Development and evaluation of a 44 Ti, 44 Sc radionuclide generator and labeling of biomolecules with 44 Sc and 68 Ga for PET imaging

Non-invasive molecular-imaging technologies are playing a key role in drug discovery, development and delivery. Positron Emission Tomography (PET) is such a molecular imaging technology and a powerful tool for the observation of various deceases in vivo. However, it is limited by the availability of vectors with high selectivity to the target and radionuclides with a physical half-life which matches the biological half-life of the observed process. The 68Ge/68Ga radionuclide generator makes the PET-nuclide anywhere available without an on-site cyclotron. Besides the perfect availability 68Ga shows well suited nuclide properties for PET, but it has to be co-ordinated by a chelator to introduce it in a radiopharmaceuticals.rnHowever, the physical half-life of 68Ga (67.7 min) might limit the spectrum of clinical applications of 68Ga-labelled radiodiagnostics. Furthermore, 68Ga-labelled analogues of endoradiotherapeuticals of longer biological half-live such as 90Y- or 177Lu-labeled peptides and proteins cannot be used to determine individual radiation dosimetry directly. rnThus, radionuclide generator systems providing positron emitting daughters of extended physical half-life are of renewed interest. In this context, generator-derived positron emitters with longer physical half-life are needed, such as 72As (T½ = 26 h) from the 72Se/72As generator, or 44Sc (T½ = 3.97 h) from the 44Ti/44Sc generator.rnIn this thesis the implementation of radioactive gallium-68 and scandium-44 for molecular imaging and nuclear medical diagnosis, beginning with chemical separation and purification of 44Ti as a radionuclide mother, investigation of pilot generators with different elution mode, building a prototype generator, development and investigation of post-processing of the generator eluate, its concentration and further purification, the labeling chemistry under different conditions, in vitro and in vivo studies of labeled compounds and, finally, in vivo imaging experiments are described.

Application of Ga(68) -DOTA-exendin-4 PET/CT to localise an occult insulinoma

A 49 year old female presented to our Neuroendocrine Tumour (NET) centre with recurrent severe and disabling hypoglycaemia. She had previously been extensively investigated with a clinical and biochemical diagnosis of endogenous hyperinsulinemic hypoglycaemia although the source of hormonal hypersecretion could not be localised with MRI, EUS and (111) In-Octreotide scans. After extensive discussion the patient opted for blind surgical resection undergoing a pylorus-preserving pancreaticoduodenectomy in December 2010. Histological examination of the resected operative specimen demonstrated a normal pancreas with no evidence of neuroendocrine tumour. Consistent with this, post-surgery her hypoglycaemic symptoms persisted with fasting capillary blood glucose of 2.1-6.0 mmol/l with increasing hypoglycaemia unawareness. Consequently she sought alternative clinical opinions from two European Neuroendocrine Tumour Society (ENETS) Centres of Excellence who investigated her collaboratively. This article is protected by copyright. All rights reserved.

Improving diagnosis of tumor-induced osteomalacia with gallium-68 DOTATATE PET/CT

Context: Tumor-induced osteomalacia (TIO) is a rarely diagnosed disorder presenting with bone pain, fractures, muscle weakness, and moderate-to-severe hypophosphatemia resulting from fibroblast growth factor 23-mediated renal phosphate wasting. Tumors secreting fibroblast growth factor 23 are often small and difficult to find with conventional imaging. Objective: We studied the utility of 68Ga-DOTA-octreotate (DOTATATE) somatostatin receptor positron emission tomography (PET)/computed tomography (CT) imaging in the diagnosis of TIO. Design and Setting: A multicenter case series was conducted at tertiary referral hospitals. Patients and Methods: Six patients with TIO diagnosed between 2003 and 2012 in Australia were referred for DOTATATE PET imaging. We reviewed the clinical history, biochemistry, imaging characteristics, histopathology, and clinical outcome of each patient. Results: Each case demonstrated delayed diagnosis despite severe symptoms. DOTATATE PET/CT imaging demonstrated high uptake and localized the tumor with confidence in each case. After surgical excision, there was resolution of clinical symptoms and serum phosphate, except in one patient who demonstrated residual disease on PET/CT. All tumors demonstrated high somatostatin receptor subtype 2 cell surface receptor expression using immunohistochemistry. Conclusions: In patients with TIO, DOTATATE PET/CT can successfully localize phosphaturic mesenchymal tumors and may be a practical first step in functional imaging for this disorder. Serum phosphate should be measured routinely in patients with unexplained muscle weakness, bone pain, or stress fractures to allow earlier diagnosis of TIO. - See more at: http://press.endocrine.org/doi/abs/10.1210/jc.2012-3642#sthash.eXD0CopL.dpuf

Macrocyclic bisphosphonates for PET-diagnosis and endoradiotherapy of bone metastases

Die Fallzahlen von Prostata- und Brustkrebs nehmen aktuell die Spitzenplätze bei Krebserkrankungen weltweit ein. Eine schwerwiegende Folge dieser Erkrankung stellen Metastasierungen in das Knochengewebe dar, welche zu einer dramatischen Verschlechterung des Allgemeinzustandes und der Lebensqualität des Patienten führen. Die Symptome sind gekennzeichnet durch enorme Schmerzen in Kombination mit osteoblastischen und osteolytischen Knochenveränderungen, bis hin zu Frakturen und spinalen Kompressionssyndromen, sowie einer metabolischen Hypercalcaemie.rnBei der Diagnose und Therapie nehmen verschiedene Radiopharmaka eine Schlüsselrolle ein. Konjugate aus makrozyklischen Chelatoren und knochenaffinen Bisphosphonaten stellen ein geeignetes Mittel dar als so genannte Theranostika, die Diagnose und Therapie in einem Molekül vereinen. Hierbei konnten mit dem Generator basierenden PET-Nuklid 68Ga(III) und dem Therapienuklid 177Lu(III) erste Erfolge mit der Verbindung BPAMD am Patienten erzielt werden. Im Rahmen der vorliegenden Arbeit ist es gelungen, die pharmakologischen Eigenschaften der BPAMD-Leitstruktur weiter zu optimieren und neue Derivate erfolgreich zu synthetisieren. Diese zeichneten sich durch eine erhöhte Knochenaffinität und eines besseren ´target to background´ Verhältnisses aus. Im Zuge der Derivatisierung ist es außerdem gelungen, erfolgreich eine Substanz darzustellen, welche über eine gesteigerte Blutretention verfügt und die letztendlich die Bioverfügbarkeit des Tracers erhöhte. Verbindungen solchen Typs können zu einem besseren Tumor zu gesundem Knochen Verhältnis beitragen und eventuell einen höheren Therapieerfolg erzielen. Eines dieser neuen vielversprechenden Bisphosphonate, [68Ga]NO2APBP konnte innerhalb einer klinischen Phase 0 bzw. I sein großes Potential als Diagnostikum zur Erfassung von Skelettmetastasen unter Beweis stellen. Innerhalb einer Testreihe mit 12 Patienten wurde eine hohe diagnostische Übereinstimmung mit dem Goldstandard 18F-Fluorid erreicht. In ausgesuchten Metastasen konnte sogar eine höhere Tracer-Aufnahme erzielt werden.rnIn Zukunft können makrozyklische Bisphosphonate eine wichtige Rolle bei der palliativen Schmerztherapie von Knochenmetastasen einnehmen. rn

Localization of Hidden Insulinomas with 68Ga-DOTA-Exendin-4 PET/CT: A Pilot Study.

UNLABELLED (111)In-DOTA-exendin-4 SPECT/CT has been shown to be highly efficient in the detection of insulinomas. We aimed at determining whether novel PET/CT imaging with [Nle(14),Lys(40)(Ahx-DOTA-(68)Ga)NH2]exendin-4 ((68)Ga-DOTA-exendin-4) is feasible and sensitive in detecting benign insulinomas. METHODS (68)Ga-DOTA-exendin-4 PET/CT and (111)In-DOTA-exendin-4 SPECT/CT were performed in a randomized cross-over order on 5 patients with endogenous hyperinsulinemic hypoglycemia. The gold standard for comparison was the histologic diagnosis after surgery. RESULTS In 4 patients histologic diagnosis confirmed a benign insulinoma, whereas one patient refused surgery despite a positive (68)Ga-DOTA-exendin-4 PET/CT scan. In 4 of 5 patients, previously performed conventional imaging (CT or MR imaging) was not able to localize the insulinoma. (68)Ga-DOTA-exendin-4 PET/CT correctly identified the insulinoma in 4 of 4 patients, whereas (111)In-DOTA-exendin-4 SPECT/CT correctly identified the insulinoma in only 2 of 4 patients. CONCLUSION These preliminary data suggest that the use of (68)Ga-DOTA-exendin-4 PET/CT in detecting hidden insulinomas is feasible.

Clinical application of biomarkers in prostate cancer in men with metabolic syndrome project: Prostate Specific Membrane Antigen (PSMA) Positron Emission Tomography (PET) in diagnosing localised prostate cancer

Localised prostate cancer is a heterogenous disease and a multi-modal approach is required to accurately diagnose and stage the disease. Whilst the use of magnetic resonance imaging (MRI) has become more common, small volume and multi-focal disease are oft en diffi cult to characterise. Prostate specifi c membrane antigen is a cell surface protein, which is expressed in nearly all prostate cancer cells. Its expression is signifi cantly higher in high grade prostate cancer cells. In this study, we compare multi-parametric magnetic resonance imaging and 68-Gallinium-PSMA PET with whole-mount pathology of the prostate to evaluate the applicability of multiparameteric (MP) MRI and 68Ga-PSMA PET in detecting and locating tumour foci in patients with localised prostate cancer.

A meta-analysis of pigmentary characteristics, sun sensitivity, freckling and melanocytic nevi and risk of basal cell carcinoma of the skin

Objective: To calculate pooled risk estimates of the association between pigmentary characteristics and basal cell carcinoma (BCC) of the skin. Methods: We searched three electronic databases and reviewed the reference lists of the retrieved articles until July 2012 to identify eligible epidemiologic studies. Eligible studies were those published in between 1965 and July 2012 that permitted quantitative assessment of the association between histologically-confirmed BCC and any of the following characteristics: hair colour, eye colour, skin colour, skin phototype, tanning and burning ability, and presence of freckling or melanocytic nevi. We included 29 studies from 2236 initially identified. We calculated summary odds ratios (ORs) using weighted averages of the log OR, using random effects models. Results: We found strongest associations with red hair (OR 2.02; 95% CI: 1.68, 2.44), fair skin colour (OR 2.11; 95% CI: 1.56, 2.86), and having skin that burns and never tans (OR 2.03; 95% CI: 1.73, 2.38). All other factors had weaker but positive associations with BCC, with the exception of freckling of the face in adulthood which showed no association. Conclusions: Although most studies report risk estimates that are in the same direction, there is significant heterogeneity in the size of the estimates. The associations were quite modest and remarkably similar, with ORs between about 1.5 and 2.5 for the highest risk level for each factor. Given the public health impact of BCC, this meta-analysis will make a valuable contribution to our understanding of BCC.

Graph theory based representation of building information models for access control applications

Building information models are increasingly being utilised for facility management of large facilities such as critical infrastructures. In such environments, it is valuable to utilise the vast amount of data contained within the building information models to improve access control administration. The use of building information models in access control scenarios can provide 3D visualisation of buildings as well as many other advantages such as automation of essential tasks including path finding, consistency detection, and accessibility verification. However, there is no mathematical model for building information models that can be used to describe and compute these functions. In this paper, we show how graph theory can be utilised as a representation language of building information models and the proposed security related functions. This graph-theoretic representation allows for mathematically representing building information models and performing computations using these functions.

内蒙古锡林河流域湿地植被研究及道路对该区草地退化的影响

通过群落生态学和景观生态学方法，结合GIS、RS技术对锡林河流域湿地植被进行了研究。结果表明：流域湿地面积为301.62km2，占流域面积的3%左右。尽管面积相对较小，但是物种丰富，群落结构多样。植被调查数据显示基本确定的植被型4个，植被亚型6个，群系组16个，群系68个，区系成分以泛北极种为主，占69%，相对简单;按照水分生态型划分，中生物种占最多，为44.32％;按生活型分以多年生草本为主占50％以上;科属分布相对复杂，隶属39个科，其中禾本科和菊科是最大的两个科，所占比例仅有17.30％和12.43％，其他科没有明显的优势性，充分说明湿地优越的生境可以满足多种植物共同生长。 多度分布是研究物种多样性分布的重要组分，同时反映了群落结构的特性。以常用的Lognormal、Logseries和Weibull、Exp、Power模型来拟和6个典型草甸群落和踏头草甸群落的物种多度分布，分log-相对多度-物种级数和物种-游程两种形式进行比较;同时，对于典型草甸群落和踏头群落区分常见种、偶然种等进行细化，深入分析群落多度的变化。结果表明，5个模型对于log-相对多度-物种级数在整个群落水平上均不能很好的拟和，50%以上的点都落在95%置信区间以外;但是对常见种和偶然种的拟和情况要好，Weibull、Power和Logseris模型分别对典型草甸群落常见种、偶然种和中间种能很好的拟和，而Logseries和Power模型对于踏头群落的常见种和偶然种拟和较好。5个模型都能较好的拟和物种-游程分布，其中K—S检验结果表明：Lognormal模型对于无脉苔草、针苔草和荸荠这类相对湿润环境下的典型草甸群落拟和较好，对于长叶火绒草和密花风毛菊群落Weibull拟和最好，Power 模型拟和箭叶橐吾最好，踏头草甸拟和最好的是Logseries模型，踏头间拟合最好的是Exp模型。不同的拟和模型应用于不同的群落类型，可以看出湿地群落的复杂性和生境的多样性。区分常见种和偶然种的拟合结果表明典型群落和踏头群落表现一致，即Lognormal模型对所有种拟和是最好的，而Power模型对偶然种的拟和是最好的，同时，Lognormal对典型草甸群落的中间种拟和也是最好。从中可以看出典型草甸群落和踏头群落尽管在表现形式上不同，但是群落的内部仍存在相似的联系，可能跟相似物种的作用有关。 根据湿地表观类型、植被水分状态和航片判别能力，结合实地调查，采用监督分类的方法将锡林河流域的湿地划分为低湿地草甸、盐化草甸和沼泽三种类型。自1984年以来20多年的时间中，锡林河流域的湿地发生了巨大的变化。尽管总的面积没有太大变化，但是湿地类型发生转化。中上游的低湿地草甸面积减少8.94％，沼泽面积减少30.82％，同时，盐化草甸的面积增加了15.98％。增加的盐化草甸主要是另外两种湿地类型转化而成的，中游水库截流，加速中下游草甸的盐化是锡林河流域湿地变化的主要原因。利用GIS技术依据探讨不同湿地的空间变化，分析沙化对湿地变化的影响，结果表明：沙化只对少数湿地有影响，发育良好的湿地即使处在相对强烈的沙化环境下，仍能保持不变。接着，分析了人类直接干扰对湿地变化的影响，缓冲区居民点分析结果表明：近20年来，位于湿地周边的居民点分布格局发生显著的变化。1980年代，居民点分布在盐化草甸周边的最多，到2004年，居民点在沼泽草甸分布数量为最多，该类湿地水、草和资源最为丰富，人类直接的干扰最大，进而转化成另外两类，减少面积最大。低湿地草甸是物种丰富，结构复杂的一种湿地，抗干扰能力强，恢复能力也强，因此相对的变化面积较小。以锡林浩特市水库上下游的湿地植被物种和群落结构的变化，证明了水量减少是湿地数量、结构改变的直接影响因子。

武汉东湖的轮虫

本文根据1973—1975、1979—1982年在武汉东湖进行的调查资料,并与1962—1963年他人的研究结果对比,总结了20年来,在东湖2个采样站上轮虫的种类演替和数量的变动。轮虫的种类明显地减少。Ⅰ站由1962—1963年的68种至1982年减为44种;Ⅱ站由56种减为49种。由原来Ⅰ站种类多于Ⅱ站演变为Ⅱ站多于Ⅰ站。轮虫的数量急剧增加。Ⅰ站轮虫的年平均值由1962—1963年的687个/升至1982年上升为3,555个/升;Ⅱ站由332个/升上升为1,538个/升。轮虫总数的变动曲线呈夏季和秋季二

利用多重示踪技术研究正常鼠和肿瘤鼠的微量元素代谢(英文)

利用25 MeV/u40Ar +Se中能重离子核反应,制备包含24种元素在内的多重示踪剂,通过对元素γ谱的分析,研究了正常鼠和肿瘤鼠体内微量元素的分布及代谢。Mg,Sr, Ga, As,Sc, V, Cr, Mo, Co,Fe, Y,Zr, Nb和Ru等元素在肿瘤鼠的粪便和尿液中的排泄时间与正常鼠不同。肿瘤鼠与正常鼠相比,Na, Mn,Fe和Co的排泄变化较大,肿瘤鼠的排泄率较正常鼠高;而Ca, Y,Zr和Mo的排泄率肿瘤鼠则较正常鼠低;在正常鼠脏器、组织和血液样品中测出了Na,Rb,Ga,Sc, As,Zn, V,Cr, Mn,Co,Fe、Y,Zr, Tc, Ru, Ag和In等17种元素,肿瘤鼠检测出了除Zn和As之外的其它15种元素。几乎所有的元素在正常鼠中的吸收均比肿瘤鼠高。大部分元素分布在肝、肾和毛皮以及实体瘤中,而Fe和Na在肿瘤组织则没有检测到。

杉木人工林土壤可溶性有机质及其与土壤养分的关系

通过在福建省来舟林场对不同栽植代数杉木人工林土壤可溶性有机碳(DOC)和氮(DON)及土壤养分的研究,其结果表明,随着杉木栽植代数的增加林地土壤DOC和DON含量逐渐下降,在0～10cm土层内第3代杉木林土壤DOC和DON含量分别是第1代杉木林的83.9%和87.1%、第2代杉木林的90.6%和96.9%,在10～20cm土层内第3代杉木林土壤DOC和DON含量分别是第1代杉木林的80.2%和81.5%、第2代杉木林的81.8%和90.0%。在不同林地和土层内土壤DOC含量之间的差异性达到了显著或极显著水平,而DON含量之间的差异性不显著。不同栽植代数杉木林土壤养分的变化趋势与DOM一致,随着杉木连栽,土壤养分含量呈下降趋势。在0～10cm土层内第3代杉木林土壤全氮、全钾、铵态氮和速效钾含量分别是第1代杉木林的83.1%、60.4%、68.1%和44.3%,是第2代杉木林的84.6%、68.5%、74.4%和58.7%;在10～20cm土层内第3代杉木林土壤全氮、全钾、铵态氮和速效钾含量分别是第1代杉木林的74.0%、53.4%、57.6%和54.6%,是第2代杉木林的94.8%、59.5%、74.3%和65.5%。经相关性分析,在各土层内土壤DOC和DON含量与土壤全氮、全钾、铵态氮和速效钾等土壤养分含量存在着不同程度的相关性。

贵州修文小山坝铝土矿中镓等伴生元素分布规律研究

通过ICP-MS等分析方法对贵州小山坝铝土矿中伴生元素的研究，发现该矿床TiO2、Ga、Ge、Sc、Nb、Li和REE等有用伴生元素在铝土矿矿体中均有较高富集，其含量大多接近或超过了工业综合利用标准，具有较大的经济价值，特别是矿区富铁铝土矿石中Ga和Sc等含量异常高。贵州铝土矿资源丰富，其伴生元素在铝土矿冶炼过程中所产生的赤泥中更为富集，因此，贵州铝土矿综合利用前景十分巨大，这些元素潜在的经济价值，在某种程度上，甚至会超过主导产品氧化铝的价值。开展铝土矿中镓等伴生有用元素的分布及赋存状态的研究，对于镓等稀散元素在特殊地质地球化学环境中超常富集机制、矿产资源综合价值的重新认识评估和矿产资源的综合利用将十分重要，不仅可为铝工业注入新的活力，增加新的经济增长点，而且还可以解决大量赤泥堆放和利用问题，同时获得较大的社会效益与环境效益。