DeRossi, C. et al. Ablation of mouse phosphomannose isomerase (Mpi) causes mannose 6-phosphate accumulation, toxicity, and embryonic lethality.

Nuclear medicine imaging offers the possibility to study in vivo different aspects of inflammatory process by the use of radio-labeled molecules that bind to specific receptor targets on cells and tissues. This noninvasive technique, combined with pathogens engineered to express luciferase, allows quantification in the same animal of the spatial and temporal progression of the infection and identification of animal-to-animal variations in pathogen replication and dissemination. One strategy to use optical imaging in living animals is the use of luciferase reporter genes as internal sources of light called bioluminescence imaging (BLI). This enables real-time noninvasive imaging of infections and gene expression in living organisms. Nuclear medicine imaging is characterized by the use of radio pharmaceuticals (radiolabeled probes) that, administered in pico- and nanomolar amounts. These probes can also be used for early diagnosis of diseases, in susceptible subjects, for detection of disease relapse and radio-guided surgery

There may be differences between this version and the published version. You are advised to consult the publisher's version if you wish to cite from it. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58

No abstract

PurposeThe rationale of the present study was to radiolabel rituximab with 99m-technetium and to image B lymphocytes infiltration in the affected tissues of patients with chronic inflammatory autoimmune diseases, in particular, the candidates to be treated with unlabelled rituximab, in order to provide a rationale for ‘evidence-based’ therapy.ProceduresRituximab was labelled with 99mTc via 2-ME reduction method. In vitro quality controls of 99mTc-rituximab included stability assay, cysteine challenge, SDS-PAGE, immunoreactive fraction assay and competitive binding assay on CD20+ve Burkitt lymphoma-derived cells. For the human pilot study, 350–370 MBq (100 μg) of 99mTc-rituximab were injected in 20 patients with different chronic inflammatory autoimmune diseases. Whole body anteroposterior planar scintigraphic images were acquired 6 and 20 h p.i.ResultsRituximab was labelled to a high labelling efficiency (>98%) and specific activity (3515–3700 MBq/mg) with retained biochemical integrity, stability and biological activity. Scintigraphy with 99mTc-rituximab in patients showed a rapid and persistent spleen uptake, and the kidney appeared to be a prominent source for the excretion of radioactivity. Inflamed joints showed a variable degree of uptake at 6 h p.i. in patients with rheumatoid arthritis indicating patient variability; similarly, the salivary and lacrimal glands showed variable uptake in patients with Sjögren’s syndrome, Behçet’s disease and sarcoidosis. Inflammatory disease with particular characteristics showed specific uptake in inflammatory lesions, such as, dermatopolymyositis patients showed moderate to high skin uptake, a sarcoidosis patient showed moderate lung uptake, a Behçet’s disease patient showed high oral mucosa uptake and a polychondritis patient showed moderate uptake in neck cartilages. In one patient with systemic lupus erythematosus, we did not find any non-physiological uptake.ConclusionRituximab can be efficiently labelled with 99mTc with high labelling efficiency. The results suggest that this technique might be used to assess B lymphocyte infiltration in affected organs in patients with autoimmune diseases; this may provide a rationale for anti-CD20 therapies.

Inhibition of the androgen receptor (AR) is the main strategy to treat advanced prostate cancers. AR-independent treatmentresistant prostate cancer is a major unresolved clinical problem. Patients with prostate cancer with alterations in canonical WNT pathway genes, which lead to b-catenin activation, are refractory to AR-targeted therapies. Here, using clinically relevant murine prostate cancer models, we investigated the significance of b-catenin activation in prostate cancer progression and treatment resistance. b-Catenin activation, independent of the cell of origin, cooperated with Pten loss to drive AR-independent castrationresistant prostate cancer. Prostate tumors with b-catenin activation relied on the noncanonical WNT ligand WNT5a for sustained growth. WNT5a repressed AR expression and maintained the expression of c-Myc, an oncogenic effector of b-catenin activation, by mediating nuclear localization of NFkBp65 and b-catenin. Overall, WNT/b-catenin and AR signaling are reciprocally inhibited. Therefore, inhibiting WNT/b-catenin signaling by limiting WNT secretion in concert with AR inhibition may be useful for treating prostate cancers with alterations in WNT pathway genes. Significance: Targeting of both AR and WNT/b-catenin signaling may be required to treat prostate cancers that exhibit alterations of the WNT pathway.

The closing of the last century opened a wide variety of approaches for inflammation imaging and treatment of patients with rheumatoid arthritis (RA). The introduction of biological therapies for the management of RA started a revolution in the therapeutic armamentarium with the development of several novel monoclonal antibodies (mAbs), which can be murine, chimeric, humanised and fully human antibodies. Monoclonal antibodies specifically bind to their target, which could be adhesion molecules, activation markers, antigens or receptors, to interfere with specific inflammation pathways at the molecular level, leading to immune-modulation of the underlying pathogenic process. These new generation of mAbs can also be radiolabelled by using direct or indirect method, with a variety of nuclides, depending upon the specific diagnostic application. For studying rheumatoid arthritis patients, several monoclonal antibodies and their fragments, including anti-TNF-α, anti-CD20, anti-CD3, anti-CD4 and anti-E-selectin antibody, have been radiolabelled mainly with 99mTc or 111In. Scintigraphy with these radiolabelled antibodies may offer an exciting possibility for the study of RA patients and holds two types of information: (1) it allows better staging of the disease and diagnosis of the state of activity by early detection of inflamed joints that might be difficult to assess; (2) it might provide a possibility to perform ‘evidence-based biological therapy’ of arthritis with a view to assessing whether an antibody will localise in an inflamed joint before using the same unlabelled antibody therapeutically. This might prove particularly important for the selection of patients to be treated since biological therapies can be associated with severe side-effects and are considerably expensive. This article reviews the use of radiolabelled mAbs in the study of RA with particular emphasis on the use of different radiolabelled monoclonal antibodies for therapy decision-making and follow-up.

Poly(ADP-ribose) polymerase (PARP) is involved in repair of DNA breaks and is over-expressed in a wide variety of tumors, making PARP an attractive biomarker for positron emission tomography (PET) and single photon emission computed tomography imaging. Consequently, over the past decade, there has been a drive to develop nuclear imaging agents targeting PARP. Here, we report the discovery of a PET tracer that is based on the potent PARP inhibitor olaparib (1). Our lead PET tracer candidate, [18F]20, was synthesized and evaluated as a potential PARP PET radiotracer in mice bearing subcutaneous glioblastoma xenografts using ex vivo biodistribution and PET–magnetic resonance imaging techniques. Results showed that [18F]20 could be produced in a good radioactivity yield and exhibited specific PARP binding allowing visualization of tumors over-expressing PARP. [18F]20 is therefore a potential candidate radiotracer for in vivo PARP PET imaging.