Search

While PD-1/PD-L1 blockade is a potent antitumor treatment strategy, it is effective in only limited subsets of cancer patients, emphasizing the need for the identification of additional immune checkpoints. Butyrophilin 1A1 (BTN1A1) has been reported to exhibit potential immunoregulatory activity, but its ability to function as an immune checkpoint remains to be systematically assessed and the mechanisms underlying such activity have yet to be characterized. Here, BTN1A1 expression was validated in primary tumor tissue samples, and its ability to suppress T cell activation and T cell-dependent tumor clearance was examined. The relationship between BTN1A1 and PD-L1 expression was further characterized, and an anti-BTN1A1 antibody was developed and administered to tumor-bearing mice to test the amenability of this target to immune checkpoint inhibition. BTN1A1 was confirmed to suppress T cell activation in vitro and in vivo. Robust BTN1A1 expression was detected in a range of solid tumor tissue samples, and BTN1A1 expression was mutually exclusive with that of PD-L1 as a consequence of its inhibition of JAK/STAT signaling-induced PD-L1 upregulation. Antibody-mediated BTN1A1 blockade suppressed tumor growth and enhanced immune cell infiltration in syngeneic tumor-bearing mice. Together, these results confirm that BTN1A1 is a bona fide immune checkpoint and viable immunotherapeutic target for the treatment of anti-PD1/PD-L1 refractory or resistant patients, opening new avenues to improving survival outcomes for patients with a range of cancers.

A Phase I clinical trial is currently underway to test Nelmastobart (hSTC810), an antibody targeting butyrophilin 1A1 (BTN1A1), a novel immune checkpoint protein. This Phase I clinical trial is using a standard 3 + 3 escalation design to (i) explore safety, tolerability, dose-limiting toxicities, and pharmacokinetics, (ii) define a recommended Phase II dose, and (iii) evaluate preliminary efficacy in patients with advanced solid tumors. The current dose range for the clinical trial is 0.3 mg/kg to 15 mg/kg. Currently, all the dose levels have been completed without any dose-limiting toxicity having been observed. Here, we provide an update on the clinical trial data shown previously. First, we provide the results of the pharmacokinetics study of these patients for the selected doses and dosing intervals, including the peak plasma concentration (Cmax), the time to reach Cmax (tmax), and the average plasma concentration of hSTC810 over the dosing interval in steady state (Cavg). The change in cytokine expression and immune cell concentrations in patient blood samples were also analyzed. Specifically, a panel of cytokines was measured including IFN- γ, IL-2, IL-4, IL-6, IL-10, TNF-α, MCP-1, and TGF- β, while flow cytometry was used to detect a panel of immunological marker proteins including CD3, CD4, CD8, CD19, CD14, CD16, CD56, CD25, CD45. For pharmacokinetic studies, the concentrations of hSTC810 and anti-hSTC810 antibodies were quantified. Immunohistochemistry was performed on patient tumor biopsies that were stained for PD-L1, CD3, CD4, CD8, and BTN1A1 expression. The resultant slides were analyzed for PD-L1 tumor proportional score (TPS), PD-L1 combined positive score (CPS), BTN1A1 scoring, the percentage of CD3+ lymphocytes, CD4+ lymphocytes, CD8+ lymphocytes, tumor-infiltrating lymphocytes, and necrosis. Citation Format: Stephen Sunghan Yoo, Soohyeon Lee, Sangjoon Shin, Hyunjin Jung, David S. Hong. Pharmacokinetic analyses and immunophenotyping of patients treated with Nelmastobart (hSTC810), a novel immune checkpoint inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT238.

The reversibly stable formation and rupture processes of electrical percolative pathways in organic and inorganic insulating materials are essential prerequisites for operating non-volatile resistive memory devices. However, such resistive switching has not yet been reported for dynamically cross-linked polymers capable of intrinsic stretchability and self-healing. This is attributable to the uncontrollable interplay between the conducting filler and the polymer. Herein, we present the development of the self-healing, stretchable, and reconfigurable resistive random-access memory. The device was fabricated via the self-assembly of a silver-gradient nanocomposite bilayer which is capable of easily forming the metal-insulator-metal structure. To realize stable resistive switching in dynamic molecular networks, our device features the following properties: i) self-reconstruction of nanoscale conducting fillers in dynamic hydrogen bonding for self-healing and reconfiguration and ii) stronger interaction among the conducting fillers than with polymers for the formation of robust percolation paths. Based on these unique features, we successfully demonstrated stable data storage of cardiac signals, damage-reliable memory triggering system using a triboelectric energy-harvesting device, and touch sensing via pressure-induced resistive switching.

High-performance photodetecting materials with intrinsic stretchability and colour sensitivity are key requirements for the development of shape-tunable phototransistor arrays. Another challenge is the proper compensation of optical aberrations and noises generated by mechanical deformation and fatigue accumulation in a shape-tunable phototransistor array. Here we report rational material design and device fabrication strategies for an intrinsically stretchable, multispectral and multiplexed 5 × 5 × 3 phototransistor array. Specifically, a unique spatial distribution of size-tuned quantum dots, blended in a semiconducting polymer within an elastomeric matrix, was formed owing to surface energy mismatch, leading to highly efficient charge transfer. Such intrinsically stretchable quantum-dot-based semiconducting nanocomposites enable the shape-tunable and colour-sensitive capabilities of the phototransistor array. We use a deep neural network algorithm for compensating optical aberrations and noises, which aids the precise detection of specific colour patterns (for example, red, green and blue patterns) both under its flat state and hemispherically curved state (radius of curvature of 18.4 mm).

Soft biomimetic electronic devices primarily comprise an electronic skin (e-skin) capable of implementing various wearable/implantable applications such as soft human–machine interfaces, epidermal healthcare systems, and neuroprosthetics owing to its high mechanical flexibility, tissue conformability, and multifunctionality. The conformal contact of the e-skin with living tissues enables more precise analyses of physiological signals, even in the long term, as compared to rigid electronic devices. In this regard, e-skin can be considered as a promising formfactor for developing highly sensitive and transparent pressure sensors. Specifically, to minimize the modulus mismatch at the biotic–abiotic interface, transparent-conductive hydrogels have been used as electrodes with exceptional pressing durability. However, critical issues such as dehydration and low compatibility with elastomers remain a challenge. In this paper, we propose a skin-like transparent polymer-hydrogel hybrid pressure sensor (HPS) with microstructures based on the polyacrylamide/sodium-alginate hydrogel and p-PVDF-HFP-DBP polymer. The encapsulated HPS achieves conformal contact with skin due to its intrinsically stretchable, highly transparent, widely sensitive, and anti-dehydrative properties. We believe that the HPS is a promising candidate for a robust transparent epidermal stretchable-skin device.

Although skin-like pressure sensors exhibit high sensitivity with a high performance over a wide area, they have limitations owing to the critical issue of being linear only in a narrow strain range. Various strategies have been proposed to improve the performance of soft pressure sensors, but such a nonlinearity issue still exists and the sensors are only effective within a very narrow strain range. Herein, we fabricated a highly sensitive multi-channel pressure sensor array by using a simple thermal evaporation process of conducting nanomembranes onto a stretchable substrate. A rigid-island structure capable of dissipating accumulated strain energy induced by external mechanical stimuli was adopted for the sensor. The performance of the sensor was precisely controlled by optimizing the thickness of the stretchable substrate and the number of serpentines of an Au membrane. The fabricated sensor exhibited a sensitivity of 0.675 kPa−1 in the broad pressure range of 2.3–50 kPa with linearity (~0.990), and good stability (&gt, 300 Cycles). Finally, we successfully demonstrated a mapping of pressure distribution.

Intracellular antibodies have become powerful tools for imaging, modulating and neutralizing endogenous target proteins. Here, we describe an optogenetically activated intracellular antibody (optobody) consisting of split antibody fragments and blue-light inducible heterodimerization domains. We expanded this optobody platform by generating several optobodies from previously developed intracellular antibodies, and demonstrated that photoactivation of gelsolin and β2-adrenergic receptor (β2AR) optobodies suppressed endogenous gelsolin activity and β2AR signaling, respectively.

An organic UV absorber, cinnamic acid, was intercalated into the interlayer gallery of layered yttrium hydroxynitrate (LYH) via the anion-exchange reaction. The complete replacement of interlayer nitrate by cinnamate was confirmed by thermogravimetric analysis of the obtained intercalation compound (cin-LYH). FT-IR spectra and powder X-ray diffraction patterns before and after intercalation reaction of LYH provided an information on the interaction of cinnamate anions with the inorganic host layer. Measured chemical composition and interlayer distance of cin-LYH and van der Waals dimensions of cinnamate proposed partially interdigitated bilayer arrangement of cinnamate anions in the interlayer space of LYH. The intercalation of cinnamate into the inorganic LYH layers highly improved its thermal stability in comparison with pure cinnamic acid. The comparison of reflectance spectra of pure cinnamic acid and cin-LYH before and after exposure to solar-simulated radiation showed that the trans- to cis- photoisomerization of cinnamate accompanied with a significant change of the molecular packing is not facilitated in the interlayer space of LYH. In contrast, only a slight variation in width and position of absorption band indicated no strong interaction between aromatic groups of cinnamate in the interlayer space of LYH. Quartz glasses coated with cin-LYH could be readily obtained by a simple dip-coating method in colloidal solutions and showed effective UV-filtering ability particularly in UV-B region (280–320 nm) without significant loss of the transparency of quartz glass. The release studies revealed that the interlayer space of LYH is effective for the retention of cinnamate for long time and this release reaching an equilibrium state at low concentration is suitable for long-term UV-screening service.

Chronic inflammation is a critical risk factor in the context of cancer development that promotes the expression of immune checkpoint proteins including PD-1, PD-L1, LAG-3, and TIM-3, which in turn suppress T-cell mediated cytotoxic tumor cell killing. Inflammation induced by treatments including chemotherapy and radiotherapy (RT) can also promote immune checkpoint upregulation and consequent tumor immune escape. However, whether the acute inflammation associated with standard chemotherapy and RT can engage distinct immune checkpoints to further support tumor persistence remains unknown. Using an in vivo screening platform in which tumors were irradiated with high-dose γ-radiation, we identified the B7-related immunoglobulin superfamily protein butyrophilin 1A1 (BTN1A1) as an acute stress-inducible immune checkpoint. Herein, we aimed to investigate how BTN1A1 contributes to post-irradiation intratumoral immunosuppression. To assess BTN1A1 induction in response to γ-radiation, human cell lines were exposed to a range of radiation doses, and cell death and BTN1A1 expression were examined by flow cytometry. Radiation promoted apoptosis and BTN1A1 expression in a dose-dependent manner, and PD-L1 was downregulated by increasing the dosage of γ-radiation. As radiation-induced cell death results in cytosolic DNA accumulation within tumors, which in turn activates the production of type I interferons (IFNs) via the cGAS/STING pathway, we examined the effect of BTN1A1 on cGAS and STING expression. BTN1A1 overexpression in human prostate adenocarcinoma PC3 cells suppressed cGAS and STING expression. IFNs can promote antigen presenting cell activation, thus priming T cell responses. We then examined the impact of BTN1A1 overexpression on type I IFN production as assessed via qRT-PCR, revealing that BTN1A1 overexpression enhanced IFN-β expression in the presence of the STING agonist cGAMP. BTN1A1 was also found to harbor a C-terminal B30.2 domain that was able to specifically interact with xanthine oxidoreductase (XOR), an oxidizing enzyme involved in purine metabolism. BTN1A1 expression induced high levels of intracellular reactive oxygen species (ROS), which have the potential to be more toxic in lymphocytes as compared to tumor cells, and BTN1A1 knockdown decreased these ROS levels. In light of these observations, we assessed the combination therapeutic efficacy of RT and anti-BTN1A1 antibodies in a syngeneic murine Lewis lung carcinoma (LLC) model system, revealing that these two treatments exhibited synergistic anti-tumor activity. FACS and IHC further confirmed that BTN1A1 was upregulated within tumors following irradiation. Together, these data offer new insights regarding the immunomodulatory role of radiation-induced BTN1A1 within tumors, providing a more robust foundation for the development of BTN1A1 as an immunologic target for cancer therapy. Citation Format: Ezra Chung, Young-Seung Kim, Andrew Park, Steven H. Lin, Hyunjin Jung, Stephen S. Yoo. Anti-BTN1A1 exhibits synergistic anti-tumor immunotherapeutic efficacy in combination with radiation therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6321.

Butyrophilin 1A1 (BTN1A1) is a novel immune checkpoint protein that exhibits an expression pattern mutually exclusive to that of PD-1/PD-L1 and may represent a promising therapeutic target for tumors that are anti-PD-1/PD-L1 antibody refractory. BTN1A1 was identified as a potential stress-inducible candidate immune checkpoint using the STCube in vivo immune target discovery platform. Additional analyses revealed that BTN1A1 was highly expressed in multiple human tumor types including urothelial carcinoma and NSCLC, with no overlap between BTN1A1 and PD-1/PDL-1 expression patterns. Mouse studies demonstrated that an anti-BTN1A1 antibody exhibited antitumor activity both as a single agent and in combination with anti-PD-1/PD-L1 or radiation therapy. A humanized anti-BTN1A1 antibody, hSTC810, was developed and found to suppress tumor growth in A549 CDX humanized murine models. Further studies identified Galectin 9 (Gal9) as a BTN1A1 receptor that can form a three protein complex with BTN1A1 and PD-1, thereby suppressing T cell receptor signaling and T cell activation. As high Gal9 expression levels are correlated with poor prognosis in multiple cancers, our results highlight this BTN1A1-Gal9-PD-1 axis as a novel therapeutic target for immunotherapeutic drug development. Given these findings, a first in human study of hSTC810 is in development to evaluate the safety profile of this therapy and to identify a dose for its further evaluation as an anticancer therapy. PK modeling including allometric scaling was performed to conduct simulations to predict the PK profile of hSTC810 after IV administration in humans and to identify possible doses needed to achieve tumor concentrations corresponding to the minimum anticipated biological effect level (MABEL) of 20% receptor occupancy (RO), 80% RO, or 95% RO. The partition coefficient was used to predict concentrations at the tumor site based on predicted serum concentrations. Simulations were performed for 100 subjects after the administration of multiple Q2W doses. The dose of 0.1 mg/kg was predicted to have Citation Format: Lynn Jackson Howie, Ezra M. Chung, Young-Seung Kim, Yujin Jung, Hyunjin Jung, Stephen Yoo. Humanized STC10 is a monoclonal antibody to BTN1A1, a novel immunotherapeutic target to be evaluated in a planned phase 1 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5318.

Plasma membrane (PM) phosphatidylinositol 4-phosphate (PI4P) plays a crucial role in diverse cellular functions, but its role beyond being a precursor of phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) in secretory pathways including neurotransmitter release and hormone secretion remains unclear. Here, using structured illumination microscopy on the PM of PC12 cells, we show that PI4P is an inner-leaflet lipid that is clustered in microdomain and involved in clustering of t-SNARE protein syntaxin 1 essential for vesicle docking. We found that PI4P interacted with the C2 domain of synaptotagmin 1 and synaptotagmin-like protein 4 in a Ca2+-independent manner, resulting in recruiting SNARE proteins to the target membrane. Interestingly, the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) was decreased by PI4P depletion in cultured hippocampal neurons, particularly it was most significantly decreased when PI(4,5)P2 depleted together. Thus, PI4P contributes to anionic PM lipid pool for SNARE-lipid interaction at vesicle docking stage of neuronal exocytosis.

Layered rare-earth hydroxides (LRHs) with high anion exchangeability between the hydroxocation layers, where a large variety of organic anions can be sheltered, are employed to construct hybrid systems that slowly release active organic ingredients. More importantly, it is possible to endow LRHs with a photoluminescence capability by doping activator ions such as Ce3+, Eu3+, and Tb3+ into matrices. In the present work, we explored Tb3+-doped layered yttrium hydroxide Y1.80Tb0.20(OH)5Cl· nH2O (LYH:Tb) nanosheets as a luminescent carrier for sustained release of salicylic acid (2-hydroxybenzoic acid), an example of nonsteroidal anti-inflammatory drugs and antimicrobial agents. Salicylate (sal) was intercalated into the interlayer gallery of LYH:Tb via a direct ion-exchange reaction. An observed variation in basal spacing suggested that salicylate anions are arranged in an interdigitated bilayer manner in the interlayer space of LYH:Tb. As generally observed in organic/inorganic hybrid systems, the thermal and photostabilities of salicylate were significantly improved after intercalation compared to its free state. The release kinetics of salicylate from sal-LYH:Tb hybrids in a saline solution at pH = 7.4 showed a highly sustained release of salicylate. Among various examined mathematical models, the parabolic diffusion equation best described the cumulative salicylate release. In particular, the salicylate intercalation led to the characteristic 5D4 → 7F J ( J = 6, 5, and 4) green emission of Tb3+ by its sensitization followed by the energy transfer to sal-LYH:Tb, whereas typical blue emission of salicylate was recovered after its release from the interlayer gallery of the LYH:Tb carrier. This green/blue luminescence change behavior provides a useful technique for in situ monitoring of the delivery and release of salicylate at target sites. The sal-LYH:Tb hybrid, with antimicrobial properties, was readily dispersed into a biodegradable polymer, polyvinyl alcohol, to prepare a transparent, UV-shielding, and luminescent composite that is applicable as an antimicrobial polymer to retard or prevent microbial growth.

The use of rare earths (REs) provides various advantages for removal and recovery of phosphate from water because they have high affinity to form stable complexes with phosphates even at low concentrations. Very low solubility of rare earth phosphate REPO4 in water was expected to induce a high phosphate adsorption rate and capacity. In this study, layered rare earth hydroxides, l-RE(OH)3 (RE = Sm, Gd, Er, and Y), have been employed to remove or recover phosphate from aqueous solution. This layered polymorph of l-RE(OH)3, which is composed of hydroxocation layers, exhibited a high point of zero charge (pHpzc > 10) and significantly enhanced adsorptive ability for phosphates over a wide pH range. The isotherm and kinetics of phosphate adsorption on l-RE(OH)3 were explained dominantly by the Langmuir isotherm model and pseudo-second-order kinetic model, respectively. A strong dependence of isotherm and kinetic parameters on RE demonstrated that the adsorption of phosphate on l-RE(OH)3 is a chemisorption dominated process involving the replacement of –OH by phosphate ion to be included into the coordination polyhedra of RE. The desorption of phosphate from l-RE(OH)3 was slow but the desorption efficiency for all RE members was higher than 97% in a 1.0 M NaOH solution after 4 days at room temperature. Considering high capacity and stability as well as no significant interference in recovery of phosphate from waters containing common competing anions, this rare earth adsorbent series is proposed as a promising alternative for efficient and sensitive phosphate recovery from natural and wastewaters.

Butyrophilin (BTN) proteins are members of the B7 immunoglobulin superfamily and exhibit well-characterized immunomodulatory functions in mammals. We have recently identified BTN1A1 as an immune checkpoint protein prominently upregulated in response to acute inflammatory insults. Further in vitro and in vivo assays have validated BTN1A1 as an immune checkpoint target, particularly for patients refractory to anti-PD-1/PD-L1 antibody treatment. We have also developed a humanized antibody targeting human BTN1A1, hSTC810, which is expected to enter into Phase I clinical trials in the first quarter of 2022. In this study, a cell microarray from Retrogenix (Whaley Bridge, UK) was used to identify binding partner(s) for the extracellular domain of human BTN1A1. Through this screening approach, we found that BTN1A1 binds to galectin-1 (Gal1), galectin-9 (Gal9), and neuropilin 2 (NRP2). These three putative binding partners could specifically bind to wild-type BTN1A1 but not to this protein's unglycosylated (2NQ) form. Of these three targets, immunoprecipitation and Biacore binding assays revealed that Gal9 exhibited the greatest affinity for human BTN1A1, followed by Gal1, with respective KD values of 22.7 nM and 1.88 μM - an 83-fold difference. Gal9 binding to human BTN1A1 was dependent on BTN1A1 glycosylation status and required the carbohydrate recognition domain (CRD) of Gal9. As Gal9 is a known PD-1-binding protein, the KD of Gal9 for PD-1 was additionally assessed and found to be 19.7 nM. These results thus predicted the potential formation of BTN1A1/Gal9/PD-1 complexes. Consistent with these predictions, immunoprecipitation assays performed using cells expressing Myc-tagged versions of these three proteins demonstrated the formation of BTN1A1/Gal9, PD-1/Gal9, and BTN1A1/Gal9/PD-1 complexes. CRISPR-mediated BTN1A1 knockout in Jurkat T cells induced both PD-1 expression and T cell activation. BTN1A1 also suppressed T cell receptor (TCR) signaling in Jurkat cells, and the addition of exogenous recombinant Gal9 protein further blunted such BTN1A1-mediated TCR-signaling downregulation. Such downregulation was not observed in PD-1 knockout Jurkat cells. Together with the observation that BTN1A1 does not bind to PD-1 directly, the data suggest that BTN1A1 suppresses T cell activation by interacting with PD-1 through Gal9. As high Gal9 expression levels are correlated with poor prognosis in multiple cancers, our results highlight this BTN1A1-Gal9-PD-1 axis as a novel therapeutic target for immunotherapeutic drug development. (1) Chung EM, Bong YS, Kim YS, Park A, You YO, Sharma A, Lin SH, Lee YJ, Jung H, Yoo SS. BTN1A1: a novel immune checkpoint for cancer immunotherapy beyond the PD-1/PD-L1 axis. Cancer Res 2021;81(13_Suppl): Abstract nr 1643. Citation Format: Ezra M Chung, Young-Seung Kim, Chunai Wu, Andrew H Park, Hyunjin Jung, Stephen S Yoo. The immune checkpoint protein BTN1A1 suppresses T cell activation through interactions with Gal9 and PD-1 [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr LBA019.

Soft bioelectronic systems with a unique mechanical property, namely modulus matching between human skin (or tissue) and the device, have gained widespread attention. This is because of their closed-loop strain-insensitive electrical performance ranging from application in the long-term stable measurements of physiological signals and feedback modulation to human skin (or organs). Various materials and integration/fabrication strategies such as buckled, rigid islands, and wavy designs addressed for soft bioelectronic systems require complex device fabrication with time-consuming packaging and integration processes. In this study, we developed a soft bio-integrated multifunctional device (SBMD) fabricated through the simple thermal evaporation and transfer processes. The intrinsically stretchable Au–SEBS film composed of thermally evaporated gold (Au) nanomembranes and an elastomeric substrate was applied to various functional modules that are capable of sensing the strain (up to ~300%), temperature (with a thermal sensitivity of ~0.6 Ω/°C), chemicals (at a concentration of NaCl of ~0.5 wt%), and even electrophysiological cardiac/muscle signals and showing thermal actuations (80 °C at 9 V). Specifically, such multifunctions of the SBMD were stably performed even on skin. Thus, we believe the SBMD would be a promising candidate for realizing soft bioelectronic systems.

Cancer immunotherapy is an effective treatment against individuals with late-stage cancer forms. The PD-1/PD-LI axis is a main therapeutic target used in clinical settings, but only 15-20% of cancer patients are responsive. Thus, there is an urgent unmet need to identify other immuno-therapeutic targets to overcome this limitation. Butyrophilin (BTN) belongs to the B7 family, peripheral membrane proteins containing an immunoglobulin domain found in PD-L1 and CTLA4. Among the BTN family, BTN2A2 and BTN3A1 are shown as alternative co-inhibitory or co-stimulatory cancer immune checkpoint(s) in the effector T cell compartment. However, the immune-modulatory roles of BTN1A1 are largely unknown, especially in vivo. Here, we report the immune-modulatory role of BTN1A1 in T cell proliferation and activation in vitro and in vivo. We have found that BTN1A1 inhibits the proliferation of T cells that are activated by anti-CD3 and anti-CD28 antibodies in vitro. The overexpression of BTN1A1 in PC3 cells also inhibits T cell-mediated cancer cell killing. BTN1A1-overexpressing B16-Ova melanoma cancer cell lines also accelerate tumor growth compared to B16-Ova wild type in a syngeneic mouse model. The effect of BTN1A1 was fully attenuated in an immune-compromised SCID mouse. BTN1A1-deficient MC38 colorectal cancer cell lines also grew significantly slower than wild-type MC38 cell lines when they were inoculated subcutaneously into a syngeneic mouse model. This result strongly supports BTN1A1's role in immune evasion. BTN1A1 is expressed on immune cells. These cells include macrophages, B cells or activated CD8 T cells. We found that BTN1A1 is expressed in human tumors, with an expression that was mutually exclusive to PD-L1. We have developed the monoclonal antibody (STC810) against the human BTN1A1. STC810 has anti-tumor activity in a human immune environment in vitro and ex vivo. Since STC810 has no cross-reactivity with mouse BTN1A1 proteins, we generated mouse surrogate antibodies to study the effects of blocking BTN1A1 in vivo in mice tumor models. The anti-BTN1A1 surrogate antibody not only exhibits a single agent but has a synergistic effect in combination with the anti-PD-L1 antibody. Overall, using mouse models, genetic ablation, and antibody tests ex vivo we demonstrate that BTN1A1 is a bona fide immune checkpoint inhibitor. Late-stage preclinical studies of humanized STC810 are underway. The Phase I clinical trial is set to start in late 2021. Citation Format: Ezra M. Chung, Yong-Sik Bong, Young-Seung Kim, Andrew Park, Young-Ok You, Amrish Sharma, Steven H. Lin, Young-Joon Lee, Hyunjin Jung, Stephen S. Yoo. BTN1A1: a novel immune checkpoint for cancer immunotherapy beyond the PD-1/PD-L1 axis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1643.

Intracellular antibodies have become powerful tools for imaging, modulating and neutralizing endogenous target proteins. Here, we describe an optogenetically activated intracellular antibody (optobody) consisting of split antibody fragments and blue-light inducible heterodimerization domains. We expanded this optobody platform by generating several optobodies from previously developed intracellular antibodies, and demonstrated that photoactivation of gelsolin and β2-adrenergic receptor (β2AR) optobodies suppressed endogenous gelsolin activity and β2AR signaling, respectively.

Layered rare-earth hydroxides (LRHs) with high anion exchangeability between the hydroxocation layers, where a large variety of organic anions can be sheltered, are employed to construct hybrid systems that slowly release active organic ingredients. More importantly, it is possible to endow LRHs with a photoluminescence capability by doping activator ions such as Ce

Actin waves are filamentous actin (F-actin)-rich structures that initiate in the somato-neuritic area and move toward neurite ends. The upstream cues that initiate actin waves are poorly understood. Here, using an optogenetic approach (Opto-cytTrkB), we found that local activation of the TrkB receptor around the neurite end initiates actin waves and triggers neurite elongation. During actin wave generation, locally activated TrkB signaling in the distal neurite was functionally connected with preferentially localized Rac1 and its signaling pathways in the proximal region. Moreover, TrkB activity changed the location of ankyrinG--the master organizer of the axonal initial segment-and initiated the stimulated neurite to acquire axonal characteristics. Taken together, these findings suggest that local Opto-cytTrkB activation switches the fate from minor to major axonal neurite during neuronal polarization by generating actin waves.

The damages from greenhouses collapsing due to heavy snowfall in winter are increasing, and the current frames of greenhouse are required to be improved. This study was conducted to seek solutions to improve intensities of greenhouse frame to bear heavy snows. We investigated a structural safety of greenhouses by calculating axial force, bending moment and combined stress when snow load was increased up to 30% of the current standard ground snow load of the conventional greenhouse types (07-single type 3, 07-single type 18) in the three regions (Gyeongju, Sokcho, and Gangneung) where were most damaged by recent heavy snows. In addition, we determined what structural type was most efficiently bear snow loads by measuring the differences between the load bearing strength according to the changes of tube diameter and thickness or the rafter spacing of greenhouses circular pipe. MIDAS GEN program was used in the analysis. As a result, with the snow load increase of 30%, greenhouse in Gyongju was still safe, but in Sokcho was at a risk, and in Gangneung was possible to be collapsed even in the current snow load. Increased pipe diameter than increased pipe thickness was more efficient in terms of improved performance of greenhouse structure. Accordingly, it is suggested to revise standards of greenhouse to increase pipe diameter of rafter for minimizing damages by heavy snow.

Demand Forecasting is a key to effective inventory management. In forecasting fields, intermittent demand forecasting remains to be a very important but challenging problem. Intermittent demand is characterized by many empty demands, stochastic periods between them, and high variance of non-zero values. These characteristics make intermittent demand forecasting a difficult task, for both parametric and non-parametric approaches. The parametric methods have shown many limitations to provide accurate information. Though non-parametric methods provide better information for decision making than parametric case, they cannot forecast any exact information of point values. This paper proposes a new simulation framework that takes into consideration the correlation structure between demand of assembly and demand of parts, leading to more precise information of point values. In particular, we demonstrate how sub-parts for classification can affect to prediction performance of the overall model via an experiment using artificial data.

Gait speed (GS) of older people has been usually measured manually using stop watch. However, new simple devices allow automated GS measurement in clinic. We sought whether automatically measured GS differs from manually measured GS in distributions and associations with geriatric conditions including frailty index. A total of 260 community-dwelling older participants in Aging Study of Pyeongchang Rural Area (ASPRA) cohort had comprehensive geriatric assessment including automatically measured GS and manually acquired GS in December 2017. For automated GS, we used ultrasound sensor deployed at the start and finish point of 4 meter section. GS measured by automated device (mean 1.19 m/s, standard deviation [SD] 0.02 m/s) were faster than manually acquired GS (mean 0.87 m/s, SD 0.02 m/s, P < 0.001). Differences between two method was greater (P 1 m/s (mean difference 0.31), compared to slower working participants with GS < 1m/s (mean difference 0.20). Automated GS and manually acquired GS correlated each other (R2 = 0.944, manually acquired GS = Automated GS * 0.697 + 0.044). GS measured by both method associated with frailty index, and both method could screen vulnerability (combining prefrailty and frailty defined by the Cardiovascular Health Study frailty criteria), without statistical differences in C-statistics (P = 0.203). GS measured manually was appeared to be slower when compared to automatically measured GS. For clinical use of automated GS, we may adjust reference values of GS that was originally measured manually to reflect differences between two instruments.

This research is aimed to determine the clinically meaningful change of self-reported and performance-based frailty measures. We analyzed data from a prospective cohort study of 1,084 community-dwelling older adults (mean age: 75.9 years; male 48.0%) who underwent assessments of frailty and health-related quality of life using the EuroQol-5D (range: 0–1) at baseline and 1 year later. Frailty measures included a deficit-accumulation frailty index (FI) (29 self-reported items alone or with additional 5 performance items), the frailty phenotype, the FRAIL questionnaire, and the Study of Osteoporotic Fracture (SOF) index. A clinically meaningful change was determined for each frailty measure that corresponded to a small decline (0.1–0.2) or large decline (>0.2) in the EuroQol-5D score over 1 year. After excluding people who died (n=16), were institutionalized (n=78), and were lost to follow-up (n=122), repeat frailty measures were available in 868 participants (80.1%). Using the change in EuroQol-5D score as the anchor, small and large clinically meaningful changes of frailty measures were 0.032 and 0.070 for the self-reported FI; 0.028 and 0.059 for the full FI; 0.076 and 0.588 for the frailty phenotype; 0.241 and 0.379 for the FRAIL questionnaire; and 0.034 and 0.293 for the SOF index. Based on responsiveness indices, per-group sample sizes to achieve 80% power in clinical trials ranged from 66 (self-reported FI) to 4941 (SOF index) for small change and 15 (self-reported FI) to 126 (FRAIL questionnaire) for large change. These results can inform the choice of frailty measures in interventional studies targeting frailty.

Di- and triblock copolymers of poly(ethylene oxide) (PEO) and poly( dl -valine-co- dl -leucine) were synthesized by ring-opening polymerization of N-carboxyanhydride (NCA)s of dl -valine and dl -leucine initiated by amine-terminated PEOs. The resulting block copolymers were characterized by 1 H NMR , FT-IR, DSC, and wide-angle X-ray diffraction (WAXD). Differential scanning calorimeter revealed that the melting temperature of triblock copolymer was lower than that of diblock copolymer and the study of WAXD patterns of triblock copolymer indicated that PEO segments are stretched during the copolymerization as shown in the formation of complex. The self-assembly behaviors of these di- and triblock copolymers in the aqueous solution showed various forms.

Receptor tyrosine kinases (RTKs) are a family of cell-surface receptors that have a key role in regulating critical cellular processes. Here, to understand and precisely control RTK signalling, we report the development of a genetically encoded, photoactivatable Trk (tropomyosin-related kinase) family of RTKs using a light-responsive module based on Arabidopsis thaliana cryptochrome 2. Blue-light stimulation (488 nm) of mammalian cells harbouring these receptors robustly upregulates canonical Trk signalling. A single light stimulus triggers transient signalling activation, which is reversibly tuned by repetitive delivery of blue-light pulses. In addition, the light-provoked process is induced in a spatially restricted and cell-specific manner. A prolonged patterned illumination causes sustained activation of extracellular signal-regulated kinase and promotes neurite outgrowth in a neuronal cell line, and induces filopodia formation in rat hippocampal neurons. These light-controllable receptors are expected to create experimental opportunities to spatiotemporally manipulate many biological processes both in vitro and in vivo.

Objectives To assess the effectiveness of a comprehensive workplace stress management program consisting of participatory action-oriented training (PAOT) and individual management. Methods A comprehensive workplace stress management program was conducted in a medium-sized enterprise. The baseline survey was conducted in September 2011, using the Korean Occupational Stress Scale (KOSS) and Worker’s Stress Response Inventory (WSRI). After implementing both organizational and individual level interventions, the follow up evaluation was conducted in November 2011. Results Most of the workers participated in the organizational level PAOT and made Team-based improvement plans. Based on the stress survey, 24 workers were interviewed by a researcher. After the organizational and individual level interventions, there was a reduction of several adverse psychosocial factors and stress responses. In the case of blue-collar workers, psychosocial factors such as the physical environment, job demands, organizational system, lack of rewards, and occupational climate were significantly improved; in the case of white-collar workers, the occupational climate was improved. Conclusions In light of these results, we concluded that the comprehensive stress management program was effective in reducing work-related stress in a short-term period. A persistent long-term follow up is necessary to determine whether the observed effects are maintained over time. Both team-based improvement activities and individual interviews have to be sustainable and complementary to each other under the long-term plan.