ABSTRACT Testicular cancer is an increasing burden in modern societies and the most common malignancy among young adult males. Environment contaminants, especially endocrine disrupting compounds (EDC), may play a significant role in the development of these cancers through epigenetic alterations occurring during fetal and neonatal development. As long-term studies in humans and suitable experimental models with the potential to develop testicular cancer are lacking, no causal link can be established between endocrine disruptor exposure and testicular cancer incidence. Therefore, we developed an experimental model that recapitulates the differentiation of germ cells from primordial germ cells (pluripotency) into spermatocytes (meiosis) by using xenografted human fetal testis combined with germ cell transplantation into adult testis compartments. Using this model, we demonstrate that long-term fetal exposure (until 12 weeks) to a mixture of Di-2-ethylhexylphthalate (DEHP) and Bisphenol A (BPA), two most prevalent plasticizers, could interfere with fetal germ cell differentiation, leading to carcinogenesis and seminomas. Transcriptome, methylome, and histological analyses reveal that BPA/DEHP exposure induced some significant hallmarks of germ cell tumors to occur: persistent pluripotent and proliferative germ cells, global hypomethylation of CpGs in germ cells, abnormal expression of meiotic markers and fibrotic signatures in fetal testis. Additionally, we found that EDC-exposed fetal germ cells were more likely to develop seminoma in a context that allows spermatogenesis to begin. This study proposes the first experimental evidence that EDC exposure can cause long-term, irreversible lesions in fetal germ cells, which then lead to testicular tumorigenesis in adults.

The ex vivo production of platelets depleted of human leukocyte antigen class I (HLA-I) could serve as a universal measure to overcome platelet transfusion refractoriness caused by HLA-I incompatibility. Here, we developed human induced pluripotent cell-derived HLA-I-deficient platelets (HLA-KO iPLATs) in a clinically applicable imMKCL system by genetic manipulation and assessed their immunogenic properties including natural killer (NK) cells, which reject HLA-I downregulated cells. HLA-KO iPLATs were deficient for all HLA-I but did not elicit a cytotoxic response by NK cells in vitro and showed circulation equal to wild-type iPLATs upon transfusion in our newly established Hu-NK-MSTRG mice reconstituted with human NK cells. Additionally, HLA-KO iPLATs successfully circulated in an alloimmune platelet transfusion refractoriness model of Hu-NK-MISTRG mice. Mechanistically, the lack of NK cell-activating ligands on platelets may be responsible for evading the NK cell response. This study revealed the unique non-immunogenic property of platelets and provides a proof of concept for the clinical application of HLA-KO iPLATs.
Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

The cell membrane glycolipid GD2 is expressed by multiple solid tumors, including 88% of osteosarcomas and 98% of neuroblastomas. However, osteosarcomas are highly heterogeneous, with many tumors exhibiting GD2 expression on <50% of the individual cells, while some tumors are essentially GD2-negative. Anti-GD2 immunotherapy is the current standard of care for high-risk neuroblastoma, but its application to recurrent osteosarcomas, for which no effective therapies exist, has been extremely limited. This is, in part, because the standard assays to measure GD2 expression in these heterogeneous tumors are not quantitative and are subject to tissue availability and sampling bias. To address these limitations, we evaluated a novel, sensitive radiotracer [64Cu]Cu-Bn-NOTA-hu14.18K322A to detect GD2 expression in osteosarcomas (six patient-derived xenografts and one cell line) in vivo using positron emission tomography (PET). Tumor uptake of the radiolabeled, humanized anti-GD2 antibody [64Cu]Cu-Bn-NOTA-hu14.18K322A was 7-fold higher in modestly GD2-expressing osteosarcomas (32% GD2-positive cells) than in a GD2-negative tumor (9.8% vs. 1.3% of the injected dose per cc, respectively). This radiotracer also identified lesions as small as 29 mm3 in a 34% GD2-positive model of metastatic osteosarcoma of the lung. Radiolabeled antibody accumulation in patient-derived xenografts correlated with GD2 expression as measured by flow cytometry (Pearson r = 0.88, P = 0.01), distinguishing moderately GD2-expressing osteosarcomas (32%-69% GD2-positive cells) from high GD2 expressors (>99%, P < 0.05). These results support the utility of GD2 imaging with PET to measure GD2 expression in osteosarcoma and thus maximize the clinical impact of anti-GD2 immunotherapy. SIGNIFICANCE: In situ assessment of all GD2-positive osteosarcoma sites with a novel PET radiotracer could significantly impact anti-GD2 immunotherapy patient selection and enable noninvasive probing of correlations between target expression and therapeutic response.
©2019 American Association for Cancer Research.

We report on the diagnostic capability of magnetic resonance imaging (MRI)-based tracking of ferumoxytol-labeled human neural progenitor cells (hNPCs) transplanted into the porcine spinal cord. hNPCs prelabeled with two doses of ferumoxytol nanoparticles (hNPC-FLow and hNPC-FHigh ) were injected into the ventral horn of the spinal cord in healthy minipigs. Ferumoxytol-labeled grafts were tracked in vivo up to 105 days after transplantation with MRI. Injection accuracy was assessed in vivo at day 14 and was predictive of "on" or "off" target cell graft location assessed by histology. No difference in long-term cell survival, assessed by quantitative stereology, was observed among hNPC-FLow , hNPC-FHigh , or control grafts. Histological iron colocalized with MRI signal and engrafted human nuclei. Furthermore, the ferumoxytol-labeled cells retained nanoparticles and function in vivo. This approach represents an important leap forward toward facilitating translation of cell-tracking technologies to clinical trials by providing a method of assessing transplantation accuracy, delivered dose, and potentially cell survival. Stem Cells Translational Medicine 2017;6:139-150.
© 2016 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.