Biotronik (Singapore)

Abstract Background: Tumor-infiltrating lymphocytes (TILs) are heterogeneous populations of lymphocytes residing in tumor tissues, comprising various T-cell clones with specificity towards tumor or viral antigens. TIL therapy has been recently approved for advanced melanoma treatment with high-dose interleukin-2 (IL-2) as a concomitant treatment. However, the accessibility of tumor tissues, the varied abundance and effectiveness of tumor-reactive T-cells, and the toxicity of IL-2 infusion limit the clinical application of TILs toward a broader range of tumor indications. To address the high individual variance, we have engineered TILs expressing chimeric antigen receptor (CAR) constructs targeting glycoproteins on the hepatocellular carcinoma (HCC) cell surface. However, heavy glycosylation of these glycoproteins may mask peptidic epitopes to single-chain antibodies. Previous studies have revealed that the glucose/mannose analog, 2-deoxy-D-glucose (2-DG) treatment of pancreatic cancer cells can disrupt the synthesis of N-glycan moieties on the cell surface and enhance CAR T-cell activity. 2-DG treatment of T cells augmented antitumor activity and cell surface retention of IL-2R of T cells. In this study, we investigated whether the anti-tumor function of CAR-TILs against HCC lines would also benefit from the 2-DG treatment. Methods: TILs were isolated from fresh or cryopreserved tumor biopsy samples and stimulated with anti-CD3/CD28 antibodies. Thereafter, TILs were lentiviral transduced with Glypican 3 (GPC3) CAR and membrane bound-interleukins, expanded with γ-irradiated feeder cells in an optimized rapid expansion process (REP), and cryopreserved until use. Phenotypic analyses were performed by flow cytometry. HCC lines were pre-treated with or without 2-DG, and the antigen recognition by antibodies targeting GPC3, CD133, and CD44v6 was evaluated by flow cytometry. In vitro effector function was assessed by IFN-γ release (ELISA) and killing assay (Incucyte). The anti-tumor efficacy of CAR-TILs with or without 2-DG treatment was further assessed in the immunocompromised xenograft model. Results: Pre-treatment of HCC cell lines with 2-DG (1∼10 mM) enhanced the antibody recognition of GPC3 in a dose-dependent fashion while showing no improvement in mAb binding towards CD133/CD44v6. CAR-TILs showed enhanced killing and more IFNγ release towards 2-DG pre-treated GPC3+ HCC lines. The synergistic effect of 2-DG with CAR-TILs was further validated in the immunocompromised murine model, and no apparent toxicity was observed. The proliferation and the CD4/CD8 ratio of CAR-TILs were not affected by 2-DG treatment. Conclusion: 2-DG sensitized GPC3 antigen recognition, thus boosting CAR-TIL cytotoxic activity against GPC3+ HCC cells. These data prompt further investigation before pursuing a combination therapy. Citation Format: Mingyu Liu, Deping Han, Jean-Paul Thiery, Xi Zhang. 2-deoxy-D-glucose sensitizes the antigen recognition of chimeric antigen receptor-expressing tumor-infiltrating lymphocytes toward hepatocellular carcinoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 873.

Abstract To guarantee the reliability of high‐performance and environmentally friendly novel polypropylene (PP) for use as the primary insulation in cables, an assessment of the electrical ageing life of SiO 2 /PP composite materials was carried out using a step‐stress accelerated ageing test based on the inverse power law. The study involved an analysis of microstructural characteristics and performance testing to investigate the bonding between the SiO 2 under different surface treatment methods and matrixes. Furthermore, the impact of SiO 2 on charge capture performance in PP insulation was analysed through polarisation–depolarisation current testing. The results show that silica with long alkane chains and amino groups grafted on the surface has good compatibility with PP insulating layers, which can increase the trap energy level of captured electrons and thus reduce the damage of high‐energy electrons to the composites. SiO 2 increased the life index of the PP insulating layer by 19.95%, which contributed to the improvement of the electrical ageing life of the PP insulating layer.

BackgroundTumor Infiltrating Lymphocytes (TILs) comprise various T cell clones with specificity towards tumor or viral antigens. TIL therapy has been approved for melanoma treatment with high-dose interleukin-2 (IL-2). However, the accessibility of TILs, the small fraction of antigen-specific T cells, limited persistence in vivo, exhausted phenotype, and toxicity of high-dose IL-2 infusion restrict its application to the treatment of other solid tumors. We developed multiple signaling elements (MSE)-TIL platform to expand and engineer TILs derived from liver cancer biopsies (figure 1). These TILs (MSE-TIL) showed increased memory T-cell percentage, improved proliferation capacity, and enhanced anti-tumor potential towards various liver cancer cells without IL-2 administration.MethodsTILs were isolated from fresh or cryopreserved tumor biopsy samples and stimulated with anti-CD3/CD28 antibodies. Thereafter, TILs were modified by lentiviral transduction and further expanded with γ-irradiated feeder cells in an optimized rapid expansion process (REP) to induce memory CD8+ T cells. The final product was cryopreserved for storing and shipping. Phenotypic analyses were performed by flow cytometry. IFN-γ ELISA, RTCA Xcelligence, and IncuCyte were used to evaluate in vitro activation and cytotoxicity. Anti-tumor efficacy was further evaluated in immunocompromised xenograft models.ResultsThe successful rate for MSE-TIL production from two tumor biopsies was ~ 95%, reaching 1011 TILs on day 26. Compared with traditional REP, the percentage of central memory CD8+ T cells was increased by 5-fold to promote persistent anti-tumor function in vitro (figure 2). TILs were additionally engineered with CAR recognizing tumor antigens including CD133 and CD44v6, cofactors such as membrane-bound interleukins and mitochondrial homeostasis regulators, to sustain their in vivo proliferation and long-term anti-tumor efficacy. The lentiviral transduction rate was stably maintained at over 30% (Day 28: CAR, 48.8 ± 9.1%; cofactor, 58.6 ± 12.6%) for up to 7 weeks ex vivo. MSE-TIL shows potent killing efficacy towards liver cancer cell lines. Moreover, MSE-TIL can accumulate in tumors and inhibit their growth without toxicity in an immunocompromised murine model (figure 3).ConclusionsEngineered MSE-TILs demonstrated persistent therapeutic efficacy with no obvious toxicities in the mouse model, supporting its further clinical applications.Ethics ApprovalAll animal studies were conducted by Biosyngen staff at Guangzhou Regenerative Medicine and Health, Guangdong Laboratory (GRMH-GDL) as approved by the Ruiye model animal (Guangzhou) Biotechnology Co., Ltd facility as approved by its Experimental Animal Care and Use Committee (approval No. RYEth20220516-1). 467 Figure 1MSE-TIL Platform for R&D Translation & Immunotherapy Drug Development against Solid Tumors 467 Figure 2The MSE-TIL manufacturing process markedly increases memory T-cell frequency with persistent killing ability in vitro. (A) TIL expansion curve; (B) Frequency of central memory (TCM) and terminal differentiation (TD) T cells; (C) Experimental flow; (D) Repeated stimulation assay; (E) In vitro killing assay 467 Figure 3Genetically engineered MSE-TIL shows potent killing efficacy against liver cancer. (A) Transduction rate; (B) Cell proliferation curve; (C) The persistent killing ability of MSE-TIL, detected by IncuCyte; (D) Number of TILs in mouse peripheral blood after infusion; (E) Anti-tumor efficacy in vivo

Recently, 3D printing technology has become more popular in the field of construction. For the extrusion-based 3D concrete printing (3DCP) process, the cementitious material needs to be strong and flowable enough to ensure buildability and pumpability. Nanostructured silica, a kind of additive, has been used to modify the 3DCP concrete to meet these requests. However, most previous studies focused on the effect of nanostructured silica on rheological properties and failed to link the obtained rheological properties of nanostructured-silica-modified cementitious materials to the performance in 3D printing. In this paper, the 3DCP mixture based on premix cement, river sand, silica fume, and water was modified by different dosages of nanostructured silica (from 0.25% to 1.00% by the total weight of the 3DCP mixture). The effects of nanostructured silica on the rheological, hydration, printing, and microstructural properties were determined by rheological tests, stress growth tests, setting time tests, printing tests, and scanning electron microscopy (SEM) tests, respectively. This paper revealed that the nanostructured silica has a positive effect on 3DCP buildability but negatively affects the printing quality, which fits the effect of nanostructured silica on the rheological properties. Hence, the determined rheological properties can qualitatively evaluate the printing performance of nanostructured-silica-modified cementitious materials.

High-precision aspherical cylindrical (acylindrical) lenses are difficult to directly measure because of the phase deviation in the off-axis region. To achieve rapid and non-contact measurement of the acylindrical lens surface, a novel optical structure phase measurement, to the best of our knowledge, is presented in this work. Both common finite-difference and noise-reduction finite-difference methods were used for solving the transport of intensity equation (TIE) for reconstruction of high-resolution surface measurement. The results suggest that both common finite-difference and noise-reduction finite-difference methods can obtain good measurement results. The proposed method allows for the direct measurement of surface information without interference stitching. The accuracy of the TIE measurement has been verified through direct contact measurement.

Nanostructured silica particles are common additives in polymer-based coating applications and therefore of great interest to obtain better properties of light-curable three-dimensional (3D) printed polymer parts. This work studies the effect of nanostructured silica additives on the mechanical properties of printed parts. Three types of silica particles with distinct nanostructured morphologies, namely, (1) fumed fractal silica, (2) sponge-like precipitated silica, and (3) discrete colloidal silica, were used as additives to prepare nanocomposite photopolymer resins for the digital light projection (DLP) 3D printing. The effect of particulate nanostructures and their interfacial interactions with the resin matrices on the rheology of resin constituents, the curing, and mechanical properties were evaluated. The addition of 10 wt % fumed or precipitated silica improved the mechanical properties such as hardness and tensile strength by as much as 58 and 141%, respectively. Sponge-like precipitated silica tends to lower the critical energy of photopolymerization by up to 17%. The findings in this work provide useful guidelines when tailoring the mechanical properties of 3D printed parts with nanostructured silica additives. In the quest for light-curable printing materials, while the strategy to modify/alternate polymer backbone structures to achieve higher mechanical strength is important, the means of obtaining such enhancement through "printing suitable filler"-polymer matrix interaction have indeed proved to be a target within immediate reach.

BACKGROUND Virtual reality is increasingly being utilized by clinicians to facilitate analgesia and anxiolysis within an inpatient setting. There is however, a lack of a clinically relevant review to guide its use for this purpose. OBJECTIVE To systematically review the current evidence for the efficacy of virtual reality as an analgesic in the management of acute pain and anxiolysis in an inpatient setting. METHODS A comprehensive search was conducted up to and including January 2019 on PubMed, Ovid Medline, EMBASE, and Cochrane Database of Systematic reviews according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Search terms included virtual reality, vr, and pain. Primary articles with a focus on acute pain in the clinical setting were considered for the review. Primary outcome measures included degree of analgesia afforded by virtual reality therapy, degree of anxiolysis afforded by virtual reality therapy, effect of virtual reality on physiological parameters, side effects precipitated by virtual reality, virtual reality content type, and type of equipment utilized. RESULTS Eighteen studies were deemed eligible for inclusion in this systematic review; 67% (12/18) of studies demonstrated significant reductions in pain with the utilization of virtual reality; 44% (8/18) of studies assessed the effects of virtual reality on procedural anxiety, with 50% (4/8) of these demonstrating significant reductions; 28% (5/18) of studies screened for side effects with incidence rates of 0.5% to 8%; 39% (7/18) of studies evaluated the effects of virtual reality on autonomic arousal as a biomarker of pain, with 29% (2/7) demonstrating significant changes; 100% (18/18) of studies utilized a head mounted display to deliver virtual reality therapy, with 50% being in active form (participants interacting with the environment) and 50% being in passive form (participants observing the content only). CONCLUSIONS Available evidence suggests that virtual reality therapy can be applied to facilitate analgesia for acute pain in a variety of inpatient settings. Its effects, however, are likely to vary by patient population and indication. This highlights the need for individualized pilot testing of virtual reality therapy’s effects for each specific clinical use case rather than generalizing its use for the broad indication of facilitating analgesia. In addition, virtual reality therapy has the added potential of concurrently providing procedural anxiolysis, thereby improving patient experience and cooperation, while being associated with a low incidence of side effects (nausea, vomiting, eye strain, and dizziness). Furthermore, findings indicated a head mounted display should be utilized to deliver virtual reality therapy in a clinical setting with a slight preference for active over passive virtual reality for analgesia. There, however, appears to be insufficient evidence to substantiate the effect of virtual reality on autonomic arousal, and this should be considered at best to be for investigational uses, at present.

BackgroundNon-invasive fetal electrocardiogram (NIFECG) is an evolving technology in fetal surveillance which is attracting increasing research interest. There is however, only limited data outlining the reference ranges for normal cardiac time intervals (CTIs). The objective of our group was to carry out a systematic review to outline normal fetal CTIs using NIFECG.MethodsA systematic review of peer reviewed literature was performed, searching PUBMED,Ovid MEDLINE and EMBASE. The outcomes of interest included fetal CTIs (P wave duration, PR interval, QRS duration and QT interval) and a descriptive summary of relevant studies as well. The outcomes were grouped as early pre-term (≤ 32 weeks), moderate to late pre-term (32–37 weeks) and term (37–41 weeks).Results8 studies were identified as suitable for inclusion. Reference ranges of CTIs were generated. Both PR interval and QRS duration demonstrated a linear correlation with advancing gestation. Several studies also demonstrated a reduction in signal acquisition between 27 and 32 weeks due to the attenuation by vernix caseosa. In this group, both the P wave and T waves were difficult to detect due to signal strength and interference.ConclusionNIFECG demonstrates utility to quantify CTIs in the fetus, particularly at advanced gestations. Larger prospective studies should be directed towards establishing reliable CTIs across various gestations.