Purpose: We generated a humanized antibody, HuLuc63, which specifically targets CS1 (CCND3 subset 1, CRACC, and SLAMF7), a cell surface glycoprotein not previously associated with multiple myeloma. To explore the therapeutic potential of HuLuc63 in multiple myeloma, we examined in detail the expression profile of CS1, the binding properties of HuLuc63 to normal and malignant cells, and the antimyeloma activity of HuLuc63 in preclinical models. Experimental Design: CS1 was analyzed by gene expression profiling and immunohistochemistry of multiple myeloma samples and numerous normal tissues. HuLuc63-mediated antimyeloma activity was tested in vitro in antibody-dependent cellular cytotoxicity (ADCC) assays and in vivo using the human OPM2 xenograft model in mice.Results: CS1mRNA was expressed in >90% of 532 multiple myeloma cases, regardless of cytogenetic abnormalities. Anti-CS1antibody staining of tissues showed strong staining of myeloma cells in all plasmacytomas and bone marrow biopsies. Flow cytometric analysis of patient samples using HuLuc63 showed specific staining of CD138+ myeloma cells, natural killer (NK), NK-like Tcells, and CD8+ Tcells, with no binding detected on hematopoietic CD34+ stem cells. HuLuc63 exhibited significant in vitro ADCC using primary myeloma cells as targets and both allogeneic and autologous NK cells as effectors. HuLuc63 exerted significant in vivo antitumor activity, which depended on efficient Fc-CD16 interaction as well as the presence of NK cells in the mice. Conclusions: These results suggest that HuLuc63 eliminates myeloma cells, at least in part, via NK-mediated ADCC and shows the therapeutic potential of targeting CS1with HuLuc63 for the treatment of multiple myeloma.

Immunotherapies targeting the programmed death 1 (PD-1) coinhibitory receptor have shown great promise for a subset of patients with cancer. However, robust and safe combination therapies are still needed to bring the benefit of cancer immunotherapy to broader patient populations. To search for an optimal strategy of combinatorial immunotherapy, we have compared the antitumor activity of the anti-4-1BB/anti-PD-1 combination with that of the anti-PD-1/anti-LAG-3 combination in the poorly immunogenic B16F10 melanoma model. Pronounced tumor inhibition occurred only in animals receiving anti-PD-1 and anti-4-1BB concomitantly, while combining anti-PD-1 with anti-LAG-3 led to a modest degree of tumor suppression. The activity of the anti-4-1BB/anti-PD-1 combination was dependent on IFNg and CD8 þ T cells. Both 4-1BB and PD-1 proteins were elevated on the surface of CD8 þ T cells by anti-4-1BB/anti-PD-1 cotreatment. In the tumor microenvironment, an effective antitumor immune response was induced as indicated by the increased CD8 þ /Treg ratio and the enrichment of genes such as Cd3e, Cd8a, Ifng, and Eomes. In the spleen, the combination treatment shaped the immune system to an effector/memory phenotype and increased the overall activity of tumor-specific CD8 þ CTLs, reflecting a long-lasting systemic antitumor response. Furthermore, combination treatment in C57BL/6 mice showed no additional safety signals, and only minimally increased severity of the known toxicity relative to 4-1BB agonist alone. Therefore, in the absence of any cancer vaccine, anti-4-1BB/anti-PD-1 combination therapy is sufficient to elicit a robust antitumor effector/memory T-cell response in an aggressive tumor model and is therefore a candidate for combination trials in patients.

RNA methylation is an important epigenetic modification. Recent studies on RNA methylation mainly focus on the m6A modification of mRNA, but very little is known about the m5C modification. NSUN2 is an RNA methyltransferase responsible for the m5C modification of multiple RNAs. In this study, we knocked down the NSUN2 gene in HepG2 cells by CRISPR/Cas9 technology and performed high-throughput RNA-BisSeq. An important tumor-related lncRNA H19 was identified to be targeted by NSUN2. Studies have shown that the expression of H19 lncRNA is abnormally elevated and has a carcinogenic effect in many types of tumors. Our results demonstrated that m5C modification of H19 lncRNA can increase its stability. Interestingly, m5C-modified H19 lncRNA can be specifically bound by G3BP1, a well-known oncoprotein which further leads to MYC accumulation. This may be a novel mechanism by which lncRNA H19 exerts its oncogenic effect. Besides, both the m5C methylation level and the expression level of H19 lncRNA in hepatocellular carcinoma tissues were significantly higher than those in adjacent non-cancer tissues, which were closely associated with poor differentiation of hepatocellular carcinoma (HCC). In conclusion, we found that H19 RNA is a specific target for the NSUN2 modifier. The m5C-modified H19 lncRNA may promote the occurrence and development of tumors by recruiting the G3BP1 oncoprotein. Our findings may provide a potential target and biomarker for the diagnosis and treatment of HCC.

Side-chain engineering has been considered as one of the most promising strategies to optimize non-fullerene small-molecule acceptors (NFSMAs). Previous efforts were focused on the optimization of alkyl-chain length, shape, and branching sites. In this work, we propose that asymmetric side-chain engineering can effectively tune the properties of NFSMAs and improve the power conversion efficiency (PCE) for binary non-fullerene polymer solar cells (NFPSCs). Specifically, by introducing asymmetric side chains into the central core, both of the absorption spectra and molecule orientation of NFSMAs are efficiently tuned. When blended with polymer donor PM6, NFPSCs with EH-HD-4F (2-ethylhexyl and 2-hexyldecyl side chains) demonstrate a champion PCE of 18.38% with a short-circuit current density (J SC ) of 27.48 mA cm −2 , an open circuit voltage (V OC ) of 0.84 V, and a fill factor (FF) of 0.79. Further studies manifest that the proper asymmetric side chains in NFSMAs could induce more favorable face-on molecule orientation, enhance carrier mobilities, balance charge transport, and reduce recombination losses.

ABSTRACT.Purpose: To compare the repeatability and reproducibility of central corneal thickness (CCT) measurements by high-resolution (HR) rotating Scheimpflug imaging and Fourier-domain optical coherence tomography (FD-OCT). CCT measurements were compared to those determined by ultrasound pachymetry (UP). Methods:In 35 healthy eyes, intra-observer repeatability for HR Scheimpflug (Pentacam) and FD-OCT (RTVue) systems was determined in consecutive images taken by an observer in the shortest time possible. Imaging was repeated again by a second observer to evaluate inter-observer reproducibility. The CCT measurements were compared among Scheimpflug, FD-OCT and UP images.Results: Mean coefficients of repeatability were 0.48% for Scheimpflug and 0.26% for FD-OCT. For Scheimpflug, the coefficient of inter-operator reproducibility was 0.87%. For FD-OCT, the coefficient of inter-operator reproducibility was 0.45%. The CCT measurements by Scheimpflug, OCT and UP images were (mean ± standard deviation) 521.7 ± 27.6 lm, 510.8 ± 28.6 lm and 516.5 ± 27.6 lm, respectively. The differences between instruments were statistically significant. The 95% limits of agreement in CCT were )0.7 to 22.5 lm for Pentacam-OCT, )13.4 to 24.0 lm for Pentacam-UP and )26.7 to 15.4 lm for OCT-UP. There was a high degree of correlation between CCT measured by all 3 methods.Conclusion: Noncontact measurements of CCT with HR Scheimpflug and FD-OCT systems yielded excellent repeatability and reproducibility and can be used interchangeably. Although both devices were comparable with UP; in clinical practice, the measurements acquired by optical modalities are not directly interchangeable with UP measurements.