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Stephen L Able,1 Zhanglin Cui,2, Wei Shen2 1Global Health Outcomes, Eli Lilly and Company, Indianapolis, IN, USA; 2Global Statistical Sciences, Eli Lilly and Company, Indianapolis, IN, USA Purpose: This study applied a uniform methodology for measuring and comparing duloxetine adherence in the treatment of multiple chronic medical conditions. Materials and methods: Study patients 18–64 years of age initiating duloxetine therapy during 2008 were identified from a large managed care database. The study was restricted to patients with continuous health plan eligibility for 12 months pre- and post-duloxetine initiation. Study patients had ≥1 medical claim with an inpatient or outpatient diagnosis of one (and only one) of the following conditions: major depressive disorder (MDD); generalized anxiety disorder (GAD); fibromyalgia, diabetic peripheral neuropathic pain; or chronic musculoskeletal pain, as established in studies in patients with osteoarthritis and chronic lower back pain (CLBP). Patients initiating duloxetine who had two or more of the six studied conditions were not included in this study, thereby avoiding the need to differentiate between primary and secondary diagnoses from the claims records. Adherence rate was defined as the percentage of patients with a 365-day medication possession ratio ≥0.8. Results: A total of 20,490 patients initiated duloxetine treatment during 2008 with a diagnosis of one of the studied conditions during the study period. The adherence rate in our sample was 34.6% and was highest among patients with MDD (37.3%) and lowest for patients with CLBP (29.9%). In general, adherence among patients with MDD and GAD was greater than among those with a chronic pain condition. Conclusion: Adherence among newly initiated duloxetine patients varied modestly across the medical conditions for which it was used. After adjusting for potential confounders, differences between the mental conditions (MDD and GAD) and the chronic pain conditions (CLBP, osteoarthritis, and diabetic peripheral neuropathic pain) were statistically significant. These results may be useful in the determination of expectations of adherence, and how it may differ for each of the conditions studied. Keywords: adherence, duloxetine, major depressive disorder, generalized anxiety disorder, chronic lower back pain, diabetic peripheral neuropathic pain

Abstract Background Diabetes is often associated with complications and comorbidities. The purpose of this research is to compare medical resources used by patients with the following diagnoses: diabetes mellitus (DM), diabetic neuropathy (DN), and diabetes mellitus combined with comorbid depression (DD). Methods Adult patients who were diagnosed with DM, DN, or DD were included in the study. There were 55,972 patients in the DM cohort, 2,146 in the DN, and 2,379 in the DD. P values for comparisons between the three mutually exclusive cohorts were conducted using the Tukey-Kramer method. Cost comparisons among the cohorts were conducted using a stepwise multivariate regression that controlled for patient characteristics and comorbid conditions. Results Individuals in the DM or DN cohorts were generally more likely to use antidiabetic medications than patients in the DD group. Those diagnosed with DN or DD generally used more pain medications than individuals in the DM cohort. The DM cohort had significantly lower diabetes-related total medical costs ($1,297 v $5,125, p < 0.0001) and lower total medical costs ($4,819 v $24,765, p < 0.0001) than the DN cohort. The DM cohort also had significantly lower diabetes-related total medical costs ($1,297 v $3,264, p < 0.0001) as well as significantly lower total medical costs ($4,819 v $19,298, p < 0.0001) than the DD cohort. Conclusion Results from this study indicated significant differences in demographic characteristics, comorbidities, and medication use among individuals diagnosed with DM, DN, or DD. These differences translated into significant cost differences. Patients diagnosed with DN or DD had higher diabetes-related costs than patients diagnosed with DM.

The intracellular environment hosts a large number of cancer- and other disease-relevant human proteins. Targeting these with internalized antibodies would allow therapeutic modulation of hitherto undruggable pathways, such as those mediated by protein-protein interactions. However, one of the major obstacles in intracellular targeting is the entrapment of biomacromolecules in the endosome. Here we report an approach to delivering antibodies and antibody fragments into the cytosol and nucleus of cells using trimeric cell-penetrating peptides (CPPs). Four trimers, based on linear and cyclic sequences of the archetypal CPP Tat, are significantly more potent than monomers and can be tuned to function by direct interaction with the plasma membrane or escape from vesicle-like bodies. These studies identify a tricyclic Tat construct that enables intracellular delivery of functional immunoglobulin-G antibodies and Fab fragments that bind intracellular targets in the cytosol and nuclei of live cells at effective concentrations as low as 1 μM., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Triple negative breast cancer (TNBC) poses a serious clinical challenge as it is an aggressive form of the disease that lacks estrogen receptor, progesterone receptor, and ERBB2 (formerly HER2) gene amplification, which limits the treatment options. The Warburg phenotype of upregulated glycolysis in the presence of oxygen has been shown to be prevalent in TNBC. Elevated glycolysis satisfies the energy requirements of cancer cells, contributes to resistance to treatment by maintaining redox homeostasis and generating nucleotide precursors required for cell proliferation and DNA repair. Expression of the monocarboxylate transporter 1 (MCT1), which is responsible for the bidirectional transport of lactate, correlates with an aggressive phenotype and poor outcome in several cancer types, including breast cancer. In this study, 3-bromopyruvate (3BP), a lactate/pyruvate analog, was used to selectively target TNBC cells that express MCT1., Methods: The cytotoxicity of 3BP was tested in MTT assays using human TNBC cell lines: BT20 (MCT1 + /MCT4 - ), MDA-MB-23 (MCT1 - /MCT4 + ), and BT20 in which MCT1 was knocked down (siMCT1-BT20). The metabolite profile of 3BP-treated and 3BP-untreated cells was investigated using LC-MS/MS. The extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) of BT20 and MDA-MB-231 cells treated with 3BP were measured using a Seahorse XF96 extracellular flux analyzer. The impact of ionizing radiation on cell survival, alone or in combination with 3BP pre-treatment, was evaluated using clonogenic assays., Results: Metabolomic analyses showed that 3BP causes inhibition of glycolysis, disturbance of redox homeostasis, decreased nucleotide synthesis, and was accompanied by a reduction in medium acidification. In addition, 3BP potentiated the cytotoxic effect of ionizing radiation, a treatment that is frequently used in the management of TNBC., Conclusions: Overall, MCT1-mediated metabolic perturbation in combination with radiotherapy is shown to be a promising strategy for the treatment of glycolytic tumors such as TNBC, overcoming the selectivity challenges of targeting glycolysis with glucose analogs., (© 2021. The Author(s).)

Telomerase represents an attractive target in oncology as it is expressed in cancer but not in normal tissues. The oligonucleotide inhibitors of telomerase represent a promising anticancer strategy, although poor cellular uptake can restrict their efficacy. In this study, gold nanoparticles (AuNPs) were used to enhance oligonucleotide uptake. "match" oligonucleotides complementary to the telomerase RNA template subunit (hTR) and "scramble" (control) oligonucleotides were conjugated to diethylenetriamine pentaacetate (DTPA) for 111 In-labeling. AuNPs (15.5 nm) were decorated with a monofunctional layer of oligonucleotides (ON-AuNP) or a multifunctional layer of oligonucleotides, PEG(polethylene glycol)800-SH (to reduce AuNP aggregation) and the cell-penetrating peptide Tat (ON-AuNP-Tat). Match-AuNP enhanced the cellular uptake of radiolabeled oligonucleotides while retaining the ability to inhibit telomerase activity. The addition of Tat to AuNPs increased nuclear localization. 111 In-Match-AuNP-Tat induced DNA double-strand breaks and caused a dose-dependent reduction in clonogenic survival of telomerase-positive cells but not telomerase-negative cells. hTR inhibition has been reported to sensitize cancer cells to ionizing radiation, and 111 In-Match-AuNP-Tat therefore holds promise as a vector for delivery of radionuclides into cancer cells while simultaneously sensitizing them to the effects of the emitted radiation.

Treatment options for patients with pancreatic cancer are limited and survival prospects have barely changed over the past 4 decades. Chemoradiation treatment (CRT) has been used as neoadjuvant therapy in patients with borderline resectable disease to reduce tumour burden and increase the proportion of patients eligible for surgery. Antimetabolite drugs such as gemcitabine and 5-fluorouracil are known to sensitise pancreatic tumours to radiation treatment. Likewise, photodynamic therapy (PDT) has also been shown to enhance the effect of radiation therapy. However, PDT is limited to treating superficial lesions due to the attenuation of light by tissue. The ability of the related technique, sonodynamic therapy (SDT), to enhance CRT was investigated in two murine models of pancreatic cancer (PSN-1 and BxPC-3) in this study. SDT uses low intensity ultrasound to activate an otherwise non-toxic sensitiser, generating toxic levels of reactive oxygen species (ROS) locally. It is applicable to greater target depths than PDT due to the ability of ultrasound to propagate further than light in tissue. Both CRT and the combination of CRT plus SDT delayed tumour growth in the two tumour models. In the PSN-1 model, but not the BxPC-3 model, the combination treatment caused an increase in survival relative to CRT alone (p = 0.038). The improvement in survival conferred by the addition of SDT in this model may be related to differences in tumour architecture between the two models. MRI and US images showed that PSN-1 tumours were less well perfused and vascularised than BxPC-3 tumours. This poor vascularisation may explain why PSN-1 tumours were more susceptible to the effects of vascular damage exerted by SDT treatment., (Copyright © 2021. Published by Elsevier B.V.)

Theranostic radionuclides that emit Auger electrons (AE) can generate highly localised DNA damage and the accompanying gamma ray emission can be used for single-photon emission computed tomography (SPECT) imaging. Mismatched DNA base pairs (mismatches) are DNA lesions that are abundant in cells deficient in MMR (mismatch mediated repair) proteins. This form of genetic instability is prevalent in the MMR-deficient subset of colorectal cancers and is a potential target for AE radiotherapeutics. Herein we report the synthesis of a mismatch DNA binding bis-ruthenium(ii) dipyridophenazine (dppz) complex that can be radiolabelled with the Auger electron emitting radionuclide indium-111 ( 111 In). Greater stabilisation accompanied by enhanced MLCT (metal to ligand charge-transfer) luminescence of both the bis-Ru(dppz) chelator and non-radioactive indium-loaded complex was observed in the presence of a TT mismatch-containing duplex compared to matched DNA. The radioactive construct [ 111 In]In-bisRu(dppz) ([ 111 In][In- 2 ] 4+ ) targets cell nuclei and is radiotoxic towards MMR-deficient human colorectal cancer cells showing substantially less detrimental effects in a paired cell line with restored MMR function. Additional cell line studies revealed that [ 111 In][In- 2 ] 4+ is preferentially radiotoxic towards MMR-deficient colorectal cancer cells accompanied by increased DNA damage due to 111 In decay. The biodistribution of [ 111 In][In- 2 ] 4+ in live mice was demonstrated using SPECT. These results illustrate how a Ru(ii) polypyridyl complex can incorporate mismatch DNA binding and radiometal chelation in a single molecule, generating a DNA-targeting AE radiopharmaceutical that displays selective radiotoxicity towards MMR-deficient cancer cells and is compatible with whole organism SPECT imaging., (This journal is © The Royal Society of Chemistry 2020.)

Approximately 50% of all colorectal cancer (CRC) patients will develop metastasis to the liver. 90 Y selective internal radiation therapy (SIRT) is an established treatment for metastatic CRC. There is still a fundamental lack of understanding regarding the radiobiology underlying the dose response. This study was designed to determine the radiosensitivity of two CRC cell lines (DLD-1 and HT-29) to 90 Y β - radiation exposure, and thus the relative effectiveness of 90 Y SIRT in relation to external beam radiotherapy (EBRT). A 90 Y-source dish was sandwiched between culture dishes to irradiate DLD-1 or HT-29 cells for a period of 6 d. Cell survival was determined by clonogenic assay. Dose absorbed per 90 Y disintegration was calculated using the PENELOPE Monte Carlo code. PENELOPE simulations were benchmarked against relative dose measurements using EBT3 GAFchromic ™ film. Statistical regression based on the linear-quadratic model was used to determine the radiosensitivity parameters [Formula: see text] and [Formula: see text] using R. These results were compared to radiosensitivity parameters determined for 6 MV clinical x-rays and 137 Cs γ-ray exposure. Equivalent dose of EBRT in 2 Gy ([Formula: see text]) and 10 Gy ([Formula: see text]) fractions were derived for 90 Y dose. HT-29 cells were more radioresistant than DLD-1 for all treatment modalities. Radiosensitivity parameters determined for 6 MV x-rays and 137 Cs γ-ray were equivalent for both cell lines. The [Formula: see text] ratio for 90 Y β - -particle exposure was over an order of magnitude higher than the other two modalities due to protraction of dose delivery. Consequently, an 90 Y SIRT absorbed dose of 60 Gy equates to an [Formula: see text] of 28.7 and 54.5 Gy and an [Formula: see text] of 17.6 and 19.3 Gy for DLD-1 and HT-29 cell lines, respectively. We derived radiosensitivity parameters for two CRC cell lines exposed to 90 Y β - -particles, 6 MV x-rays, and 137 Cs γ-ray irradiation. These radiobiological parameters are critical to understanding the dose response of CRC lesions and ultimately informs the efficacy of 90 Y SIRT relative to other radiation therapy modalities.

The spatial distribution of radiopharmaceuticals that emit short-range high linear-energy-transfer electrons greatly affects the absorbed dose and their biological effectiveness. The purpose of this study was to investigate the effect of heterogeneous radionuclide distribution on tumor control probability (TCP) in a micrometastases model. Methods: Cancer cell lines; MDA-MB-468, SQ20B and 231-H2N were grown as spheroids to represent micrometastases. The intracellular distribution of a representative radiopeptide ( 111 In-labelled epidermal growth factor, EGF) and radioimmunotherapeutic ( 111 In-labelled Trastuzumab) was determined in cell internalization experiments. The intratumoral distribution was evaluated by microautoradiography of spheroids. γH2AX staining was performed on spheroid sections to correlate DNA damage with radionuclide distribution. Experimental surviving fractions ( SF exp ) were obtained using clonogenic assays. A random closed-packed algorithm, which models the random packing behavior of cells and reflects variation in the radii of cells and nuclei, was used to simulate 3-D spheroids. Calculated survival fractions ( SF cal ) were generated using an iterative modelling method based on Monte Carlo determined absorbed dose with the PENELOPE code and were compared to ( SF exp ). Radiobiological parameters deduced from experimental results and MC simulations were used to predict the TCP for a 3-D spheroid model. Results: Calculated SFs were in good agreement with experimental data, particularly when an increased value for relative biological effectiveness (RBE) was applied to self-dose deposited by sources located in the nucleus and when radiobiological parameters were adjusted to account for dose protraction. Only in MDA-MB-468 spheroids treated with 111 In-EGF was a TCP>0.5 achieved, indicating that for this cell type the radiopeptide would be curative when targeting micrometastases. This is attributed to the relative radiosensitivity of MDA-MB-468 cells, high nuclear uptake of the radiopeptide and uniform distribution of radioactivity throughout the spheroid. Conclusion: It is imperative to include biological endpoints when evaluating the distribution of radionuclides in models emulating micrometastatic disease. The spatial distribution of radioactivity is a clear determinant of biological effect and TCP as demonstrated in this study., (Copyright © 2018 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Radiolabelled, drug-loaded nanoparticles may combine the theranostic properties of radionuclides, the controlled release of chemotherapy and cancer cell targeting. Here, we report the preparation of poly(lactic-co-glycolic acid) (PLGA) nanoparticles surface conjugated to DTPA-hEGF (DTPA = diethylenetriaminepentaacetic acid, hEGF = human epidermal growth factor) and encapsulating the ruthenium-based DNA replication inhibitor and radiosensitizer Ru(phen)2(tpphz)2+ (phen = 1,10-phenanthroline, tpphz = tetrapyridophenazine) Ru1. The functionalized PLGA surface incorporates the metal ion chelator DTPA for radiolabelling and the targeting ligand for EGF receptor (EGFR). Nanoparticles radiolabelled with 111In are taken up preferentially by EGFR-overexpressing oesophageal cancer cells, where they exhibit radiotoxicity through the generation of cellular DNA damage. Moreover, nanoparticle co-delivery of Ru1 alongside 111In results in decreased cell survival compared to single-agent formulations; an effect that occurs through DNA damage enhancement and an additive relationship between 111In and Ru1. Substantially decreased uptake and radiotoxicity of nanoparticles towards normal human fibroblasts and oesophageal cancer cells with normal EGFR levels is observed. This work demonstrates nanoparticle co-delivery of a therapeutic radionuclide plus a ruthenium-based radiosensitizer can achieve combinational and targeted therapeutic effects in cancer cells that overexpress EGFR.

Background: The ability to image vascular endothelial growth factor (VEGF) could enable prospective, non-invasive monitoring of patients receiving anti-angiogenic therapy. This study investigates the specificity and pharmacokinetics of 111 In-bevacizumab binding to VEGF and its use for assessing response to anti-angiogenic therapy with rapamycin. Specificity of 111 In-bevacizumab binding to VEGF was tested in vitro with unmodified radiolabelled bevacizumab in competitive inhibition assays. Uptake of 111 In-bevacizumab in BALB/c nude mice bearing tumours with different amounts of VEGF expression was compared to that of isotype-matched control antibody ( 111 In-IgG1κ) with an excess of unlabelled bevacizumab. Intratumoural VEGF was evaluated using ELISA and Western blot analysis. The effect of anti-angiogenesis therapy was tested by measuring tumour uptake of 111 In-bevacizumab in comparison to 111 In-IgG1κ following administration of rapamycin to mice bearing FaDu xenografts. Uptake was measured using gamma counting of ex vivo tumours and effect on vasculature by using anti-CD31 microscopy., Results: Specific uptake of 111 In-bevacizumab in VEGF-expressing tumours was observed. Rapamycin led to tumour growth delay associated with increased relative vessel size (8.5 to 10.3, P = 0.045) and decreased mean relative vessel density (0.27 to 0.22, P = 0.0015). Rapamycin treatment increased tumour uptake of 111 In-bevacizumab (68%) but not 111 In-IgGκ and corresponded with increased intratumoural VEGF 165 ., Conclusions: 111 In-bevacizumab accumulates specifically in VEGF-expressing tumours, and changes after rapamycin therapy reflect changes in VEGF expression. Antagonism of mTOR may increase VEGF in vivo, and this new finding provides the basis to consider combination studies blocking both pathways and a way to monitor effects.

Purpose: To assess the efficacy of different schedules for combining external beam radiotherapy (EBRT) with molecular radiotherapy (MRT) using 131 I-mIBG in the management of neuroblastoma., Materials and Methods: BALB/c nu/nu mice bearing SK-N-SH neuroblastoma xenografts were assigned to five treatment groups: 131 I-mIBG 24h after EBRT, EBRT 6days after 131 I-mIBG, EBRT alone, 131 I-mIBG alone and control (untreated). A total of 56 mice were assigned to 3 studies. Study 1: Vessel permeability was evaluated using dynamic contrast-enhanced (DCE)-MRI (n=3). Study 2: Tumour uptake of 131 I-mIBG in excised lesions was evaluated by γ-counting and autoradiography (n=28). Study 3: Tumour volume was assessed by longitudinal MR imaging and survival was analysed (n=25). Tumour dosimetry was performed using Monte Carlo simulations of absorbed fractions with the radiation transport code PENELOPE., Results: Given alone, both 131 I-mIBG and EBRT resulted in a seven-day delay in tumour regrowth. Following EBRT, vessel permeability was evaluated by DCE-MRI and showed an increase at 24h post irradiation that correlated with an increase in 131 I-mIBG tumour uptake, absorbed dose and overall survival in the case of combined treatment. Similarly, EBRT administered seven days after MRT to coincide with tumour regrowth, significantly decreased the tumour volume and increased overall survival., Conclusions: This study demonstrates that combining EBRT and MRT has an enhanced therapeutic effect and emphasizes the importance of treatment scheduling according to pathophysiological criteria such as tumour vessel permeability and tumour growth kinetics., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

The successful use of targeted radionuclide therapy in the treatment of solid tumours may be limited by radioresistance, which necessitates delivery of a high dose of radioactivity. Nanoparticle (NP)-based delivery systems possess a large surface area for attachment of radioisotopes and so offer a solution to this challenge. However, tumour uptake may be limited by rapid hepatic clearance of NP via the mononuclear phagocyte system. Liver uptake is further compounded when epidermal growth factor (EGF) is used as a targeting ligand, as EGF-tagged NP bind the EGF receptor (EGFR), which is expressed to a moderate extent by hepatocytes. This report describes an indium-111 ( 111 In)-labelled PEGylated EGF-tagged gold (Au) NP ( 111 In-EGF-Au-PEG) and an effective strategy of coadministration of targeting ligand to address these issues. Direct attachment of EGF to the surface of Au NP did not compromise surface coating with long-chain PEG. In vitro experiments showed that 111 In-EGF-Au-PEG targets EGFR-positive cancer cells (MDA-MB-468): >11% of radioactivity was internalised after incubation for 4 h. In in vivo studies accumulation of NP was observed in MDA-MB-468 xenografts and tumour uptake was enhanced by the coadministration of 15 µg of the unlabelled targeting ligand, EGF, to block hepatic EGFR. Uptake was 3.9% versus 2.8% injected dose/g (%ID/g) of tumour tissue with and without unlabelled EGF, respectively. Coadministration of EGF reduced liver uptake by 25.95% to 7.56 %ID/g. This suggests that the coadministration of unlabelled targeting ligand with radiolabelled PEGylated NP offers a promising strategy for targeting EGFR-positive cancer and for minimising liver uptake., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

The surface overexpression of nucleolin provides an anchor for the specific attachment of biomolecules to cancer and angiogenic endothelial cells. The peptide F3 is a high-affinity ligand of the nucleolin receptor (NR) that has been investigated as a carrier to deliver biologically active molecules to tumors for both therapeutic and imaging applications. A site-specific PEGylated F3 derivative was radiolabeled with [ 18 F]Al-F. The binding affinity and cellular distribution of the compound was assessed in tumor (H2N) and tumor endothelial (2H-11) cells. Specific uptake via the NR was demonstrated by the siRNA knockdown of nucleolin in both cell lines. The partition and the plasma stability of the compound were assessed at 37°C. The enzyme-mediated site-specific modification of F3 to give NODA-PEG-F3 (NP-F3) was achieved. Radiolabeling with [ 18 F]Al-F gave 18 F-NP-F3. 18 F-NP-F3 demonstrated high affinity for cancer and tumor endothelial cells. The siRNA knockdown of nucleolin resulted in a binding affinity reduction of 50% to 60%, confirming cell surface binding via the NR. NP-F3 was stable in serum for 2 h. 18 F-NP-F3 is reported as the first 18 F-labeled F3 derivative. It was obtained in a site-specific, high-yield, and efficient manner and binds to surface NR in the low nanomolar range, suggesting it has potential as a tumor and angiogenesis tracer., (Copyright © 2016 The Authors. Journal of Labelled Compounds and Radiopharmaceuticals published by John Wiley & Sons, Ltd.)

Unlabelled: A prominent feature of many human cancers is oncogene-driven activation of the DNA damage response (DDR) during early tumorigenesis. It has been shown previously that noninvasive imaging of the phosphorylated histone H2A variant H2AX, γH2AX, a DNA damage signaling protein, is possible using (111)In-labeled anti-γH2AX antibody conjugated to the cell-penetrating peptide transactivator of transcription (TAT). The purpose of this study was to investigate whether (111)In-anti-γH2AX-TAT detects the DDR during mammary oncogenesis in BALB-neuT mice., Methods: Mammary fat pads from BALB-neuT and wild-type mice (age, 40-106 d) were immunostained for γH2AX. (111)In-anti-γH2AX-TAT or a control probe was administered intravenously to BALB-neuT mice. SPECT was performed weekly and compared with tumor detection using palpation and dynamic contrast-enhanced MR imaging., Results: γH2AX expression was elevated in hyperplastic lesions in the mammary fat pads of BALB-neuT mice aged 76-106 d, compared with normal fat pads from younger mice and carcinomas from older mice (13.5 ± 1.2 γH2AX foci/cell vs. 5.2 ± 1.5 [P < 0.05] and 3.4 ± 1.1 [P < 0.001], respectively). Serial SPECT imaging revealed a 2.5-fold increase in (111)In-anti-γH2AX-TAT accumulation in the mammary fat pads of mice aged 76-106 d, compared with control probe (P = 0.01). The median time to detection of neoplastic lesions by (111)In-anti-γH2AX-TAT (defined as >5% injected dose per gram of tissue) was 96 d, compared with 120 and 131 d for dynamic contrast-enhanced MR imaging and palpation, respectively (P < 0.001)., Conclusion: DDR imaging using (111)In-anti-γH2AX-TAT identified mammary tumors significantly earlier than MR imaging. Imaging the DDR holds promise for the detection of preneoplasia and as a technique for screening cancer-prone individuals., (© 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Nanographene oxide (NGO) is a novel nano-wall material that tracks to tumors in vivo, and which, as a consequence of its large surface area, has the capacity to carry a large payload. This study explores the use of anti-HER2 antibody (trastuzumab)-conjugated NGO, radiolabeled with (111)In-benzyl-diethylenetriaminepentaacetic acid (BnDTPA) via ππ-stacking, for functional imaging. In two HER2-overexpressing murine models of human breast cancer, high tumor-to-muscle ratio was achieved, resulting in clear visualization of tumor using single-photon emission computed tomography (SPECT). In the BALB/neuT model and in BALB/c nu/nu mice bearing 231/H2N xenografts, tumor accumulation amounted to 12.7 ± 0.67 and 15.0 ± 3.7% of the injected dose/g (%ID/g) of tumor tissue at 72 h, with tumor-to-muscle ratios of 35:1 and 7:1, respectively. Radiolabeled NGO-trastuzumab conjugates demonstrated superior pharmacokinetics compared to radiolabeled trastuzumab without NGO, with more rapid clearance from the circulation. The use of NGO as a scaffold to build radiolabeled nano-immunoconstructs holds promise for molecular imaging of tumors., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Avian yolk fatty acids (FA) composition is influenced by two main factors: maternal diet and genetic factors that regulate FA metabolism. However, due to embryonic developmental requirements, yolk FA are thought to be physiologically constrained and less useful for dietary and trophic studies. We assessed the relative contributions of diet and physiological constraints in determining the yolk FA composition of a marine bird, the gentoo penguin (Pygoscelis papua) by comparing FA signatures of yolks and prey between a captive, controlled- feeding experiment and a wild population. Captive and wild yolk FA signatures differed even though both groups' yolk lipids were composed primarily of three FA (16:0, 18:0 and 18:1n-9). Differences were due to FA occurring in relatively low abundance, but which mirrored differences in the FA composition of diets. However, yolk FA signatures were correlated across three penguin species suggesting that common developmental constraints can be relatively more important than species-specific differences in diet or egg-laying physiology. While yolk FA are constrained, several minor components of yolk FA are reflective of diets and the calibration coefficients resulting from this study have the potential to be incorporated into predictive models and allow for quantitative dietary and trophic studies using FA analysis of penguin egg yolks.

The G protein-coupled chemokine (C-C motif) receptor, CCR5, was originally characterized as a protein responding functionally to a number of CC chemokines. As with chemokine receptors in general, studies indicate that CCR5 plays a role in inflammatory responses to infection, although its exact role in normal immune function is not completely defined. The vast majority of research into CCR5 has been focused on its role as an essential and predominant coreceptor for HIV-1 entry into host immune cells. Discovery of this role was prompted by the elucidation that individuals homozygous for a 32 bp deletion in the CCR5 gene do not express the receptor at the cell surface, and as a consequence, are remarkably resistant to HIV-1 infection, and apparently possess no other clear phenotype. Multiple studies followed with the ultimate aim of identifying drugs that functionally and physically blocked CCR5 to prevent HIV-1 entry, and thus provide a completely new approach to treating infection and AIDS, the world's biggest infectious disease killer. To this end, functional antagonists with potent anti-HIV-1 activity have been discovered, as best exemplified by maraviroc, the first new oral drug for the treatment of HIV-1 infection in 10 years. In this chapter, the specific methods used to characterize CCR5 primary pharmacology and apply the data generated to enable drug discovery, notably maraviroc, for the treatment of HIV infection and potentially inflammatory-based indications, are described.

Introduction: A growing body of evidence suggests that symptoms of attention-deficit/hyperactivity disorder (ADHD) persist into adulthood and are associated with ongoing impairment and co-morbidity. The absence of a conceptually sound and well-validated ADHD-specific quality-of-life measure has been an obstacle to understanding this impact. To address this gap, the Adult ADHD Quality-of-Life Scale (AAQoL) was developed based on well accepted methods for designing patient reported outcomes. The purpose of this study was to validate the AAQoL., Methods: Nine Hundred and Eighty Nine adults in a retrospective cohort study were administered the AAQoL and psychometric validation was conducted according to an a priori statistical analysis plan., Results: A 29-item AAQoL was found to have robust scale structure with four domains: Life Productivity, Psychological Health, Relationships and Life outlook. Internal consistency was adequate (0.93 for overall, 0.75-0.93 for subscales), and construct and known-groups validity were supported. conclusion: The AAQoL appears to be a valid measure of quality of life for adults with ADHD and can be considered for incorporation into future studies. The ability to quantify the quality-of-life consequences of adult ADHD should facilitate future research, assist clinicians in identifying appropriate treatment targets and contribute to the ultimate goal of improving the well-being and functioning of adults with ADHD.

Objective: To determine if the type of antidepressant drug is related to adherence to National Committee for Quality Assurance (NCQA) Antidepressant Medication Management (AMM) quality measures and to assess the 6-month health care costs among newly diagnosed depressed patients., Methods: The MarketScan Commercial Claims and Encounter database for medical and pharmacy claims from January 2001 to September 2004 was used to assess adherence to the 3 AMM quality-of-care measures. AMM measures include (a) acute phase, the percentage of eligible members who remained on antidepressant medication continuously for 3 months after the initial diagnosis as determined by at least 84 days supply of antidepressant drugs during the first 114 days following receipt of the index antidepressant; (b) continuation phase, the percentage of eligible members who remained on antidepressant medication continuously for the 6 months after the initial diagnosis as determined by at least 180 days supply of antidepressants during the first 214 days following receipt of the index antidepressant; and (c) practitioner contacts, the percentage of members who received at least 3 follow-up office visits or telephone contacts with health care providers, including at least 1 contact with a practitioner licensed to prescribe (may not necessarily be the prescriber of the antidepressant). A fourth measure, overall adherence, was added, if all 3 AMM measures were met. Multivariate regression models determined demographic, clinical (such as receipt of mental health specialty care, the Charlson Comorbidity Index score, and co-occurring bipolar or schizophrenia), and therapy-related factors associated with outcomes of adherence and costs (paid amounts for insurance-reimbursable health care services for inpatient admissions, emergency department services, outpatient services, and outpatient prescription drugs). Health care expenditures (both total and mental-health-specific costs) were measured for each patient for 6 months following the date of service for the index antidepressant., Results: A total of 60,386 adult patients (10.7%) of 562,898 patients with a depression diagnosis met NCQA inclusion criteria in the AMM Technical Specifications (e.g., aged 18 years or older, newly diagnosed with depression and initiating antidepressant therapy, 365 days of continuous enrollment; patients were excluded if there were missing data on dose or quantity of index drug in pharmacy claims or initiated therapy on 2 or more antidepressants as the index medication, exclusion criteria not in the AMM Technical Specifications). Only 19% of patients achieved overall adherence. Rates for the 3 AMM measures were 39% for practitioner contacts, 65% for acute phase, and 44% for continuation phase. Receipt of mental health specialty care was the only factor that was positively associated with greater adherence on all 4 measures (overall measure: odds ratio [OR]=3.895, 95% confidence interval [CI], 3.72-4.07; acute OR=1.38, 95% CI, 1.33-1.43; continuation OR=1.46, 95% CI, 1.41-1.51; contacts OR=5.83, 95% CI, 5.62-6.06). Most patients were initiated on selective serotonin reuptake inhibitors (SSRIs, 69.5%), followed by venlafaxine (21.4%), tricyclic antidepressants (TCAs, 21.4%), bupropion (11.0%), and other antidepressants (e.g., mirtazapine, nefazadone, trazadone; 7.2%). Before adjustment for confounding factors, patients initiated on venlafaxine, TCAs, or other antidepressants had higher rates of adherence on the overall performance measure versus initiators on SSRIs, but the absolute differences were relatively small: 21.4% for venlafaxine and TCAs and 23.1% for other antidepressants versus 18.5% for SSRIs (P <0.001). Patients initiated on venlafaxine, TCAs, or other antidepressants were also more likely to receive care from a mental health specialist, 16.8%, 15.0%, and 54.8%, respectively, compared with SSRIs (13.0%, all P <0.001). Regression analysis showed that only venlafaxine had a higher OR (1.13; 95% CI, 1.05-1.22) compared with SSRIs for adherence on the overall measure. Initiating dose level was in the target range for 70.0% of all patients (24.9% were below target dose and 5.2% above target dose), and adherent patients on all 3 AMM measures were less likely than nonadherent patients (70.4% vs. 68.4%, P <0.001) to be initiated in the target dose range. After multivariate adjustment, the initiating dose (target vs. high) was a significant factor in explaining adherence to the overall measure (OR=1.26; 95% CI, 1.16- 1.37). Adherent patients had 6-month median unadjusted total health care expenses that were nearly 2 times higher compared with nonadherent patients ($5,169 vs. $2,734) and mental health expenditures that were nearly 3 times higher ($1,922 vs. $677). After adjustment, adherent patients compared with nonadherent patients incurred an additional $644 in mental health expenditures and $806 in overall health care expenditures in the 6 months following initiation of antidepressant therapy., Conclusions: Only 19% of depressed patients initiated on antidepressants met all 3 criteria set forth in the NCQA Health Plan Employer Data and Information Set (HEDIS) AMM quality-of-care performance measures. Receipt of mental health specialty care was the single factor most strongly associated with quality treatment by these measures. Type and dosage level of initial antidepressant was associated with adherence to the NCQA HEDIS AMM measures, but the absolute difference in rates of adherence were relatively small among types of antidepressants. Costs were higher for guideline-adherent individuals in the 6 months following treatment initiation. These analyses were limited to administrative claims that lack indicators of depression disease severity.