Glioblastoma multiforme is a highly aggressive form of brain cancer whose location, tendency to infiltrate healthy surrounding tissue, and heterogeneity significantly limit survival, with scant progress having been made in recent decades. Experimental design 123 I-MAPi (Iodine-123 Meitner-Auger PARP1 inhibitor) is a precise therapeutic tool composed of a PARP1 inhibitor radiolabeled with an Auger-and gamma-emitting iodine isotope. Here, the PARP inhibitor, which binds to the DNA repair enzyme PARP1, specifically targets cancer cells, sparing healthy tissue, and carries a radioactive payload within reach of the cancer cells' DNA. Results The high relative biological efficacy of Auger electrons within their short range of action is leveraged to inflict DNA damage and cell death with high precision. The gamma ray emission of 123 I-MAPi allows for the imaging of tumor progression and therapy response, and for patient dosimetry calculation. Here we demonstrated the efficacy and specificity of this small molecule radiotheranostic in a complex preclinical model. In vitro and in vivo studies demonstrate high tumor uptake and a prolonged survival in mice treated with 123 I-MAPi when compared to vehicle controls. Different methods of drug delivery were investigated to develop this technology for clinical applications, including convection enhanced delivery (CED) and intrathecal injection. Conclusions Taken together, these results represent the first full characterization of an Augeremitting PARP inhibitor which demonstrate a survival benefit in mouse models of GBM and confirm the high potential of 123 I-MAPi for clinical translation.

IgG staining in human vagus nerves; H&E and Na v 1.7 expression in mouse sciatic nerves; tryptic digestion experiments for Hsp1a and Hsp1a-FL; epifluorescence images of sciatic nerves injected with Hsp1a-FL, block, or PBS, and the fluorescence quantification; fresh tissue confocal fluorescence microscopy (PDF) The authors declare the following competing financial interest(s): J.G., P.D.S.F., G.F.K. and T.R. are co-inventors on a Hsp1a-related patent application. S.K. and T.R. are shareholders of Summit Biomedical Imaging, LLC.

For nearly a decade since the mapping of the multiple endocrine neoplasia type 1 (MEN1) locus to 11q13 and the suggestion that it is a tumour suppressor gene, efforts have been made to identify the gene responsible for this familial cancer syndrome. Recently, we have identified the MEN1 gene by the positional cloning approach. This effort involved construction of a 2.8-Mb physical map (D11S480-D11S913) based primarily on a bacterial clone contig. Using these resources, 20 new polymorphic markers were isolated which helped to reduce the interval for candidate genes by haplotype analysis in families and by loss of heterozygosity (LOH) studies in approximately 200 tumours, utilizing laser-assisted microdissection to obtain tumour cells with minimal or no admixture by normal cells. The interval was narrowed by LOH to only 300 kb, and nearly 20 new transcripts that map to this region of 11q13 were isolated and characterized. One of the transcripts was found by dideoxyfingerprinting and cycle sequencing to harbour deleterious germline mutations in affected individuals from MEN-1 kindreds and therefore identified as the MEN1 gene. The type of germline mutations and the identification of mutations in sporadic tumours support the Knudson's two-hit model of tumorigenesis for MEN-1. Efforts are being made to identify the function of the MEN1 gene-encoded protein, menin, and to study its role in tumorigenesis.

Background. Visual inspection and biopsy is the current standard of care for oral cancer diagnosis, but is subject to misinterpretation and consequently to misdiagnosis. Topically applied PARPi-FL is a molecularly speci c, uorescent contrast-based approach that may ful l the unmet need for a simple, in vivo, non-invasive, cost-effective, point-of-care method for the early diagnosis of oral cancer. Here, we present results from a phase I safety and feasibility study on uorescent, topically applied PARPi-FL.Twelve patients with a histologically proven squamous cell carcinoma of the oral cavity (OSCC) gargled a PARPi-FL solution for 60 seconds (15 mL, 100 nM, 250 nM, 500 nM, or 1000 nM), followed by gargling a clearing solution for 60 seconds. Fluorescence measurements of the lesion and surrounding oral mucosa were taken before PARPi-FL application, after PARPi-FL application and after clearing. Blood pressure, oxygen levels, clinical chemistry and CBC were obtained before and after tracer administration.Results. PARPi-FL was well-tolerated by all patients without any safety concerns. When analyzing the uorescence signal, all malignant lesions showed a signi cant differential in contrast after administration of PARPi-FL, with the highest increase occurring at the highest dose level (1000 nM), where all patients had a tumor-to-margin uorescence signal ratio of > 3. A clearing step was essential to increase signal speci city, as it clears unbound PARPi-FL trapped in normal anatomical structures. PARPi-FL tumor cell speci city was con rmed by ex vivo tabletop confocal microscopy. We have demonstrated that the uorescence signal arose from the nuclei of tumor cells, endorsing our macroscopic ndings.Conclusions. A PARPi-FL swish & spit solution is a rapid and non-invasive diagnostic tool that preferentially localizes uorescent contrast to OSCC. This technique holds promise for the early detection of OSCC based on in vivo optical evaluation and targeted biopsy of suspicious lesions in the oral cavity.Clinicaltrials.gov -NCT03085147, registered on March 21 st , 2017.

The immune function within the tumor microenvironment has become a prominent therapeutic target, with tumor-associated macrophages (TAMs) playing a critical role in immune suppression. We propose an 89 Zr-labeled high-density lipoprotein ( 89 Zr-HDL) nanotracer as a means of monitoring response to immunotherapy. Methods: Female MMTV-PyMT mice were treated with pexidartinib, a colony-stimulating factor 1 receptor (CSF1R) inhibitor, to reduce TAM density. The accumulation of 89 Zr-HDL within the tumor was assessed using PET/CT imaging and autoradiography, whereas TAM burden was determined using immunofluorescence. Results: A significant reduction in 89 Zr-HDL accumulation was observed in PET/CT images, with 2.9% ± 0.3% and 3.7% ± 0.2% injected dose/g for the pexidartinib-and vehicle-treated mice, respectively. This reduction was corroborated ex vivo and correlated with decreased TAM density. Conclusion: These results support the potential use of 89 Zr-HDL nanoparticles as a PET tracer to quickly monitor the response to CSF1R inhibitors and other therapeutic strategies targeting TAMs.