Angiogenesis

APJ has been extensively described in the pathophysiology of angiogenesis and cell proliferation. The prognostic value of APJ overexpression in many diseases is now established. This study aimed to design a PET radiotracer that specifically binds to APJ. Apelin-F13A-NODAGA (AP747) was synthesized and radiolabeled with gallium-68 ([Ga]Ga-AP747). Radiolabeling purity was excellent (> 95%) and stable up to 2 h. Affinity constant of [Ga]Ga-AP747 was measured on APJ-overexpressing colon adenocarcinoma cells and was in nanomolar range. Specificity of [Ga]Ga-AP747 for APJ was evaluated in vitro by autoradiography and in vivo by small animal PET/CT in both colon adenocarcinoma mouse model and Matrigel plug mouse model. Dynamic of [Ga]Ga-AP747 PET/CT biodistributions was realized on healthy mice and pigs for two hours, and quantification of signal in organs showed a suitable pharmacokinetic profile for PET imaging, largely excreted by urinary route. Matrigel mice and hindlimb ischemic mice were submitted to a 21-day longitudinal follow-up with [Ga]Ga-AP747 and [Ga]Ga-RGD small animal PET/CT. [Ga]Ga-AP747 PET signal in Matrigel was significantly more intense than that of [Ga]Ga-RGD. Revascularization of the ischemic hind limb was followed by LASER Doppler. In the hindlimb, [Ga]Ga-AP747 PET signal was more than twice higher than that of [Ga]Ga-RGD on day 7, and significantly superior over the 21-day follow-up. A significant, positive correlation was found between the [Ga]Ga-AP747 PET signal on day 7 and late hindlimb perfusion on day 21. We developed a new PET radiotracer that specifically binds to APJ, [Ga]Ga-AP747 that showed more efficient imaging properties than the most clinically advanced tracer of angiogenesis, [Ga]Ga-RGD.France Life Imagin

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Sublingual Atropine Administration as a Tool to Decrease Salivary Glands&rsquo; PSMA-Ligand Uptake: A Preclinical Proof of Concept Study Using [68Ga]Ga-PSMA-11

Prostate Specific Membrane Antigen (PSMA)-directed radionuclide therapy has gained an important role in the management of advanced castration-resistant prostate cancer. Although extremely promising, the prolongation in survival and amelioration of disease-related symptoms must be balanced against the direct toxicities of the treatment. Xerostomia is amongst the most common and debilitating of these, particularly when using an alpha emitter. It is therefore of main importance to develop new preventive strategies. This preclinical study has evaluated the effect of &alpha;-adrenergic and anticholinergic drugs on [99mTc]TcO4&minus; Single Photon Emission Computed Tomography/Computed Tomography (SPECT/CT) and [68Ga]Ga-PSMA-11 Positron Emission Tomography (PET/CT). Methods: The effects of phenylephrine, scopolamine, atropine, and ipratropium on salivary glands uptake were evaluated in non-tumor-bearing mice by [99mTc]TcO4&minus; microSPECT/CT. The most efficient identified strategy was evaluated in non-tumor-bearing and xenografted mice by [68Ga]Ga-PSMA-11 PET/CT. Results: Scopolamine and atropine showed a significant decrease in the parotid glands&rsquo; uptake on SPECT/CT whereas phenylephrine and ipratropium failed. Atropine premedication (sublingual route), which was the most effective strategy, also showed a drastic decrease of [68Ga]Ga-PSMA-11 salivary glands&rsquo; uptake in both non-tumor-bearing mice (&minus;51.6% for the parotids, p &lt; 0.0001) and human prostate adenocarcinoma xenografted mice (&minus;26.8% for the parotids, p &lt; 0.0001). Conclusion: Premedication with a local administration of atropine could represent a simple, safe, and efficient approach for reducing salivary glands&rsquo; uptake

Management of adipose tumors in the limbs

International audienceAdipose tumors of the limbs are the most common soft tissue lesions and are essentially benign (lipomas). However, in some cases, they can be considered as tumors with intermediate malignancy (atypical lipomatous tumor [ALT]) or sarcoma lineage (liposarcoma [LS]). The essential work-up for a potential adipose tumor consists of a clinical examination and initial ultrasound imaging to determine the size (more or less than 5 cm), the location (over or under the fascia) and any potential atypical vascularization. As needed, MRI will complete the assessment and validate the ultrasound results and confirm the fatty nature of the lesion. Percutaneous biopsy will be done when a deep fatty lesion is larger than 5 cm (long axis), with detection by amplification of the MDM2 gene that guides the diagnosis towards ALT or dedifferentiated LS. Superficial lesions without atypia are not challenging from a surgical point of view. However, large ALT can be more difficult to manage. Their local malignancy does not justify sacrificing any critical structures. As for true LS, their treatment is well defined, with tumor excision addressed at a center belonging to the Network of Sarcomas Reference Centers in France (NETSARC+) and for potential (neo)adjuvant treatment if needed. Inappropriate treatment of a malignant tumor can have serious consequences (loss of chance to survive or to be cured) for the patient. Furthermore, treatment at a specialized cancer center has been proven to be effective as it improves overall survival and reduces local recurrences

Pharmaceutical interviews to overcome digestive artefacts on [ 99m Tc]Tc‐tetrofosmin myocardial perfusion scintigraphy

International audienc

Analysis of the interactions of xylose-based bolaforms with model membranes

Sugar-based surfactants are natural and biocompatible compounds. Among sugar-based surfactants, there is an increase of interest for the xylose-based bolaforms because of their potential applications in pharmaceutical and cosmetic fields and of their original physicochemical properties. Xylose-based bolaforms have interfacial and membrane-interacting properties making them potential molecules for drug delivery systems. For this work, we chemically synthetized by metathesis in the presence of Grubbs I catalyzer, a novel symmetric bolaform composed of two xylose polar heads connected by an ether link to a hydrocarbon chain having 18 carbon atoms with an unsaturation (BolaX). We were able to obtain two bolaforms differing only at the level of the anomeric configuration of the xylose moieties, or orBolaX). The surface activities of both compounds were analyzed. The anomeric configuration gives interfacial properties at the air-water interface contrary to the one. The interactions of the BolaX with model membranes were then analyzed in order to determine if it can be used for drug delivery systems. Our results show that BolaX were able to interact and insert within lipid monolayers containing phospholipids and sterols. In order to have informations at the molecular level of these interactions, another model membrane, called multilamellar vesicles (MLVs), containing phospholipids and sterols with or without BolaX were prepared. Both MLVs were analyzed by the means of the FTIR spectroscopy. In parallel, we have calculated the interaction energy of the BolaX with different lipid molecules by the means of the Hypermatrix method developed at our laboratory. Moreover, the insertion of the BolaX within the lipid bilayers was simulated using our IMPALA method. Taking together, our findings indicate that BolaX would be a potential candidate for drug delivery systems because of its surface active properties and its ability to insert within membranes

Sublingual Atropine Administration as a Tool to Decrease Salivary Glands’ PSMA-Ligand Uptake: A Preclinical Proof of Concept Study Using [68Ga]Ga-PSMA-11

International audienceProstate Specific Membrane Antigen (PSMA)-directed radionuclide therapy has gained an important role in the management of advanced castration-resistant prostate cancer. Although extremely promising, the prolongation in survival and amelioration of disease-related symptoms must be balanced against the direct toxicities of the treatment. Xerostomia is amongst the most common and debilitating of these, particularly when using an alpha emitter. It is therefore of main importance to develop new preventive strategies. This preclinical study has evaluated the effect of α-adrenergic and anticholinergic drugs on [99mTc]TcO4− Single Photon Emission Computed Tomography/Computed Tomography (SPECT/CT) and [68Ga]Ga-PSMA-11 Positron Emission Tomography (PET/CT). Methods: The effects of phenylephrine, scopolamine, atropine, and ipratropium on salivary glands uptake were evaluated in non-tumor-bearing mice by [99mTc]TcO4− microSPECT/CT. The most efficient identified strategy was evaluated in non-tumor-bearing and xenografted mice by [68Ga]Ga-PSMA-11 PET/CT. Results: Scopolamine and atropine showed a significant decrease in the parotid glands’ uptake on SPECT/CT whereas phenylephrine and ipratropium failed. Atropine premedication (sublingual route), which was the most effective strategy, also showed a drastic decrease of [68Ga]Ga-PSMA-11 salivary glands’ uptake in both non-tumor-bearing mice (−51.6% for the parotids, p < 0.0001) and human prostate adenocarcinoma xenografted mice (−26.8% for the parotids, p < 0.0001). Conclusion: Premedication with a local administration of atropine could represent a simple, safe, and efficient approach for reducing salivary glands’ uptake

Insight into the Self-Assembling Properties of Peptergents: A Molecular Dynamics Simulation Study.

By manipulating the various physicochemical properties of amino acids, the design of peptides with specific self-assembling properties has been emerging for more than a decade. In this context, short peptides possessing detergent properties (so-called "peptergents") have been developed to self-assemble into well-ordered nanostructures that can stabilize membrane proteins for crystallization. In this study, the peptide with "peptergency" properties, called ADA8 and extensively described by Tao et al., is studied by molecular dynamic simulations for its self-assembling properties in different conditions. In water, it spontaneously forms beta sheets with a β barrel-like structure. We next simulated the interaction of this peptide with a membrane protein, the bacteriorhodopsin, in the presence or absence of a micelle of dodecylphosphocholine. According to the literature, the peptergent ADA8 is thought to generate a belt of β structures around the hydrophobic helical domain that could help stabilize purified membrane proteins. Molecular dynamic simulations are here used to image this mechanism and provide further molecular details for the replacement of detergent molecules around the protein. In addition, we generalized this behavior by designing an amphipathic peptide with beta propensity, which was called ABZ12. Both peptides are able to surround the membrane protein and displace surfactant molecules. To our best knowledge, this is the first molecular mechanism proposed for "peptergency"