Cyclotron production of high–specific activity 55Co and in vivo evaluation of the stability of 55Co metal-chelate-peptide complexes

This work describes the production of high–specific activity 55 Co and the evaluation of the stability of 55 Co-metal-chelate-peptide complexes in vivo. 55 Co was produced via the 58 Ni(p,α) 55 Co reaction and purified using anion exchange chromatography with an average recovery of 92% and an average specific activity of 1.96 GBq/μmol. 55 Co-DO3A and 55 Co-NO2A peptide complexes were radiolabeled at 3.7 MBq/μg and injected into HCT-116 tumor xenografted mice. Positron emission tomography (PET) and biodistribution studies were performed at 24 and 48 hours postinjection and compared to those of 55 CoCl 2 . Both 55 Co-metal-chelate complexes demonstrated good in vivo stability by reducing the radiotracers’ uptake in the liver by sixfold at 24 hours with ˜ 1% ID/g and at 48 hours with ˜ 0.5% ID/g and reducing uptake in the heart by fourfold at 24 hours with ˜ 0.7% ID/g and sevenfold at 48 hours with ˜ 0.35% ID/g. These results support the use of 55 Co as a promising new radiotracer for PET imaging of cancer and other diseases

Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015 : a systematic analysis for the Global Burden of Disease Study 2015

Background Improving survival and extending the longevity of life for all populations requires timely, robust evidence on local mortality levels and trends. The Global Burden of Disease 2015 Study (GBD 2015) provides a comprehensive assessment of all-cause and cause-specific mortality for 249 causes in 195 countries and territories from 1980 to 2015. These results informed an in-depth investigation of observed and expected mortality patterns based on sociodemographic measures. Methods We estimated all-cause mortality by age, sex, geography, and year using an improved analytical approach originally developed for GBD 2013 and GBD 2010. Improvements included refinements to the estimation of child and adult mortality and corresponding uncertainty, parameter selection for under-5 mortality synthesis by spatiotemporal Gaussian process regression, and sibling history data processing. We also expanded the database of vital registration, survey, and census data to 14 294 geography-year datapoints. For GBD 2015, eight causes, including Ebola virus disease, were added to the previous GBD cause list for mortality. We used six modelling approaches to assess cause-specific mortality, with the Cause of Death Ensemble Model (CODEm) generating estimates for most causes. We used a series of novel analyses to systematically quantify the drivers of trends in mortality across geographies. First, we assessed observed and expected levels and trends of cause-specific mortality as they relate to the Socio-demographic Index (SDI), a summary indicator derived from measures of income per capita, educational attainment, and fertility. Second, we examined factors affecting total mortality patterns through a series of counterfactual scenarios, testing the magnitude by which population growth, population age structures, and epidemiological changes contributed to shifts in mortality. Finally, we attributed changes in life expectancy to changes in cause of death. We documented each step of the GBD 2015 estimation processes, as well as data sources, in accordance with Guidelines for Accurate and Transparent Health Estimates Reporting (GATHER). Findings Globally, life expectancy from birth increased from 61.7 years (95% uncertainty interval 61.4-61.9) in 1980 to 71.8 years (71.5-72.2) in 2015. Several countries in sub-Saharan Africa had very large gains in life expectancy from 2005 to 2015, rebounding from an era of exceedingly high loss of life due to HIV/AIDS. At the same time, many geographies saw life expectancy stagnate or decline, particularly for men and in countries with rising mortality from war or interpersonal violence. From 2005 to 2015, male life expectancy in Syria dropped by 11.3 years (3.7-17.4), to 62.6 years (56.5-70.2). Total deaths increased by 4.1% (2.6-5.6) from 2005 to 2015, rising to 55.8 million (54.9 million to 56.6 million) in 2015, but age-standardised death rates fell by 17.0% (15.8-18.1) during this time, underscoring changes in population growth and shifts in global age structures. The result was similar for non-communicable diseases (NCDs), with total deaths from these causes increasing by 14.1% (12.6-16.0) to 39.8 million (39.2 million to 40.5 million) in 2015, whereas age-standardised rates decreased by 13.1% (11.9-14.3). Globally, this mortality pattern emerged for several NCDs, including several types of cancer, ischaemic heart disease, cirrhosis, and Alzheimer's disease and other dementias. By contrast, both total deaths and age-standardised death rates due to communicable, maternal, neonatal, and nutritional conditions significantly declined from 2005 to 2015, gains largely attributable to decreases in mortality rates due to HIV/AIDS (42.1%, 39.1-44.6), malaria (43.1%, 34.7-51.8), neonatal preterm birth complications (29.8%, 24.8-34.9), and maternal disorders (29.1%, 19.3-37.1). Progress was slower for several causes, such as lower respiratory infections and nutritional deficiencies, whereas deaths increased for others, including dengue and drug use disorders. Age-standardised death rates due to injuries significantly declined from 2005 to 2015, yet interpersonal violence and war claimed increasingly more lives in some regions, particularly in the Middle East. In 2015, rotaviral enteritis (rotavirus) was the leading cause of under-5 deaths due to diarrhoea (146 000 deaths, 118 000-183 000) and pneumococcal pneumonia was the leading cause of under-5 deaths due to lower respiratory infections (393 000 deaths, 228 000-532 000), although pathogen-specific mortality varied by region. Globally, the effects of population growth, ageing, and changes in age-standardised death rates substantially differed by cause. Our analyses on the expected associations between cause-specific mortality and SDI show the regular shifts in cause of death composition and population age structure with rising SDI. Country patterns of premature mortality (measured as years of life lost [YLLs]) and how they differ from the level expected on the basis of SDI alone revealed distinct but highly heterogeneous patterns by region and country or territory. Ischaemic heart disease, stroke, and diabetes were among the leading causes of YLLs in most regions, but in many cases, intraregional results sharply diverged for ratios of observed and expected YLLs based on SDI. Communicable, maternal, neonatal, and nutritional diseases caused the most YLLs throughout sub-Saharan Africa, with observed YLLs far exceeding expected YLLs for countries in which malaria or HIV/AIDS remained the leading causes of early death. Interpretation At the global scale, age-specific mortality has steadily improved over the past 35 years; this pattern of general progress continued in the past decade. Progress has been faster in most countries than expected on the basis of development measured by the SDI. Against this background of progress, some countries have seen falls in life expectancy, and age-standardised death rates for some causes are increasing. Despite progress in reducing age-standardised death rates, population growth and ageing mean that the number of deaths from most non-communicable causes are increasing in most countries, putting increased demands on health systems. Copyright (C) The Author(s). Published by Elsevier Ltd.Peer reviewe

Targeting HER2 in Nuclear Medicine for Imaging and Therapy

Since its discovery, the human epidermal growth factor 2 (HER2) has been extensively studied. Presently, there are 2 standard diagnostic techniques to assess HER2 status in biopsies: immunohistochemistry and fluorescence in situ hybridization. While these techniques have played an important role in the treatment of patients with HER2-positive cancer, they both require invasive biopsies for analysis. Moreover, the expression of HER2 is heterogeneous in breast cancer and can change over the course of the disease. Thus, the degree of HER2 expression in the small sample size of biopsied tumors at the time of analysis may not represent the overall status of HER2 expression in the whole tumor and in between tumor foci in the metastatic setting as the disease progresses. Unlike biopsy, molecular imaging using probes against HER2 allows for a noninvasive, whole-body assessment of HER2 status in real time. This technique could potentially select patients who may benefit from HER2-directed therapy and offer alternative treatments to those who may not benefit. Several antibodies and small molecules against HER2 have been labeled with different radioisotopes for nuclear imaging and/or therapy. This review presents the most recent advances in HER2 targeting in nuclear medicine focusing on preclinical and clinical studies

Imaging the L-type amino acid transporter-1 (LAT1) with Zr-89 immunoPET.

The L-type amino acid transporter-1 (LAT1, SLC7A5) is upregulated in a wide range of human cancers, positively correlated with the biological aggressiveness of tumors, and a promising target for both imaging and therapy. Radiolabeled amino acids such as O-(2-[(18)F]fluoroethyl)-L-tyrosine (FET) that are transport substrates for system L amino acid transporters including LAT1 have met limited success for oncologic imaging outside of the brain, and thus new strategies are needed for imaging LAT1 in systemic cancers. Here, we describe the development and biological evaluation of a novel zirconium-89 labeled antibody, [(89)Zr]DFO-Ab2, targeting the extracellular domain of LAT1 in a preclinical model of colorectal cancer. This tracer demonstrated specificity for LAT1 in vitro and in vivo with excellent tumor imaging properties in mice with xenograft tumors. PET imaging studies showed high tumor uptake, with optimal tumor-to-non target contrast achieved at 7 days post administration. Biodistribution studies demonstrated tumor uptake of 10.5 ± 1.8 percent injected dose per gram (%ID/g) at 7 days with a tumor to muscle ratio of 13 to 1. In contrast, the peak tumor uptake of the radiolabeled amino acid [(18)F]FET was 4.4 ± 0.5 %ID/g at 30 min after injection with a tumor to muscle ratio of 1.4 to 1. Blocking studies with unlabeled anti-LAT1 antibody demonstrated a 55% reduction of [(89)Zr]DFO-Ab2 accumulation in the tumor at 7 days. These results are the first report of direct PET imaging of LAT1 and demonstrate the potential of immunoPET agents for imaging specific amino acid transporters

New Methods for the Site-Selective Placement of Peptides on a Microelectrode Array: Probing VEGF–v107 Binding as Proof of Concept

Cu­(I)-catalyzed “click” reactions cannot be performed on a borate ester derived polymer coating on a microelectrode array because the Cu­(II) precursor for the catalyst triggers background reactions between both acetylene and azide groups with the polymer surface. Fortunately, the Cu­(II)-background reaction can itself be used to site-selectively add the acetylene and azide nucleophiles to the surface of the array. In this way, molecules previously functionalized for use in “click” reactions can be added directly to the array. In a similar fashion, activated esters can be added site-selectively to a borate ester coated array. The new chemistry can be used to explore new biological interactions on the arrays. Specifically, the binding of a v107 derived peptide with both human and murine VEGF was probed using a functionalized microelectrode array

Evaluation of ⁸⁹Zr-pertuzumab in Breast Cancer Xenografts

Pertuzumab is a monoclonal antibody that binds to HER2 and is used in combination with another HER2–specific monoclonal antibody, trastuzumab, for the treatment of HER2+ metastatic breast cancer. Pertuzumab binds to an HER2 binding site distinct from that of trastuzumab, and its affinity is enhanced when trastuzumab is present. We aim to exploit this enhanced affinity of pertuzumab for its HER2 binding epitope and adapt this antibody as a PET imaging agent by radiolabeling with ⁸⁹Zr to increase the sensitivity of HER2 detection in vivo. Here, we investigate the biodistribution of ⁸⁹Zr-pertuzumab in HER2–expressing BT-474 and HER2–nonexpressing MDA-MB-231 xenografts to quantitatively assess HER2 expression in vivo. In vitro cell binding studies were performed resulting in retained immunoreactivity and specificity for HER2–expressing cells. In vivo evaluation of ⁸⁹Zr-pertuzumab was conducted in severely combined immunodeficient mice, subcutaneously inoculated with BT-474 and MDA-MB-231 cells. ⁸⁹Zr-pertuzumab was systemically administered and imaged at 7 days postinjection (p.i.) followed by terminal biodistribution studies. Higher tumor uptake was observed in BT-474 compared to MDA-MB-231 xenografts with 47.5 ± 32.9 and 9.5 ± 1.7% ID/g, respectively at 7 days p.i (<i>P</i> = 0.0009) and blocking studies with excess unlabeled pertuzumab showed a 5-fold decrease in BT-474 tumor uptake (<i>P</i> = 0.0006), confirming the in vivo specificity of this radiotracer. Importantly, we observed that the tumor accumulation of ⁸⁹Zr-pertuzumab was increased in the presence of unlabeled trastuzumab, at 173 ± 74.5% ID/g (<i>P</i> = 0.01). Biodistribution studies correlate with PET imaging quantification using max SUV (<i>r</i> = 0.98, <i>P</i> = 0.01). Collectively, these results illustrate that ⁸⁹Zr-pertuzumab as a PET imaging agent may be beneficial for the quantitative and noninvasive assessment of HER2 expression in vivo especially for patients undergoing trastuzumab therapy

An illustration of the transmembrane L-type amino acid transporter-1 (LAT1) which forms a functional heterodimer with the 4Fhc heavy chain glycoprotein and is responsible for the transport of amino acids with large neutral side chains through an exchange mechanism.

<p>An illustration of the transmembrane L-type amino acid transporter-1 (LAT1) which forms a functional heterodimer with the 4Fhc heavy chain glycoprotein and is responsible for the transport of amino acids with large neutral side chains through an exchange mechanism.</p