Development of 99mTc-labeled trivalent isonitrile radiotracer for folate receptor imaging.

Folate receptors (FR) are frequently overexpressed in a wide variety of human cancers. The aim of this study was to develop a trivalent 99mTc(CO)3-labeled folate radiotracer containing isonitrile (CN-R) as the coordinating ligand for FR target imaging. [99mTc]Tc-10 was HPLC purified (>98% chemical purity) and evaluated in vitro and in vivo as a potential agent for targeting FR-positive KB cells. [99mTc]Tc-10 is a hydrophilic compound with partition coefficient of -2.90 ±â€¯0.13 that showed high binding affinity (0.04 ±â€¯0.002 nM) in vitro. High accumulation and retention of [99mTc]Tc-10 (5.32 ±â€¯2.99% ID/g) was observed in mice with KB tumors at 4 h after injection through the tail vein, which was significantly inhibited by co-injection of free folic acid (FA). SPECT (single photon emission tomography)/CT results were in accordance with biodistribution data at all time points.

Development of (68)Ga-labeled multivalent nitroimidazole derivatives for hypoxia imaging.

Radiolabeled nitroimidazole (NI) derivatives have been extensively studied for imaging hypoxia. To increase the hypoxic tissue uptake, we developed (68)Ga-labeled agents based on mono-, bis-, and trisnitroimidazole conjugates with the chelating agent 1,4,7-triazacyclononane-1,4,7-tris[methyl(2-carboxyethyl)phosphinic acid] (TRAP). All the three agents showed high radiolabeling yields (>96%) and were found to be stable up to 4h in prepared medium at room temperature and in human serum at 37°C. The trivalent agent showed a significant increase in hypoxic to normoxic uptake ratio (p <0.005) according to the in vitro cell uptake experiments. Immunohistochemical analysis confirmed the presence of hypoxia in xenografted CT26 tumor tissue. The trivalent derivative ((68)Ga-3: 0.17±0.04, (68)Ga-4: 0.33±0.04, (68)Ga-5: 0.45±0.09, and (68)Ga-6: 0.47±0.05% ID/g) showed the highest uptake by tumor cells according to the biodistribution studies in CT-26 xenografted mice. All the nitroimidazole derivatives showed significantly higher uptake by tumor cells than the control agent (p <0.05) at 1h post-injection. The trivalent derivative ((68)Ga-3: 0.10±0.06; (68)Ga-4: 0.20±0.06; (68)Ga-5: 0.33±0.08; (68)Ga-6: 0.59±0.09) also showed the highest standard uptake value for tumor cells at 1h post-injection in animal PET studies using CT-26 xenografted mice. In conclusion, we successfully synthesized multivalent (68)Ga-labeled NI derivatives for imaging hypoxia. Among them, the trivalent agent showed the highest tumor uptake in biodistribution and animal PET studies.

A Novel Angiotensin Type I Receptor Antagonist, Fimasartan, Prevents Doxorubicin-induced Cardiotoxicity in Rats.

Angiotensin receptor blockers (ARBs) have organ-protective effects in heart failure and may be also effective in doxorubicin-induced cardiomyopathy (DOX-CMP); however, the efficacy of ARBs on the prevention of DOX-CMP have not been investigated. We performed a preclinical experiment to evaluate the preventive effect of a novel ARB, fimasartan, in DOX-CMP. All animals underwent echocardiography and were randomly assigned into three groups: treated daily with vehicle (DOX-only group, n=22), 5 mg/kg of fimasartan (Low-fima group, n=22), and 10 mg/kg of fimasartan (High-fima group, n=19). DOX was injected once a week for six weeks. Echocardiography and hemodynamic assessment was performed at the 8th week using a miniaturized conductance catheter. Survival rate of the High-fima group was greater (100%) than that of the Low-fima (75%) and DOX-only groups (50%). Echocardiography showed preserved left ventricular (LV) ejection fraction in the High-fima group, but not in the DOX-only group (P=0.002). LV dimensions increased in the DOX-only group; however, remodeling was attenuated in the Low-fima and High-fima groups. Hemodynamic assessment showed higher dP/dt in the High-fima group compared with the DOX-only group. A novel ARB, fimasartan, may prevent DOX-CMP and improve survival rate in a dose-dependent manner in a rat model of DOX-CMP and could be a treatment option for the prevention of DOX-CMP.

Translating medical effectiveness research into policy: lessons from the California Health Benefits Review Program.

CONTEXT: Legislatures and executive branch agencies in the United States and other nations are increasingly using reviews of the medical literature to inform health policy decisions. To clarify these efforts to give policymakers evidence of medical effectiveness, this article discusses the California Health Benefits Review Program (CHBRP). This program, based at the University of California, analyzes the medical effectiveness of health insurance benefit mandate bills for the California legislature, as well as their impact on cost and public health. METHODS: This article is based on the authors' experience reviewing benefit mandate bills for CHBRP and findings from evaluations of the program. General observations are illustrated with examples from CHBRP's reports. Information about efforts to incorporate evidence into health policymaking in other states and nations was obtained through a review of published literature. FINDINGS: CHBRP produces reports that California legislators, legislative staff, and other major stakeholders value and use routinely in deliberations about benefit mandate bills. Where available, the program relies on previously published meta-analyses and systematic reviews to streamline the review of the medical literature. Faculty and staff responsible for the medical effectiveness sections of CHBRP's reports have learned four major lessons over the course of the program's six-year history: the need to (1) recognize the limitations of the medical literature, (2) anticipate the need to inform legislators about the complexity of evidence, (3) have realistic expectations regarding the impact of medical effectiveness reviews, and (4) understand the consequences of the reactive nature of mandated benefit reviews. CONCLUSIONS: CHBRP has demonstrated that it is possible to produce useful reviews of the medical literature within the tight time constraints of the legislative process. The program's reports have provided state legislators with independent analyses that allow them to move beyond sifting through conflicting information from proponents and opponents to consider difficult policy choices and their implications.

Computing differential sample size for case-control studies of gene-environment interaction.

The rates for diseases such as cancer, cardiovascular disease, and diabetes are known to differ by ethnic/racial groups. However, neither genetic nor environmental factors fully explain the observed differences. Failure to account for genetic expression in the absence or presence of an environmental factor, and vice-versa, may lead to erroneous conclusions regarding the importance of these factors in disease etiology. We present a novel method for computing sample size for case-control studies involving the interaction of genetic and environmental factors. The method is based on an indirect estimate of the odds ratio for gene-environment interaction given only the odds ratio for environmental exposure and population genotype frequency. A table is presented providing sample sizes required for detecting a minimum odds ratio for gene-environment interaction given varying genotype frequencies and environmental exposure odds ratio values. Sample size increases proportionately with genotype frequency for a given environment exposure odds ratio.

Refugee Policy Implications of U.S. Immigration Medical Screenings: A New Era of Inadmissibility on Health-Related Grounds.

Refugees frequently face extended delays in their efforts to enter the United States (U.S.) and those who are successful, in many cases, encounter overwhelming obstacles, inadequate resources, and a complex system of legal barriers. Travel restrictions based on equivocal health concerns and a drop in refugee admittance ceilings have complicated the situation. The authors retrieved and analyzed peer-reviewed journal articles, government agency press releases, media postings, epidemiologic factsheets, and relevant lay publications to critically assess U.S. policy regarding refugee resettlement based on health-related grounds. While refugees arguably exhibit an increased incidence of measles and tuberculosis compared with the U.S. population, the legitimacy of the medical examination will be undermined if other diseases that are endemic to refugee populations, yet currently deemed admissible, are used to restrict refugees from entering the U.S. This paper addressees the historic refugee policy of the U.S. and its consequent effect on the health of this vulnerable population. The needs of refugees should be carefully considered in the context of increased disease burden and the associated health care challenges of the country as a whole.

Tobacco industry sponsorship of a book and conflict of interest.

AIM: The tobacco industry has hidden its involvement in the design, conduct and publication of scientific research articles and has used the articles to argue against tobacco regulation. The objective of this study is to examine tobacco industry involvement in the development of scientific books. DESIGN: Qualitative analysis of previously secret internal tobacco industry documents retrieved from the Legacy Tobacco Documents Library (http://legacy.library.ucsf.edu). Information from the documents was supplemented with material from Internet searches, the National Center for Biotechnology Information Pubmed database and interviews with individuals involved in book publication. FINDINGS: Between 1997 and 1999 the tobacco industry sponsored a monograph, entitled 'Analytical Determination of Nicotine and Related Compounds and their Metabolites', that examined the measurement and metabolism of nicotine. The tobacco industry recruited Elsevier Science to publish the monograph. Tobacco industry executives, lawyers and scientists reviewed the chapters. One use of the monograph was to stimulate collaborative efforts between academic and tobacco industry scientists. Another was to provide the book to a government regulatory agency reviewing the teratogenic effects of nicotine. CONCLUSION: Our findings show the breadth of tobacco industry engagement in scientific knowledge production and dissemination, and its motives for sponsoring scientific literature. The industry's effort to gain credibility through collaboration with academic scientists raises questions regarding the ethics of accepting tobacco industry funding for publication. Scientists who collaborate on publications sponsored by the tobacco industry must consider the full implications of these joint efforts.

Chemopreventive effects of korean red ginseng extract on rat hepatocarcinogenesis.

The objective of this study was to determine a chemopreventive activity of Korean red ginseng extract (KRG) in diethylnitrosamine (DEN) induced hepatocarcinogenesis in rats. After acclimatization for a week, Sprague-Dawley rats were randomized into five groups (n = 15) and fed either KRG (0.5, 1 or 2%) or control diets for 10 weeks. After two weeks of starting of experimental diets, the rats were initiated hepatocarcinogenesis by injection of DEN and were then subjected to two-thirds partial hepatectomy at five-week for developing the medium-term bioassay system. Both 0.5 and 1% KRG diets suppressed the area (55 and 60%; p= 0.0251 and 0.0144) and number (39 and 59%; p= 0.0433 and 0.0012) of glutathione S-transferase placental form (GST-P) positive foci when compared to the DEN-control group. The production of thiobarbituric acid reactive substances (TBARS) was significantly reduced in 0.5 and 1% KRG-treated rats. The supplementation of 1% KRG diet significantly elevated the levels of total glutathione (tGSH) and glutathione-related enzymes including cytosolic glutathione S-transferase (GST) and glutathione peroxidase (GPx) activities. It was also observed in cDNA microarray that the gene expressions (Cyp2c6, Cyp2e1, Cyp3a9, and Mgst1) involved in the xenobiotics metabolism via cytochrome P450 signaling pathway were down-regulated in the 1% KRG diet-treated group when compared to the DEN-control. The chemopreventive effects of KRG could be affected by 1) the decrease of lipid peroxidation, 2) the increase of tGSH content and GSH-dependent enzyme activities, and 3) the decrease of the gene expression profile involved in cytochrome P450 signaling pathway. These results suggest that KRG may prove to be a therapeutic agent against hepatocarcinogenesis.

Ga-68-labeled neolactosylated human serum albumin (LSA) for PET imaging of hepatic asialoglycoprotein receptor.

INTRODUCTION: The purpose of this study was the development of (68)Ga-labeled neolactosylated human serum albumin (LSA) for imaging asialoglycoprotein receptors in the liver by using positron emission tomography (PET), which would enable functional imaging with higher resolution than single-photon emission computed tomography (SPECT). METHODS: LSA was synthesized by conjugating α-lactose to human serum albumin (HSA) by reductive amination. LSA was conjugated with 2-(p-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (SCN-NOTA) and the resultant NOTA-LSA was labeled with (68)Ga at room temperature. The labeling efficiency of NOTA-LSA was evaluated as a function of pH and time. The stability of (68)Ga-NOTA-LSA in phosphate buffered saline (PBS) and human serum at 37 °C was determined. Biodistribution and PET studies of (68)Ga-NOTA-LSA were performed in mice following tail vein injection of radiotracer. RESULTS: The numbers of lactose and NOTA units per HSA were determined to be 31.7 and 4.6, respectively. When the reaction was done at room temperature, the labeling efficiency of NOTA-LSA was higher than 99% at pH 4.8 and 96% at pH 6. More than 95% of the detected radioactivity was associated with the intact molecule for at least the 4h following synthesis when incubated in PBS or human serum at 37 °C. Biodistribution and animal PET studies showed specific retention of (68)Ga-NOTA-LSA in liver following intravenous administration. CONCLUSION: (68)Ga-NOTA-LSA was successfully developed for imaging asialoglycoprotein receptors in the liver with a simple labeling method, high labeling efficiency, and high stability.

Evaluation of (111)In-labeled macrocyclic chelator-amino acid derivatives for cancer imaging.

PURPOSE: We evaluated new (111)In-labeled amino acid derivatives, in which the amino acids are conjugated with1,4,7,10-tetra-azacyclododecane-1,4,7,10-tetraacetic acid (DOTA), 1,4,7,10-tetraazacyclododecane-1,7-diacetic acid (DO2A) or 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A). METHODS: DOTA-aminoalanine (DOTA-A), DOTA-aminohomoalanine (DOTA-H), DOTA-lysine (DOTA-L), DO2A-alanine (DO2A-A), DO3A-alanine (DO3A-A) and DO3A-homoalanine (DO3A-H) were labeled with (111)In. In vitro cell uptake assays were performed usingHep3B (a human hepatoma cell line), CT26 (a mouse colon cancer cell line) and U87MG (a human glioma cell line). In vitro cell uptake inhibition assays were performed using U87MG and (111)In-DO3A-H. U87MG bearing xenografted mice were subject to biodistribution, SPECT imaging, autoradiography, and immunohistochemistry studies. RESULTS: Of the amino acid derivatives and cell lines examined, U87MG and (111)In-DO3A-H showed highest uptake in vitro. This uptake was blocked by 2-aminobicyclo-[2,2,1] heptane-2-carboxylic acid (BCH) and by tryptophan. (111)In-DO3A-HSPECT imaging of U87MG bearing xenografted mice visualized tumors (mean tumor-to-muscle ratio 3.16±0.74). Autoradiography and immunohistochemistry revealed that (111)In-DO3A-H uptake matched L-type amino acid transporter 1 expression. CONCLUSION: Tumor uptake was successfully imaged using (111)In-DO3A-H in U87MG bearing xenografted mice. (111)In-DO3A-H appears to be useful for imaging tumors expressing L-type amino acid transporter.

West Coast study of childhood brain tumours and maternal use of hair-colouring products.

The immature nervous system of the fetus is characterised by rapid cell growth and division and is particularly vulnerable to carcinogens and mutagens. Several epidemiological studies have reported an increased risk for childhood brain tumours (CBT) associated with exposure to N-nitroso compounds (NOC). Hair-colouring products (hair "dyes") that contain NOC-related aromatic amines have shown mutagenicity in vitro and carcinogenic properties in vivo. The potential public health impact of the relationship between hair dye use and carcinogenesis has prompted epidemiological research, given that a large proportion of American women have used hair dyes. A large population-based case-control study was conducted on the west coast of the USA to investigate risk factors for CBT including exposure to NOC. Eligible CBT patients (<20 years of age and diagnosed between 1984 and 1991) were identified from cancer registries in Los Angeles County, the San Francisco Bay Area in California and the Seattle area in Washington state. A total of 540 biological mothers of these children were interviewed, and 801 control subjects who were frequency matched to the CBT patients on birth year and sex were obtained using random digit dialling. Mothers were asked details about personal use of hair dyes during the index pregnancy including frequency of use, trimester of use and type of dye used. Results from age- and sex-adjusted unconditional logistic regression analyses showed no association between risk for CBT and use of hair dyes 1 month before and/or during pregnancy nor during specific trimesters. A nearly twofold increased risk for CBT was associated with single-interval use during the 1 month before pregnancy, but the confidence interval (CI) was imprecise and the estimate was not different from unity (OR = 1.9, 95% CI [0.5, 7.0]). Exclusive use of permanent dye, temporary dye or hair darkeners was not associated with risk for CBT. A twofold increased risk (OR = 2.0, 95% CI [0.83, 4.7]) was observed with exclusive use of semi-permanent dye during the month before or during pregnancy. Exclusive use of semi-permanent dye during the month before pregnancy and/or first trimester also was associated with an elevated risk for CBT, again not different from unity and with an imprecise CI (OR = 2.5, 95% CI = [0.58, 10.3]). There was no evidence of an association between risk for CBT by histological subtypes and use of hair dyes during the index pregnancy or the month before conception. Together with results from previous studies, these results provide no consistent evidence of an association between risk for CBT and use of hair dyes during pregnancy.