Targeting IGF2-IGF1R Signaling to Reprogram the Tumor Microenvironment for Enhanced Viro-Immunotherapy.

BACKGROUND: The FDA approval of oncolytic herpes simplex-1 virus (oHSV) therapy underscores its therapeutic promise and safety as a cancer immunotherapy. Despite this promise, the current efficacy of oHSV is significantly limited to a small subset of patients largely due to the resistance in tumor and tumor microenvironment (TME). METHODS: RNA sequencing (RNA-Seq) was used to identify molecular targets of oHSV resistance. Intracranial human and murine glioma or breast cancer brain metastasis (BCBM) tumor-bearing mouse models were employed to elucidate the mechanism underlying oHSV therapy-induced resistance. RESULTS: Transcriptome analysis identified IGF2 as one of the top secreted proteins following oHSV treatment. Moreover, IGF2 expression was significantly upregulated in 10 out of 14 recurrent GBM patients after treatment with oHSV, rQNestin34.5v.2 (71.4%) (p=0.0020) (ClinicalTrials.gov, NCT03152318). Depletion of IGF2 substantially enhanced oHSV-mediated tumor cell killing in vitro and improved survival of mice bearing BCBM tumors in vivo. To mitigate the oHSV-induced IGF2 in the TME, we constructed a novel oHSV, oHSV-D11mt, secreting a modified IGF2R domain 11 (IGF2RD11mt) that acts as IGF2 decoy receptor. Selective blocking of IGF2 by IGF2RD11mt significantly increased cytotoxicity, reduced oHSV-induced neutrophils/PMN-MDSCs infiltration, and reduced secretion of immune suppressive/proangiogenic cytokines, while increased CD8+cytotoxic T lymphocytes (CTLs) infiltration, leading to enhanced survival in GBM or BCBM tumor-bearing mice. CONCLUSION: This is the first study reporting that oHSV-induced secreted IGF2 exerts a critical role in resistance to oHSV therapy, which can be overcome by oHSV-D11mt as a promising therapeutic advance for enhanced viro-immunotherapy.

Multi-to-binary network (MTBNet) for automated multi-organ segmentation on multi-sequence abdominal MRI images.

Fully convolutional neural network (FCN) has achieved great success in semantic segmentation. However, the performance of the FCN is generally compromised for multi-object segmentation. Multi-organ segmentation is very common while challenging in the field of medical image analysis, where organs largely vary with scales. Different organs are often treated equally in most segmentation networks, which is not quite optimal. In this work, we propose to divide a multi-organ segmentation task into multiple binary segmentation tasks by constructing a multi-to-binary network (MTBNet). The proposed MTBNet is based on the FCN for pixel-wise prediction. Moreover, we build a plug-and-play multi-to-binary block (MTB block) to adjust the influence of the feature maps from the backbone. This is achieved by parallelizing multiple branches with different convolutional layers and a probability gate (ProbGate). The ProbGate is set up for predicting whether the class exists, which is supervised clearly via an auxiliary loss without using any other inputs. More reasonable features are achieved by summing branches' features multiplied by the probability from the accompanying ProbGate and fed into a decoder module for prediction. The proposed method is validated on a challenging task dataset of multi-organ segmentation in abdominal MRI. Compared to classic medical and other multi-scale segmentation methods, the proposed MTBNet improves the segmentation accuracy of small organs by adjusting features from different organs and reducing the chance of missing or misidentifying these organs.

New Exact Quantization Condition for Toric Calabi-Yau Geometries.

We propose a new exact quantization condition for a class of quantum mechanical systems derived from local toric Calabi-Yau threefolds. Our proposal includes all contributions to the energy spectrum which are nonperturbative in the Planck constant, and is much simpler than the available quantization condition in the literature. We check that our proposal is consistent with previous works and implies nontrivial relations among the topological Gopakumar-Vafa invariants of the toric Calabi-Yau geometries. Together with the recent developments, our proposal opens a new avenue in the long investigations at the interface of geometry, topology and quantum mechanics.