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Melodic contour is central to our ability to perceive and produce music. We propose to represent melodic contours as a combination of cosine functions, using the discrete cosine transform. The motivation for this approach is twofold: (1) it approximates a maximally informative contour representation (capturing most of the variation in as few dimensions as possible), but (2) it is nevertheless independent of the specifics of the data sets for which it is used. We consider the relation with principal component analysis, which only meets the first of these requirements. Theoretically, the principal components of a repertoire of random walks are known to be cosines. We find, empirically, that the principal components of melodies also closely approximate cosines in multiple musical traditions. We demonstrate the usefulness of the proposed representation by analyzing contours at three levels (complete songs, melodic phrases and melodic motifs) across multiple traditions in three small case studies.

Many musics across the world are structured around multiple modes, which hold a middle ground between scales and melodies. We study whether we can classify mode in a corpus of 20,865 medieval plainchant melodies from the Cantus database. We revisit the traditional ‘textbook’ classification approach (using the final, the range and initial note) as well as the only prior computational study we are aware of, which uses pitch profiles. Both approaches work well, but largely reduce modes to scales and ignore their melodic character. Our main contribution is a model that reaches 93–95% F1 score on mode classification, compared to 86– 90% using traditional pitch-based musicological methods. Importantly, it reaches 81–83% even when we discard all absolute pitch information and reduce a melody to its contour. The model uses tf–idf vectors and strongly depends on the choice of units: i.e., how the melody is segmented. If we borrow the syllable or word structure from the lyrics, the model outperforms all of our baselines. This suggests that, like language, music is made up of ‘natural’ units, in our case between the level of notes and complete phrases, a finding that may well be useful in other musics.

A novel pretargeted SPECT imaging strategy based on the HaloTag enzyme has been evaluated for the first time in a living system. To determine the efficacy of this approach, two clinically relevant cancer biomarkers, HER2 and TAG-72, were selected to represent models of internalizing and non-internalizing antigens, respectively. In MDA-MB-231/H2N (HER2-expressing) and LS174T (TAG-72-expressing) xenograft tumors in mice, pretargeting experiments were performed in which HaloTag-conjugated derivatives of the antibodies Trastuzumab (anti-HER2) or CC49 (anti-TAG-72) were utilized as primary agents, and the small molecule HaloTag ligands 111In-HTL-1, -2, and -3 were evaluated as secondary agents. While this approach was not sufficiently sensitive to detect the internalizing HER2 antigen, pretargeting experiments involving the most optimal secondary agent, 111In-HTL-3, were successful in detecting the non-internalizing antigen TAG-72 and provided high contrast SPECT images at 4 and 24 h post-injection.

Molecular radiotherapy using177Lu-DOTATATE is a most effective treatment for somatostatin receptor–expressing neuroendocrine tumors. Despite its frequent and successful use in the clinic, little or no radiobiologic considerations are made at the time of treatment planning or delivery. On positive uptake on octreotide-based PET/SPECT imaging, treatment is usually administered as a standard dose and number of cycles without adjustment for peptide uptake, dosimetry, or radiobiologic and DNA damage effects in the tumor. Here, we visualized and quantified the extent of DNA damage response after177Lu-DOTATATE therapy using SPECT imaging with111In-anti-γH2AX-TAT. This work was a proof-of-principle study of this in vivo noninvasive biodosimeter with β-emitting therapeutic radiopharmaceuticals.Methods:Six cell lines were exposed to external-beam radiotherapy (EBRT) or177Lu-DOTATATE, after which the number of γH2AX foci and the clonogenic survival were measured. Mice bearing CA20948 somatostatin receptor–positive tumor xenografts were treated with177Lu-DOTATATE or sham-treated and coinjected with111In-anti-γH2AX-TAT,111In-IgG-TAT control, or vehicle.Results:Clonogenic survival after external-beam radiotherapy was cell-line–specific, indicating varying levels of intrinsic radiosensitivity. Regarding in vitro cell lines treated with177Lu-DOTATATE, clonogenic survival decreased and γH2AX foci increased for cells expressing high levels of somatostatin receptor subtype 2. Ex vivo measurements revealed a partial correlation between177Lu-DOTATATE uptake and γH2AX focus induction between different regions of CA20948 xenograft tumors, suggesting that different parts of the tumor may react differentially to177Lu-DOTATATE irradiation.Conclusion:111In-anti-γH2AX-TAT allows monitoring of DNA damage after177Lu-DOTATATE therapy and reveals heterogeneous damage responses.

Site-selective labelling of antibodies (Abs) can circumvent problems from heterogeneity of conventional conjugation. Here, we evaluate the industrially-applied chemoenzymatic ‘Q-tag’ strategy based on transglutaminase-mediated (TGase) amide-bond formation in the generation of 89Zr-radiolabelled antibody conjugates. We show that, despite previously suggested high regioselectivity of TGases, in the anti-Her2 Ab Herceptin™ more precise native MS indicates only 70–80% functionalization at the target site (Q298H), in competition with modification at other sites, such as Q3H critically close to the CDR1 region.

Purpose:Increased activity of matrix metalloproteinases (MMPs) is associated with worse prognosis in different cancer types. The protective antigen (PA-WT) of the binary anthrax lethal toxin was modified to form a pore in cell membranes only when cleaved by MMPs (PA-L1). Anthrax lethal factor (LF) is then able to translocate through these pores. Here, we used an111In-radiolabelled form of LF with the PA/LF system for non-invasive in vivo imaging of MMP activity in tumour tissue by single photon emission computed tomography (SPECT). Methods:MMP-mediated activation of PA-L1 was correlated to anthrax receptor expression and MMP activity in a panel of cancer cells (HT1080, MDA-MB-231, B8484 and MCF7). Uptake of111In-radiolabelled PA-L1,111In-PA-WTK563Cor111In-LFE687A(a catalytically inactive LF mutant) in tumour and normal tissues was measured using SPECT/CT imaging in vivo. Results:Activation of PA-L1 in vitro correlated with anthrax receptor expression and MMP activity (HT1080>MDA-MB-231>B8484>MCF7). PA-L1-mediated delivery of111In-LFE687Awas demonstrated, and corroborated using confocal microscopy with fluorescently labelled LFE687A. Uptake was blocked by the broad-spectrum MMP inhibitor GM6001. In vivo imaging showed selective accumulation of111In-PA-L1 in MDA-MB-231 tumour xenografts (5.7±0.9%ID/g) at 3 h post intravenous administration.111In-LFE687A was selectively delivered to MMP-positive MDA-MB-231 tumour tissue by MMP-activatable PA-L1 (5.98±0.62%ID/g), but not by furin cleavable PA-WT (1.05±0.21%ID/g), or a non-cleavable PA variant control, PA-U7 (2.74 ± 0.24%ID/g). Conclusion:Taken together, our results indicate that radiolabelled forms of mutated anthrax lethal toxin hold promise for non-invasive imaging of MMP activity in tumour tissue.

While radiolabelled antibodies have found great utility as PET and SPECT imaging agents in oncological investigations, a notable shortcoming of these agents is their propensity to accumulate non-specifically within tumour tissue. The degree of this non-specific contribution to overall tumour uptake is highly variable and can ultimately lead to false conclusions. Therefore, in an effort to obtain a reliable measure of inter-individual differences in non-specific tumour uptake of radiolabelled antibodies, we demonstrate that the use of dual-isotope imaging overcomes this issue, enables true quantification of epitope expression levels, and allows non-invasive in vivo immunohistochemistry. The approach involves co-administration of (i) an antigen-targeting antibody labelled with zirconium-89 (89Zr), and (ii) an isotype-matched non-specific control IgG antibody labelled with indium-111 (111In). As an example, the anti-HER2 antibody trastuzumab was radiolabelled with 89Zr, and co-administered intravenously together with its 111In-labelled non-specific counterpart to mice bearing human breast cancer xenografts with differing HER2 expression levels (MDA-MB-468 [HER2-negative], MDA-MB-231 [low-HER2], MDA-MB-231/H2N [medium-HER2], and SKBR3 [high-HER2]). Simultaneous PET/SPECT imaging using a MILabs Vector4 small animal scanner revealed stark differences in the intratumoural distribution of [89Zr]Zr-trastuzumab and [111In]In-IgG, highlighting regions of HER2-mediated uptake and non-specific uptake, respectively. Normalisation of the tumour uptake values and tumour-to-blood ratios obtained with [89Zr]Zr-trastuzumab against those obtained with [111In]In-IgG yielded values which were most strongly correlated (R = 0.94; P = 0.02) with HER2 expression levels for each breast cancer type determined by Western blot and in vitro saturation binding assays, but not non-normalised uptake values. Normalised intratumoural distribution of [89Zr]Zr-trastuzumab correlated well with intratumoural heterogeneity HER2 expression.

Poly(ADP-ribose) polymerase (PARP) inhibitors are increasingly being studied as cancer drugs, as single agents, or as a part of combination therapies. Imaging of PARP using a radiolabeled inhibitor has been proposed for patient selection, outcome prediction, dose optimization, genotoxic therapy evaluation, and target engagement imaging of novel PARP-targeting agents. Methods: Here, via the copper-mediated 18F-radiofluorination of aryl boronic esters, we accessed, for the first time (to our knowledge), the 18F-radiolabeled isotopolog of the Food and Drug Administration-approved PARP inhibitor olaparib. The use of the 18F-labeled equivalent of olaparib allows direct prediction of the distribution of olaparib, given its exact structural likeness to the native, nonradiolabeled drug. Results: 18F-olaparib was taken up selectively in vitro in PARP-1-expressing cells. Irradiation increased PARP-1 expression and 18F-olaparib uptake in a radiation-dose-dependent fashion. PET imaging in mice showed specific uptake of 18F-olaparib in tumors expressing PARP-1 (3.2% ± 0.36% of the injected dose per gram of tissue in PSN-1 xenografts), correlating linearly with PARP-1 expression. Two hours after irradiation of the tumor (10 Gy), uptake of 18F-olaparib increased by 70% (P = 0.025). Conclusion: Taken together, we show that 18F-olaparib has great potential for noninvasive tumor imaging and monitoring of radiation damage.