Nucleoporins cooperate with Polycomb silencers to promote transcriptional repression and repair at DNA double strand breaks.

DNA Double-strand breaks (DSBs) are harmful lesions and major sources of genomic instability. Studies have suggested that DSBs induce local transcriptional silencing that consequently promotes genomic stability. Several factors have been proposed to actively participate in this process, including ATM and Polycomb repressive complex 1 (PRC1). Here we found that disrupting PRC1 clustering disrupts DSB-induced gene silencing. Interactome analysis of PHC2, a PRC1 subunit that promotes the formation of the Polycomb body, found several nucleoporins that constitute the Nuclear Pore Complex (NPC). Similar to PHC2, depleting the nucleoporins also disrupted the DSB-induced gene silencing. We found that some of these nucleoporins, such as NUP107 and NUP43, which are members of the Y-complex of NPC, localize to DSB sites. These nucleoporin-enriched DSBs were distant from the nuclear periphery. The presence of nucleoporins and PHC2 at DSB regions were inter-dependent, suggesting that they act cooperatively in the DSB-induced gene silencing. We further found two structural components within NUP107 to be necessary for the transcriptional repression at DSBs: ATM/ATR-mediated phosphorylation at Serine37 residue within the N-terminal disordered tail, and the NUP133-binding surface at the C-terminus. These results provide a new functional interplay among nucleoporins, ATM and the Polycomb proteins in the DSB metabolism, and underscore their emerging roles in genome stability maintenance. *Hongseon Song, Yubin Bae, Sangin Kim, and Dante Deascanis contributed equally to this work.

Radon concentration and affecting environmental conditions in water-curtain heated cultivation facilities.

Farmers cultivate plants in the winter using water curtain cultivation (WCC) facilities by spraying groundwater to keep them warm. In this study, the WCC facilities exhibited high radon concentrations during winter. The risk varied significantly depending on the facility operation, peaking in the early morning and then decreasing upon ventilation. At all measurement sites, radon concentrations were low when groundwater was not used. Even during the period of facility groundwater use, if water vapor condensation does not occur, there is no significant difference from soil-only emissions. However, once water vapor condensation occurs, radon accumulates rapidly, depending on the degree of radon contamination in the groundwater. Because groundwater contamination varies according to dilution by regional rainfall or inflow from other regions due to groundwater movement, abnormal changes in radon content occur. We found that in the absence of water vapor condensation in the facility, all the radon emitted from the soil and groundwater quickly escaped to the atmosphere, resulting in significantly lower indoor radon concentrations. These findings pave the way for the development of new methods to mitigate radon in WCC facilities.

Epigenetic age prediction using costal cartilage for the investigation of disaster victims and missing persons.

The DNA intelligence tool, DNA methylation-based age prediction, can help identify disaster victims and suspects in criminal investigations. In this study, we developed a costal cartilage-based age prediction tool that uses massive parallel sequencing (MPS) of age-associated DNA methylation markers. Costal cartilage samples were obtained from 85 deceased Koreans, aged between 26 and 89 years. An MPS library was prepared using two rounds of multiplex polymerase chain reaction of nine genes (TMEM51, MIR29B2CHG, EDARADD, FHL2, TRIM59, ELOVL2, KLF14, ASPA, and PDE4C). The DNA methylation status of 45 CpG sites was determined and used to train an age prediction model via stepwise regression analysis. Nine CpGs in MIR29B2CHG, FHL2, TRIM59, ELOVL2, KLF14, and ASPA were selected for regression model construction. A leave-one-out cross-validation analysis revealed the high performance of the age prediction model, with a mean absolute error (MAE) and root mean square error of 4.97 and 6.43 years, respectively. Additionally, our model showed good performance with a MAE of 6.06 years in the analysis of data of 181 costal cartilage samples collected from Europeans. Our model effectively estimates the age of deceased individuals using costal cartilage samples; therefore, it can be a valuable forensic tool for disaster victim and missing person investigation.

Using Oncolytic Virus to Retask CD19-Chimeric Antigen Receptor T Cells for Treatment of Pancreatic Cancer: Toward a Universal Chimeric Antigen Receptor T-Cell Strategy for Solid Tumor.

BACKGROUND: Chimeric antigen receptor (CAR) T cells targeting the B-cell antigen CD19 are standard therapy for relapsed or refractory B-cell lymphoma and leukemia. CAR T cell therapy in solid tumors is limited due to an immunosuppressive tumor microenvironment and a lack of tumor-restricted antigens. We recently engineered an oncolytic virus (CF33) with high solid tumor affinity and specificity to deliver a nonsignaling truncated CD19 antigen (CD19t), allowing targeting by CD19-CAR T cells. Here, we tested this combination against pancreatic cancer. STUDY DESIGN: We engineered CF33 to express a CD19t (CF33-CD19t) target. Flow cytometry and ELISA were performed to quantify CD19t expression, immune activation, and killing by virus and CD19-CAR T cells against various pancreatic tumor cells. Subcutaneous pancreatic human xenograft tumor models were treated with virus, CAR T cells, or virus+CAR T cells. RESULTS: In vitro, CF33-CD19t infection of tumor cells resulted in >90% CD19t cell-surface expression. Coculturing CD19-CAR T cells with infected cells resulted in interleukin-2 and interferon gamma secretion, upregulation of T-cell activation markers, and synergistic cell killing. Combination therapy of virus+CAR T cells caused significant tumor regression (day 13): control (n = 16, 485 ± 20 mm 3 ), virus alone (n = 20, 254 ± 23 mm 3 , p = 0.0001), CAR T cells alone (n = 18, 466 ± 25 mm 3 , p = NS), and virus+CAR T cells (n = 16, 128 ± 14 mm 3 , p < 0.0001 vs control; p = 0.0003 vs virus). CONCLUSIONS: Engineered CF33-CD19t effectively infects and expresses CD19t in pancreatic tumors, triggering cell killing and increased immunogenic response by CD19-CAR T cells. Notably, CF33-CD19t can turn cold immunologic tumors hot, enabling solid tumors to be targetable by agents designed against liquid tumor antigens.

Peritoneal-directed chimeric oncolytic virus CF17 prevents malignant ascites and improves survival in gastric cancer peritoneal metastases.

Gastric cancer (GC) peritoneal metastasis (PM) is fatal without effective therapy. We investigated CF17, a new replication-competent chimeric poxvirus, against GC cell lines in vitro and PM in an aggressive GCPM mouse model. We performed viral proliferation and cytotoxicity assays on intestinal-type and diffuse-type human GC cell lines following CF17 treatment. At lower MOIs of 0.01, 0.1, there was >80% killing in most cell lines, while in the more aggressive cell lines, killing was seen at higher MOIs of 1.0 and 10.0. We observed reduced peritoneal tumor burden and prolonged survival with intraperitoneal (i.p.) CF17 treatment in nude mice implanted with the resistant GC cell line. At day 91 after treatment, seven of eight mice were alive in the CF17-treated group vs. one of eight mice in the control group. CF17 treatment inhibited ascites formation (0% vs. 62.5% with PBS). Thus, CF17 efficiently infected, replicated in, and killed GC cells in a dose- and time-dependent manner in vitro. In vivo, i.p. CF17 treatment exhibited robust antitumor activity against an aggressive GCPM model to decrease tumor burden, improve survival, and prevent ascites formation. These preclinical results inform the design of future clinical trials of CF17 for peritoneal-directed therapy in GCPM patients.

Perfect Absorption and Reflection Modulation Based on Asymmetric Slot-Assisted Gratings without Mirrors.

As a perfect graphene absorber without any external mirrors, we proposed asymmetric slot-assisted grating structures supporting two degenerate resonant modes of the guided-mode resonances (GMR) and the quasi-bound states in the continuum (quasi-BIC). The GMR mode functions as an internal mirror in conjunction with the background scattering, while the quasi-BIC, which is responsible for perfect graphene absorption, stems from the horizontal symmetry breaking by an asymmetric slot. By properly shifting the slot center from the grating center, the leakage rate of quasi-BIC can be controlled in such a way as to satisfy the critical coupling condition. We provide a comprehensive study on the coupling mechanism of two degenerate resonant modes for a one-port system mimicking the resonance. We also numerically demonstrated that our proposed grating structures show an excellent reflection-type modulation performance at optical wavelength ranges when doped double-layer graphene is applied. Due to the perfect absorption at the OFF state, a high modulation depth of ~50 dB can be achieved via a small Fermi level variation of ~0.05 eV. To obtain the lower insertion loss at the ON state, the higher Fermi level is required to decrease the graphene absorption coefficient.

Anti-Tumor Immunogenicity of the Oncolytic Virus CF33-hNIS-antiPDL1 against Ex Vivo Peritoneal Cells from Gastric Cancer Patients.

We studied the immunotherapeutic potential of CF33-hNIS-antiPDL1 oncolytic virus (OV) against gastric cancer with peritoneal metastasis (GCPM). We collected fresh malignant ascites (MA) or peritoneal washings (PW) during routine paracenteses and diagnostic laparoscopies from GC patients (n = 27). Cells were analyzed for cancer cell markers and T cells, or treated with PBS, CF33-GFP, or CF33-hNIS-antiPDL1 (MOI = 3). We analyzed infectivity, replication, cytotoxicity, CD107α upregulation of CD8+ and CD4+ T cells, CD274 (PD-L1) blockade of cancer cells by virus-encoded anti-PD-L1 scFv, and the release of growth factors and cytokines. We observed higher CD45-/large-size cells and lower CD8+ T cell percentages in MA than PW. CD45-/large-size cells were morphologically malignant and expressed CD274 (PD-L1), CD252 (OX40L), and EGFR. CD4+ and CD8+ T cells did not express cell surface exhaustion markers. Virus infection and replication increased cancer cell death at 15 h and 48 h. CF33-hNIS-antiPDL1 treatment produced functional anti-PD-L1 scFv, which blocked surface PD-L1 binding of live cancer cells and increased CD8+CD107α+ and CD4+CD107α+ T cell percentages while decreasing EGF, PDGF, soluble anti-PD-L1, and IL-10. CF33-OVs infect, replicate in, express functional proteins, and kill ex vivo GCPM cells with immune-activating effects. CF33-hNIS-antiPDL1 displays real potential for intraperitoneal GCPM therapy.

An Oncolytic Poxvirus Encoding hNIS, Shows Antitumor Efficacy and Allows Tumor Imaging in a Liver Cancer Model.

Oncolytic viruses (OV) are live viruses that can selectively replicate in cancer cells. We have engineered an OV (CF33) to make it cancer-selective through the deletion of its J2R (thymidine kinase) gene. In addition, this virus has been armed with a reporter gene, human sodium iodide symporter (hNIS), to facilitate noninvasive imaging of tumors using PET. In this study, we evaluated the oncolytic properties of the virus (CF33-hNIS) in liver cancer model, and its usefulness in tumor imaging. The virus was found to efficiently kill liver cancer cells and the virus-mediated cell death exhibited characteristics of immunogenic death based on the analysis of 3 damage-associated molecular patterns: calreticulin, ATP, and high mobility group box-1. Furthermore, local or systemic administration of a single dose of the virus showed antitumor efficacy against a liver cancer xenograft model in mice and significantly increased survival of treated mice. Finally, PET scanning was performed following injection of the radioisotope I-124, for imaging of tumors, and a single dose of virus as low as 1E03 pfu, administered intra-tumorally or intravenously, allowed for PET imaging of tumors. In conclusion, CF33-hNIS is safe and effective in controlling human tumor xenografts in nude mice, and it also facilitates noninvasive imaging of tumors.

PCNA Ser46-Leu47 residues are crucial in preserving genomic integrity.

Proliferating cell nuclear antigen (PCNA) is a maestro of DNA replication. PCNA forms a homotrimer and interacts with various proteins, such as DNA polymerases, DNA ligase I (LIG1), and flap endonuclease 1 (FEN1) for faithful DNA replication. Here, we identify the crucial role of Ser46-Leu47 residues of PCNA in maintaining genomic integrity using in vitro, and cell-based assays and structural prediction. The predicted PCNAΔSL47 structure shows the potential distortion of the central loop and reduced hydrophobicity. PCNAΔSL47 shows a defective interaction with PCNAWT leading to defects in homo-trimerization in vitro. PCNAΔSL47 is defective in the FEN1 and LIG1 interaction. PCNA ubiquitination and DNA-RNA hybrid processing are defective in PCNAΔSL47-expressing cells. Accordingly, PCNAΔSL47-expressing cells exhibit an increased number of single-stranded DNA gaps and higher levels of γH2AX, and sensitivity to DNA-damaging agents, highlighting the importance of PCNA Ser46-Leu47 residues in maintaining genomic integrity.

An oncolytic poxvirus encoding hNIS, shows anti-tumor efficacy and allows tumor imaging in a liver cancer model.

Oncolytic viruses (OVs) are live viruses that can selectively replicate in cancer cells. We have engineered an OV (CF33) to make it cancer-selective through the deletion of its J2R (thymidine kinase) gene. Additionally, this virus has been armed with a reporter gene, human sodium iodide symporter (hNIS), to facilitate non-invasive imaging of tumors using positron emission tomography (PET). In this study we evaluated the oncolytic properties of the virus (CF33-hNIS) in liver cancer model, and its usefulness in tumor imaging. The virus was found to efficiently kill liver cancer cells and the virus-mediated cell death exhibited characteristics of immunogenic death based on the analysis of 3 damage associate molecular patterns (DAMPs): calreticulin, ATP and HMGB1. Furthermore, local or systemic administration of a single dose of the virus showed anti-tumor efficacy against a liver cancer xenograft model in mice and significantly increased survival of treated mice. Lastly, PET scanning was performed following injection of the radioisotope I-124, for imaging of tumors, and a single dose of virus as low as 1E03 pfu, administered intratumorally (I.T.) or intravenously (I.V.), allowed for PET imaging of tumors. In conclusion, CF33-hNIS is safe and effective in controlling human tumor xenografts in nude mice, and it also facilitates non-invasive imaging of tumors.

Development of the oncolytic virus, CF33, and its derivatives for peritoneal-directed treatment of gastric cancer peritoneal metastases.

BACKGROUND: Gastric cancer (GC) that metastasizes to the peritoneum is fatal. CF33 and its genetically modified derivatives show cancer selectivity and oncolytic potency against various solid tumors. CF33-hNIS and CF33-hNIS-antiPDL1 have entered phase I trials for intratumoral and intravenous treatments of unresectable solid tumors (NCT05346484) and triple-negative breast cancer (NCT05081492). Here, we investigated the antitumor activity of CF33-oncolytic viruses (OVs) against GC and CF33-hNIS-antiPDL1 in the intraperitoneal (IP) treatment of GC peritoneal metastases (GCPM). METHODS: We infected six human GC cell lines AGS, MKN-45, MKN-74, KATO III, SNU-1, and SNU-16 with CF33, CF33-GFP, or CF33-hNIS-antiPDL1 at various multiplicities of infection (0.01, 0.1, 1.0, and 10.0), and performed viral proliferation and cytotoxicity assays. We used immunofluorescence imaging and flow cytometric analysis to verify virus-encoded gene expression. We evaluated the antitumor activity of CF33-hNIS-antiPDL1 following IP treatment (3×105 pfu × 3 doses) in an SNU-16 human tumor xenograft model using non-invasive bioluminescence imaging. RESULTS: CF33-OVs showed dose-dependent infection, replication, and killing of both diffuse and intestinal subtypes of human GC cell lines. Immunofluorescence imaging showed virus-encoded GFP, hNIS, and anti-PD-L1 antibody scFv expression in CF33-OV-infected GC cells. We confirmed GC cell surface PD-L1 blockade by virus-encoded anti-PD-L1 scFv using flow cytometry. In the xenograft model, CF33-hNIS-antiPDL1 (IP; 3×105 pfu × 3 doses) treatment significantly reduced peritoneal tumors (p<0.0001), decreased amount of ascites (62.5% PBS vs 25% CF33-hNIS-antiPDL1) and prolonged animal survival. At day 91, seven out of eight mice were alive in the virus-treated group versus one out of eight in the control group (p<0.01). CONCLUSIONS: Our results show that CF33-OVs can deliver functional proteins and demonstrate effective antitumor activity in GCPM models when delivered intraperitoneally. These preclinical results will inform the design of future peritoneal-directed therapy in GCPM patients.

Simply structured polarization-independent high efficiency multilayer dielectric gratings.

A polarization-independent multilayer dielectric diffraction grating with a low aspect ratio and high diffraction efficiency was designed and fabricated. The diffraction grating designed with a grating density of 1200 lines/mm had an aspect ratio of 0.59, mean polarization-independent diffraction efficiency in the Littrow angle of ±2.5∘, and 1030-1080 nm wavelength range of 97.2%. The designed grating was fabricated using ion assisted deposition and reactive ion etching techniques. The mean polarization-independent diffraction efficiency of the fabricated grating was 96.1%, and its standard deviation was 0.68%. The fabricated diffraction grating was irradiated with a 1064 nm cw laser, with a power density of 30kW/cm2, for 1 min to measure the temperature change before and after the laser application. It was verified that the temperature variation of the diffraction grating without heat treatment was 8.8°C, and the temperature variation after heat treatment at 400°C decreased to 2.3°C.

Plug-and-play QKD architecture with a self-optical pulse train generator.

The commercialization of quantum key distribution (QKD), which enables secure communication even in the era of quantum computers, has acquired significant interest. In particular, plug-and-play (PnP) QKD has garnered considerable attention owing to its advantage in system stabilization. However, a PnP QKD system has limitations on miniaturization owing to a bulky storage line (SL) of tens of kilometers. And, the secure key rate is relatively low because Bob transmits the signal pulses only at the dedicated time slots to circumvent backscattering noise. This study proposes a new method that can eliminate the SL by realizing an optical pulse train generator based on an optical cavity structure. Our method allows Alice to generate optical pulse trains herself by duplicating Bob's seed pulse and excludes the need for Bob's strong signal pulses that trigger backscattering noise as much as the conventional PnP QKD. Accordingly, our method can naturally overcome the miniaturization limitation and the slow secure key rate, as the storage line is no longer necessary. We conducted a proof-of-concept experiment using our method and achieved a key generation rate of 1.6×10-3 count/pulse and quantum bit error rate ≤ 5%.

Priming stroma with a vitamin D analog to optimize viroimmunotherapy for pancreatic cancer.

Pancreatic cancer resistance to immunotherapies is partly due to deficits in tumor-infiltrating immune cells and stromal density. Combination therapies that modify stroma and recruit immune cells are needed. Vitamin D analogs such as calcipotriol (Cal) decrease fibrosis in pancreas stroma, thus allowing increased chemotherapy delivery. OVs infect, replicate in, and kill cancer cells and recruit immune cells to immunodeficient microenvironments. We investigated whether stromal modification with Cal would enhance oncolytic viroimmunotherapy using recombinant orthopoxvirus, CF33. We assessed effect of Cal on CF33 replication using pancreas ductal adenocarcinoma (PDAC) cell lines and in vivo flank orthotopic models. Proliferation assays showed that Cal did not alter viral replication. Less replication was seen in cell lines whose division was slowed by Cal, but this appeared proportional to cell proliferation. Three-dimensional in vitro models demonstrated decreased myofibroblast integrity after Cal treatment. Cal increased vascular lumen size and immune cell infiltration in subcutaneous models of PDAC and increased viral delivery and replication. Cal plus serial OV dosing in the syngeneic Pan02 model caused more significant tumor abrogation than other treatments. Cal-treated tumors had less dense fibrosis, enhanced immune cell infiltration, and decreased T cell exhaustion. Calcipotriol is a possible adjunct for CF33-based oncolytic viroimmunotherapy against PDAC.

PET imaging and treatment of pancreatic cancer peritoneal carcinomatosis after subcutaneous intratumoral administration of a novel oncolytic virus, CF33-hNIS-antiPDL1.

Peritoneal carcinomatosis of gastrointestinal malignancies remains fatal. CF33-hNIS-antiPDL1, a chimeric orthopoxvirus expressing the human sodium iodide symporter (hNIS) and anti-human programmed death-ligand 1 antibody, has demonstrated robust preclinical activity against pancreatic adenocarcinoma (PDAC). We investigated the ability of CF33-hNIS-antiPDL1 to infect, help detect, and kill peritoneal tumors following intratumoral (i.t.) injection of subcutaneous (s.c.) tumors in vivo. Human PDAC AsPC-1-ffluc cells were inoculated in both the s.c. space and the peritoneal cavity of athymic mice. After successful tumor engraftment, s.c. tumors were injected with CF33-hNIS-antiPDL1 or PBS. We assessed the ability of CF33-hNIS-antiPDL1 to infect, replicate in, and allow the imaging of tumors at both sites (immunohistochemistry [IHC] and 124I-based positron emission tomography/computed tomography [PET/CT] imaging), tumor burden (bioluminescence imaging), and animal survival. IHC staining for hNIS confirmed expression in s.c. and peritoneal tumors following virus treatment. Compared to the controls, CF33-hNIS-antiPDL1-treated mice showed significantly decreased s.c. and peritoneal tumor burden and improved survival (p < 0.05). Notably, 2 of 8 mice showed complete regression of disease. PET/CT avidity for 124I uptake in s.c. and peritoneal tumors was visible starting at day 7 following the first i.t. dose of CF33-hNIS-antiPDL1. We show that CF33-hNIS-antiPDL1 can help detect and kill both s.c. and peritoneal tumors following s.c. i.t. treatment.

Graphene optical modulators using bound states in the continuum.

Graphene-based optical modulators have been widely investigated due to the high mobility and tunable permittivity of graphene. However, achieving a high modulation depth with a low insertion loss is challenging owing to low graphene-light interaction. To date, only waveguide-type modulators have been extensively studied to improve light-graphene interaction, and few free-space type modulators have been demonstrated in the optical communication wavelength range. In this study, we propose two graphene-based optical free-space type modulators in a simple silicon photonic crystal structure that supports bound states in the continuum. The designed modulator with an ultra-high quality factor from the bound states in the continuum achieves a high modulation depth (MD = 0.9972) and low insertion loss (IL = 0.0034) with a small Fermi level change at the optical communication wavelength. In addition, the proposed modulators support outstanding modulation performance in the normal chemical vapor deposition (CVD) graphene (mobility = 0.5 m2/Vs). We believe the scheme may pave the way for graphene-based optical active devices.

A comprehensive preclinical study supporting clinical trial of oncolytic chimeric poxvirus CF33-hNIS-anti-PD-L1 to treat breast cancer.

CF33-hNIS-anti-PD-L1 is an oncolytic chimeric poxvirus encoding two transgenes: human sodium iodide symporter and a single-chain variable fragment against PD-L1. Comprehensive preclinical pharmacology studies encompassing primary and secondary pharmacodynamics and biodistribution and safety studies were performed to support the clinical development of CF33-hNIS-anti-PD-L1. Most of the studies were performed in triple-negative breast cancer (TNBC) models, as the phase I trial is planned for patients with TNBC. Biological functions of virus-encoded transgenes were confirmed, and the virus demonstrated anti-tumor efficacy against TNBC models in mice. In a good laboratory practice (GLP) toxicology study, the virus did not produce any observable adverse effects in mice, suggesting that the doses proposed for the clinical trial should be well tolerated in patients. Furthermore, no neurotoxic effects in mice were seen following intracranial injection of the virus. Also, the risk for horizontal transmission of CF33-hNIS-anti-PD-L1 was assessed in mice, and our results suggest that the virus is unlikely to transmit from infected patients to healthy individuals. Finally, the in-use stability and compatibility of CF33-hNIS-anti-PD-L1 tested under different conditions mimicking the clinical scenarios confirmed the suitability of the virus in clinical settings. The results of these preclinical studies support the use of CF33-hNIS-anti-PD-L1 in a first-in-human trial in patients with TNBC.

CF33-hNIS-antiPDL1 virus primes pancreatic ductal adenocarcinoma for enhanced anti-PD-L1 therapy.

Immunotherapeutic strategies that combine oncolytic virus (OV) and immune checkpoint inhibitors have the potential to overcome treatment resistance in pancreatic ductal adenocarcinoma (PDAC), one of the least immunogenic solid tumors. Oncolytic viral chimera, CF33-hNIS-antiPDL1 genetically modified to express anti-human PD-L1 antibody and CF33-hNIS-Δ without the anti-PD-L1 gene, were used to investigate the immunogenic effects of OVs and virus-delivered anti-PD-L1 in PDAC in vitro. Western blot, flow cytometry, and immunofluorescence microscopy were used to evaluate the effects of CF33-hNIS-Δ and IFNγ on PD-L1 upregulation in AsPC-1 and BxPC-3 cells, and CF33-hNIS-antiPDL1 production of anti-PD-L1 and surface PD-L1 blockade of AsPC-1 and BxPC-3 with or without cocultured activated T cells. The cytosolic and cell surface levels of PD-L1 in PDAC cell lines varied; only BxPC-3 showed high cell surface expression. Treatment of these cells with CF33-hNIS-Δ and IFNγ significantly upregulated PD-L1 expression and translocation of PD-L1 from the cytosol onto the cell surface. Following coculture of activated T cells and BxPC-3 with CF33-hNIS-antiPDL1, the cell surface PD-L1 blockade on BxPC-3 cells by virus-delivered anti-PD-L1 antibody increased granzyme B release and prevented virus-induced decrease of perforin release from activated CD8+ T cells. Our results suggest that CF33-IOVs can prime immune checkpoint inhibition of PDAC and enhance antitumor immune killing.

Graphene perfect absorber with loss adaptive Q-factor control function enabled by quasi-bound states in the continuum.

Numerous device structures have been proposed for perfect absorption in monolayer graphene under single-sided illumination, all of which requires the critical coupling condition, i.e., the balance between the loss of graphene and the leakage rate of the device. However, due to the difficulty of the precise control of the quality of synthesized graphene and unwanted doping in graphene transferred to the substrate, the loss of graphene is rather unpredictable, so that the perfect absorption is quite difficult to achieve in practice. To solve this problem, we designed a novel perfect absorber structure with a loss adaptive leakage rate control function enabled by the quasi-bound states in the continuum (BIC) and numerically demonstrated its performance. Our designed device is based on a slab-waveguide grating supporting both the quasi-BIC and the guided-mode resonance (GMR); the quasi-BIC with an adjustable leakage rate controlled by an incident angle is responsible for absorption, while the GMR works as an internal mirror. Since the proposed device scheme can have an arbitrarily small leakage rate, it can be used to implement a perfect absorber for any kind of ultrathin absorbing media. Due to the simple structure avoiding an external reflector, the device is easy to fabricate.

Toward comprehensive imaging of oncolytic viroimmunotherapy.

Oncolytic viruses infect, replicate in, and kill cancer cells, leaving normal cells unharmed; they also recruit and activate immune cells against tumor cells. While clinical indications for viroimmunotherapy are growing, barriers to widespread treatment remain. Ensuring real-time tracking of viral replication and resulting anti-tumor immune responses will overcome some of these barriers and is thus a top priority. Clinically optimizing trackability of viral replication will promote safe dose increases, guide serial dosing, and enhance treatment effects. However, viral delivery is only half the story. Oncolytic viruses are known to upregulate immune checkpoint expression, thereby priming otherwise immunodeficient tumor immune microenvironments for treatment with checkpoint inhibitors. Novel modalities to track virus-induced changes in tumor microenvironments include non-invasive measurements of immune cell populations and responses to viroimmunotherapy such as (1) in situ use of radiotracers to track checkpoint protein expression or immune cell traffic, and (2) ex vivo labeling of immune cells followed by nuclear medicine imaging. Herein, we review clinical progress toward accurate imaging of oncolytic virus replication, and we further review the current status of functional imaging of immune responses to viroimmunotherapy.