Neoantigen-targeted CD8+ T cell responses with PD-1 blockade therapy.

Neoantigens are peptides derived from non-synonymous mutations presented by human leukocyte antigens (HLAs), which are recognized by antitumour T cells1-14. The large HLA allele diversity and limiting clinical samples have restricted the study of the landscape of neoantigen-targeted T cell responses in patients over their treatment course. Here we applied recently developed technologies15-17 to capture neoantigen-specific T cells from blood and tumours from patients with metastatic melanoma with or without response to anti-programmed death receptor 1 (PD-1) immunotherapy. We generated personalized libraries of neoantigen-HLA capture reagents to single-cell isolate the T cells and clone their T cell receptors (neoTCRs). Multiple T cells with different neoTCR sequences (T cell clonotypes) recognized a limited number of mutations in samples from seven patients with long-lasting clinical responses. These neoTCR clonotypes were recurrently detected over time in the blood and tumour. Samples from four patients with no response to anti-PD-1 also demonstrated neoantigen-specific T cell responses in the blood and tumour to a restricted number of mutations with lower TCR polyclonality and were not recurrently detected in sequential samples. Reconstitution of the neoTCRs in donor T cells using non-viral CRISPR-Cas9 gene editing demonstrated specific recognition and cytotoxicity to patient-matched melanoma cell lines. Thus, effective anti-PD-1 immunotherapy is associated with the presence of polyclonal CD8+ T cells in the tumour and blood specific for a limited number of immunodominant mutations, which are recurrently recognized over time.

Discovery of antibodies and cognate surface targets for ovarian cancer by surface profiling.

Although antibodies targeting specific tumor-expressed antigens are the standard of care for some cancers, the identification of cancer-specific targets amenable to antibody binding has remained a bottleneck in development of new therapeutics. To overcome this challenge, we developed a high-throughput platform that allows for the unbiased, simultaneous discovery of antibodies and targets based on phenotypic binding profiles. Applying this platform to ovarian cancer, we identified a wide diversity of cancer targets including receptor tyrosine kinases, adhesion and migration proteins, proteases and proteins regulating angiogenesis in a single round of screening using genomics, flow cytometry, and mass spectrometry. In particular, we identified BCAM as a promising candidate for targeted therapy in high-grade serous ovarian cancers. More generally, this approach provides a rapid and flexible framework to identify cancer targets and antibodies.

Revision and Replacement of Spinal Cord Stimulator Paddle Leads.

OBJECTIVES: Paddle leads for spinal cord stimulation (SCS) offer more efficient energy delivery and advantages in some patients. However, there is concern for how safely SCS paddles can be replaced once previously implanted because of scar tissue and the relative vulnerability of the thoracic cord. In this study, we share our experience on SCS paddle replacement. MATERIALS AND METHODS: Participants who underwent SCS replacement at Albany Medical Center between 2011 and 2020 were identified. The medical records were reviewed for demographic data and information regarding initial complications, reason for removal or revision, subsequent complications of replacement surgery and its timing, and whether the implant was ultimately removed. Percutaneous lead replacement cases performed over the same period were used as a comparison group. RESULTS: A total of 1265 patients were identified to have had an SCS-related procedure based on billing codes. Of these, 73 involved replacement of epidural leads (51 paddles, 22 percutaneous). Most paddles (48/51) were replaced at the time of removal. A total of 30 of the 51 paddle replacements required additional lamina removal. Re-operations that occurred more than one year after initial implant were significantly more likely to require additional bone removal (p < 0.001). Paddle re-operations lasted in general 1.7 ± 0.2 hours and had 35 ± 5 mL of blood loss, whereas percutaneous operations lasted 1.3 ± 0.2 hours and had 12.5 ± 2 mL of blood loss. Despite the invasive nature of paddle replacement, there was no difference in complications (p = 0.23) compared with that in percutaneous leads. CONCLUSIONS: This study characterizes the safety profile of SCS paddle replacement surgeries. Here, we demonstrate that the replacement of paddle leads at the time of removal, with additional lamina removal if needed because of scar, is associated with low rates of complications. This validates the feasibility and low-risk profile of replacing paddle leads when clinically indicated for experienced surgeons with specialization in SCS.

PVNAS: 3D Neural Architecture Search With Point-Voxel Convolution.

3D neural networks are widely used in real-world applications (e.g., AR/VR headsets, self-driving cars). They are required to be fast and accurate; however, limited hardware resources on edge devices make these requirements rather challenging. Previous work processes 3D data using either voxel-based or point-based neural networks, but both types of 3D models are not hardware-efficient due to the large memory footprint and random memory access. In this paper, we study 3D deep learning from the efficiency perspective. We first systematically analyze the bottlenecks of previous 3D methods. We then combine the best from point-based and voxel-based models together and propose a novel hardware-efficient 3D primitive, Point-Voxel Convolution (PVConv). We further enhance this primitive with the sparse convolution to make it more effective in processing large (outdoor) scenes. Based on our designed 3D primitive, we introduce 3D Neural Architecture Search (3D-NAS) to explore the best 3D network architecture given a resource constraint. We evaluate our proposed method on six representative benchmark datasets, achieving state-of-the-art performance with 1.8-23.7× measured speedup. Furthermore, our method has been deployed to the autonomous racing vehicle of MIT Driverless, achieving larger detection range, higher accuracy and lower latency.

Histone Deacetylases SRT1 and SRT2 Interact with ENAP1 to Mediate Ethylene-Induced Transcriptional Repression.

Ethylene plays pleiotropic roles in plant growth, plant development, and stress responses. Although the effects of ethylene on plants are well documented, little is known about molecular-level events that result in transcriptional repression during the ethylene response. In this study, we found that two histone deacetylases, SRT1 and SRT2, interact with ENAP1, which associates with EIN2 in the nucleus. Genetic and transcriptome analyses revealed that SRT1 and SRT2 are required for negative regulation of certain ethylene-responsive genes. The acetylation of HISTONE3 at K9 (H3K9Ac) is specifically regulated by SRT1 and SRT2 in ethylene-repressed genes. In addition, the srt1 srt2 double mutation in Arabidopsis thaliana suppresses both the ENAP1ox and the EIN3ox constitutive ethylene response phenotypes, and the ethylene-induced transcriptional repression observed in EIN3ox plants is derepressed in the EIN3ox/srt1 srt2 mutant. SRT2 and ENAP1 both bind to promoter regions of genes negatively regulated by ethylene, reducing H3K9Ac levels and resulting in transcriptional repression. This work establishes a mechanism by which histone deacetylases SRT1 and SRT2 interact with ENAP1 to mediate transcriptional repression by regulating the levels of H3K9 acetylation in the ethylene signaling.