proteasome pathway at the metaphase-anaphase transition for cells to progress normally through mitosis. Both the Rad23 and Ddi1 pds1 suppression phenotypes depend on a shared motif known as a UBA domain found in a variety of proteins associated with ubiquitin metabolism. UBA domains were found to be essential for homodimerization of Rad23 and heterodimerization between Rad23 and Ddi1, but not for homodimerization of Ddi1. This observation, coupled with the findings that Rad23 and Ddi1 UBA domains bind ubiquitin and that dimerization of Rad23 blocks ubiquitin binding, suggests a possible mechanism for regulating Rad23 and Ddi1 function.

Uncertainty and precaution in environmental management.

In this paper, two different visions of the relationship between science and policy are contrasted with one another: the "modern" vision and the "precautionary" vision. Conditions which must apply in order to invoke the Precautionary Principle are presented, as are some of the main challenges posed by the principle. The following central question remains: If scientific certainty cannot be provided, what may then justify regulatory interventions, and what degree of intervention is justifiable? The notion of "quality of information" is explored, and it is emphasized that there can be no absolute definition of good or bad quality. Collective judgments of quality are only possible through deliberation on the characteristics of the information, and on the relevance of the information to the policy context. Reference to a relative criterion therefore seems inevitable and legal complexities are to be expected. Uncertainty is presented as a multidimensional concept, reaching far beyond the conventional statistical interpretation of the concept. Of critical importance is the development of methods for assessing qualitative categories of uncertainty. Model quality assessment should observe the following rationale: identify a model that is suited to the purpose, yet bears some reasonable resemblance to the "real" phenomena. In this context, "purpose" relates to the policy and societal contexts in which the assessment results are to be used. It is therefore increasingly agreed that judgment of the quality of assessments necessarily involves the participation of non-modellers and non-scientists. A challenging final question is: How to use uncertainty information in policy contexts? More research is required in order to answer this question.

Transfer of the human NaI symporter gene enhances iodide uptake in hepatoma cells.

UNLABELLED: The characteristic feature of thyroid cells of taking up iodide enables benign thyroid diseases and differentiated thyroid carcinoma to be successfully treated with radioiodide therapy. The transport of iodide across the cell membrane is mediated by the human NaI symporter (hNIS). We therefore investigated whether the accumulation of iodide may be induced by the retroviral transfer of the hNIS gene in nonthyroid tumor cells. METHODS: With use of a bicistronic retroviral vector for the transfer of the hNIS coding sequence and the hygromycin resistance gene, rat Morris hepatoma (MH3924A) cells were infected with retroviral particles and 32 hNIS-expressing cell lines were generated by hygromycin selection. After incubation of the genetically modified and wild-type hepatoma cells and the rat thyroid cell line FRTL5 with Na125I, the uptake and efflux of iodide were determined. In addition, the iodide distribution in rats bearing wild-type and genetically modified hepatomas was monitored. RESULTS: Genetically modified MH3924A cell lines accumulated up to 235 times more iodide than did noninfected hepatoma cells. The maximal iodide uptake in the cells was observed after 60 min incubation time. Competition experiments in the presence of sodium perchlorate revealed a dose-dependent decrease of iodide uptake (87%-92%). Moreover, carbonyl cyanide p-trifluoromethoxyphenylhydrazone led to a loss of accumulated I- (32%), whereas 4,4'-diisothiocyano-2,2'-disulfonic acid stilbene increased the I- uptake into the cells (22%). However, a rapid efflux of the radioactivity (80%) was observed during the first 10 min after 125I(-)-containing medium had been replaced by nonradioactive medium. In rats, the hNIS-expressing tumors accumulated six times more iodide than did the contralateral wild-type tumor as monitored by scintigraphy. The ex vivo quantitation of the iodide content performed 1 h after tracer administration in 1 g of tumor tissue revealed a 17-fold higher iodide accumulation in the genetically modified tumors. In accordance with the in vitro data, we also observed a rapid efflux of radioactivity from the tumor in vivo. CONCLUSION: The transduction of the hNIS gene per se is sufficient to induce 125I transport in Morris hepatoma cells in vitro and in vivo. With regard to a therapeutic application, however, additional conditions need to be defined that inhibit the iodide efflux from the tumor cells.

PET imaging of somatostatin receptors using [68GA]DOTA-D-Phe1-Tyr3-octreotide: first results in patients with meningiomas.

UNLABELLED: Imaging of somatostatin receptors (SSTRs) using [111In]diethylenetriaminepentaacetic-acid-octreotide (DTPAOC) has proven to be helpful in the differentiation of meningiomas, neurinomas or neurofibromas, and metastases as well as in the follow-up of meningiomas. A drawback of the SPECT method is its limited sensitivity in detecting small meningiomas. Because of PET's increased spatial resolution and its ability to absolutely quantify biodistribution, a PET tracer for SSTR imaging would be desirable. METHODS: 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic-acid-D-Phe1-Tyr3-octreotide (DOTATOC) was labeled using the positron-emitting generator nuclide 68Ga. We acquired dynamic PET images over 120 min after intravenous injection of 175 MBq [68Ga]DOTATOC in 3 patients suffering from 8 meningiomas (WHO I degrees; 7- to 25-mm diameter). Patients' heads had been fixed using individually shaped fiber masks equipped with an external stereotactic localizer system to match PET, CT, and MRI datasets. RESULTS: [68Ga]DOTATOC was rapidly cleared from the blood (half-life alpha, 3.5 min; half-life beta, 63 min). Standardized uptake values (SUVs) of meningiomas increased immediately after injection and reached a plateau 60-120 min after injection (mean SUV, 10.6). No tracer could be found in the surrounding healthy brain tissue. All meningiomas (even the 3 smallest [7- to 8-mm diameter]) showed high tracer uptake and could be visualized clearly. Tracer boundaries showed a good correspondence with the matched CT and MRI images. PET provided valuable additional information regarding the extent of meningiomas located beneath osseous structures, especially at the base of the skull. CONCLUSION: According to our initial experiences, [68Ga]DOTATOC seems to be a very promising new PET tracer for imaging SSTRs even in small meningiomas, offering excellent imaging properties and a very high tumor-to-background ratio.

Pretargeting of human mammary carcinoma xenografts with bispecific anti-MUC1/anti-Ga chelate antibodies and immunoscintigraphy with PET.

We recently demonstrated the feasibility of combining enhanced tumor-to-tissue contrast and PET imaging for immunoscintigraphic tumor localization in pancreas and colon carcinoma bearing nude mice. Contrast enhancement was obtained with a multistep targeting technique that consists of the sequential administration of an antitumor/antihapten bispecific antibody (BS-MAb), a blocker to saturate the antihapten binding sites of the BS-MAb that remains in circulation, and a low molecular weight Ga chelate, labeled with the positron emitter 68Ga, which serves as the hapten. To evaluate the efficacy of this pretargeting technique for breast cancer localization, we synthesized a BS-MAb from the F(ab')(2) fragments of the anti-MUC1 MAb 12H12 which reacts with the vast majority of human breast carcinomas, and the F(ab') fragment of an anti-Ga chelate MAb using a bifunctional chemical linker. The BS-MAb was tested for its affinity and its biokinetics in nude mice bearing a human mammary carcinoma. Equilibrium binding of the BS-MAb for mammary carcinoma cells was low (1.2 x 10(7) M(-1)) while the binding capacity of cells was high (8.4 x 10(6) BS-MAbs per cell). Tumor uptake of the 67Ga labeled chelate in pretargeted animals was to 5.8 +/- 0.8% iD/g resulting in a tumor-to-blood ratio of 2.6 at 1h postinjection. This compares with a ratio of 0.65 and 0.85 obtained with 125I-labeled native 12H12 at 24h and 48h postinjection. No difference in the tumor uptake of both the 68Ga and 67Ga labeled chelate was observed. PET imaging of mice, started 1h postinjection of the 68Ga chelate, clearly visualized all tumors.

A new precursor for the radiosynthesis of [18F]FLT.

In order to improve the [18F]FLT production for nuclear medical purposes, the syntheses and labeling results obtained with six new thymidine derivatives involving an alternative protection group strategy are described. The syntheses of the FLT-labeling precursors were performed using the following protection groups at the 5'-O-position: trityl (Tr) and 4,4'-dimethoxytrityl (DMTr). Formation of an electrophilic center at the 3'-carbon was achieved with methylsulfonyl, p-toluenesulfonyl and 4-nitrobenzenesulfonyl groups. The major difference to previous accomplishments rested upon the 3-N-Boc-protection of the FLT-labeling precursors avoiding the deprotection with ceric ammonium nitrate (CAN). With CAN, a precipitate was formed which was found to interact unfavourably with synthesis automation. Here, deprotection resulted in homogeneous solutions which could immediately be loaded on HPLC. The radiosyntheses were performed with high doses of [18F]fluoride to obtain realistic results for routine production of the clinically interesting radiopharmaceutical, [18F]FLT. It was shown that the nosylated precursors were more favorable for radiofluorination than the mesylated or tosylated derivatives. A positive effect on the radiochemical yield was found with DMTr in comparison to Tr. Best results were obtained using 3-N-Boc-1-[5-O-(4,4'-dimethoxytrityl)-3-O-nosyl-2-deoxy-beta-D-lyxofuranosyl]thymine yielding 1.7 GBq (19.8% EOB) whithin 85 minutes.

PET findings and neuropsychological deficits in a case of Fahr's disease.

In a case of Fahr's disease with frontal lobe type dementia and hyperkinetic-hypotone syndrome, functional changes were investigated using positron emission tomography (PET) with (18)F-fluorodeoxyglucose (FDG) as a tracer. Computed tomography showed bilateral calcifications in the putamen and globus pallidus consistent with the diagnosis of Fahr's disease and a frontally pronounced brain atrophy. In contrast, reduced glucose uptake in PET was not only confined to the areas mentioned above, but extended to the temporal and parietal cortices, bilaterally. These functional changes corresponded to the neuropsychological deficits observed, i.e. disturbed selective attention and cognitive flexibility, verbal perseverations, and declarative memory deficits. It is suggested that functional changes may precede cerebral atrophy in Fahr's disease and may reflect deficits in functional circuits, which involve both the basal ganglia and the frontal, parietal, and temporal lobes.