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BackgroundHuman epidermal growth factor receptor 2 (HER2) is overexpressed in various cancers, and breakthrough HER2-targeted therapeutic agents, including antibody-drug conjugates (ADCs), have expanded treatment options for patients. However, despite clinical success, treatment with ADCs can result in safety issues and/or resistance due to drug efflux and target-associated mechanisms. T Cell Engagers (TCEs) have shown promising anti-tumor activity in solid tumor indications, but their clinical application has been challenged by significant toxicity. CT-P72/ABP-102 is a tetravalent bispecific HER2 and CD3 T-cell engager engineered with dual affinity-tuned binding to HER2 and CD3 to increase tumor selectivity and reduce off-target effects, thereby lowering the risk of safety concerns, and has potent anti-tumor activity in multiple in-vivo models, including an Enhertu-resistant model.MethodsTo assess target binding specificity, we evaluated cellular binding affinities of CT-P72/ABP-102 with ELISA, SPR analysis, and flow cytometry. We assessed the biologic activity of CT-P72/ABP-102 with cellular cytotoxicity, cytokine release, and T- cell activation assays using human PBMCs (hPBMCs). In-vivo efficacy was assessed in three murine models with hPBMCs: a HER2-expressing Enhertu-resistant gastric cancer (NCI-N87/hABCG2), a HER2-overexpressing (KPL4) xenograft tumor, and a dual xenograft of HER2-high BT-474 and HER2-low HT-55 cancer cells. Safety of CT-P72/ABP-102 was assessed in a GLP toxicity study conducted in cynomolgus monkeys.ResultsCT-P72/ABP-102 bound specifically to HER2 among the HER1-4 family and to CD3, showed cross-reactivity with cynomolgus macaque HER2 and CD3, and exhibited lower binding to both HER2 and CD3 compared to its parental antibody. CT-P72/ABP-102 demonstrated activity in T-cell activation, PBMC-mediated cytotoxicity, and cytokine release experiments comparable to the parental bispecific antibody with HER2 high-expressing tumor target cells but reduced with HER2-low tumor target cells. In vivo, in the BT-474/HT-55 dual xenograft study CT-P72/ABP-102 inhibited the growth of HER2-high BT-474 tumors but showed reduced activity against HER2-low HT-55 tumors (figure 1), demonstrating the selectivity of CT-P72/ABP-102 for high HER2 tumors over low HER2 normal tissues. The anti-tumor efficacy of CT-P72/ABP-102 has also been demonstrated in a cell line-derived xenograft (CDX) mouse model established with human breast cancer cell line (KPL-4) and in an Enhertu-resistant gastric cancer cell line in hPBMC-engrafted immunodeficient mice (figure 2). CT-P72/ABP-102 was well tolerated in 4-week repeated-dose toxicity study with 4-week recovery period in cynomolgus monkeys, being well tolerated up to the highest dose (80mg/kg) tested.ConclusionsCT-P72/ABP-102 effectively addressed key limitations of current HER2-targeted therapies by combining potent, selective anti-tumor activity with a favorable safety profile.Abstract 967 Figure 1Anti-tumor activity of CT-P72/ABP-102 in a dual xenograft (HER2 high-expressing BT 474 and HER2 low-expressing HT-55) model in immunodeficient C NKG mice engrafted with hPBMCs (n=3/group). Note: Data points represent group mean; error bars represent standard error of the mean (SEM). The arrowheads indicate the time points of administration of the test articles. One-way ANOVA with Dunnett’s post-hoc analysis was performed to compare results to the control group up to Day 28. *p<0.05; **p<0.01; ***p<0.001; ***p<0.0001[Image Omitted. See PDF.]Abstract 967 Figure 2Anti-tumor activity of CT-P72/ABP-102 in an Enhertu-resistant NCI-N87/hABCG2 xenograft model in immunodeficient NOG Mice, engrafted with hPBMCs (n=5/group). Note: Data points represent group mean; error bars represent standard error of the mean (SEM). The arrowheads indicate the time points of administration of the test articles. . One-way ANOVA with Dunnett’s post-hoc analysis was performed to compare results to the control group up to Day 28. *p<0.05; **p<0.01; ***p<0.001; ***p<0.0001[Image Omitted. See PDF.]

Background Wilms’ tumor 1-associating protein (WTAP) is a nuclear protein that has been associated with the regulation of proliferation and apoptosis. Although its dynamic expression and physiological functions in vascular cells have been reported, its expression and roles in cholangiocarcinoma cells are poorly characterized. Methods To examine the expression of WTAP in patient tissues, we performed immunohistochemistry. To examine motility of cholangiocarcinoma cells, we employed Boyden chamber, wound healing and Matrigel invasion assays, and a liver xenograft model. Results Immunohistochemistry in patient tissues showed WTAP overexpression in cholangiocarcinoma tissues and correlation of WTAP expression with metastasis of cholangiocarcinoma cells. Overexpression or knockdown of WTAP significantly increased or decreased the motility of cholangiocarcinoma cells. Moreover, WTAP overexpression or knockdown significantly increased or decreased tumorigenicity of cholangiocarcinoma cells in an orthotopic xenograft model. Furthermore, microarray study showed that WTAP induce the expressions of MMP7, MMP28, cathepsin H and Muc1. Conclusion WTAP is overexpressed in cholangiocarcinoma and regulates motility of cholangiocarcinoma cells

The reconstruction of transcriptional regulatory networks (TRNs) is a long-standing challenge in human genetics. Numerous computational methods have been developed to infer regulatory interactions between human transcriptional factors (TFs) and target genes from high-throughput data and their performance evaluation requires gold-standard interactions. Here we present a database of literature-curated human TF-target interactions, TRRUST ( t ranscriptional r egulatory r elationships u nravelled by s entence-based t ext-mining, http://www.grnpedia.org/trrust ), which currently contains 8,015 interactions between 748 TF genes and 1,975 non-TF genes. A sentence-based text-mining approach was employed for efficient manual curation of regulatory interactions from approximately 20 million Medline abstracts. To the best of our knowledge, TRRUST is the largest publicly available database of literature-curated human TF-target interactions to date. TRRUST also has several useful features: i) information about the mode-of-regulation; ii) tests for target modularity of a query TF; iii) tests for TF cooperativity of a query target; iv) inferences about cooperating TFs of a query TF; and v) prioritizing associated pathways and diseases with a query TF. We observed high enrichment of TF-target pairs in TRRUST for top-scored interactions inferred from high-throughput data, which suggests that TRRUST provides a reliable benchmark for the computational reconstruction of human TRNs.

Objective As a component of Endosomal Sorting Complex Required for Transport (ESCRT) complex I, the tumor susceptibility gene 101 (Tsg101) carries out multiple functions. In this work, we report that oocyte‐specific deletion of tumor susceptibility gene 101 (Tsg101) leads to age‐dependent oocyte demise in mice. Materials and Method Tsg101 floxed mice (Tsg101f/f) were bred with Zp3cre transgenic mice to examine oocyte‐specific roles of Tsg101. Multiple cellular and molecular biological approaches were taken to examine what leads to oocyte demise in the absence of Tsg101. Results The death of oocytes from Zp3cre/Tsg101f/f (Tsg101d/d thereafter) mice showed a strong correlation with sexual maturation, as gonadotropin‐releasing hormone antagonist injections improved the survival rate of oocytes from 5‐week‐old Tsg101d/d mice. Maturation of oocytes from prepubertal Tsg101d/d mice proceeded normally, but was largely abnormal in oocytes from peripubertal Tsg101d/d mice, showing shrinkage or rupture. Endolysosomal structures in oocytes from peripubertal Tsg101d/d mice showed abnormalities, with aberrant patterns of early and late endosomal markers and a high accumulation of lysosomes. Dying oocytes showed plasma membrane blebs and leakage. Blockage of endocytosis in oocytes at 4°C prevented cytoplasmic shrinkage of oocytes from Tsg101d/d mice until 9 h. The depletion of tsg‐101 in Caenorhabditis elegans increased the permeability of oocytes and embryos, suggesting a conserved role of Tsg101 in maintaining membrane integrity. Conclusions Collectively, Tsg101 plays a dual role in maintaining the integrity of membranous structures, which is influenced by age in mouse oocytes. Tsg101 deficiency in mouse oocytes leads to a complex phenotype involving the plasma membrane (PM). These oocytes are normal until mice reach five weeks of age when oocytes begin to show PM rupture, PM blebbing, and cytoplasmic shrinkage. PM blebbing and cytoplasmic shrinkage can be postponed with a general endocytosis block, but death ensues. In both mouse and in Caenorhabditis elegans, Tsg101 plays a crucial role in maintaining the integrity of PM.

Inorganic electrolytes dominate all-solid-state batteries (ASSBs), but face critical limitations, including interfacial instability, complex manufacturing, and challenges in operating under commercially viable conditions. Here, we present a transformative approach using zwitterionic dry polymer electrolytes (ZPEs) designed via a conflicting entropy strategy to enable scalable energy-dense ASSBs. Guided by Flory–Huggins theory, liquid-state zwitterionic monomers exhibit higher mixing entropy with Li salts compared to conventional long-chain polymers, forming homogeneous monomer/salt mixtures with enhanced intermolecular electrostatic interactions to promote salt dissociation. In situ polymerization of these mixtures yields directionally aligned ion channels decoupled from the polymer backbone, characterized by reduced conformational entropy, allowing rapid Li⁺ migration via an ion-hopping mechanism under ambient conditions. The ZPEs are seamlessly incorporated as a solid catholyte into pre-fabricated high-areal-capacity (10.0 mAh cm⁻²) LiNi 0.8 Co 0.1 Mn 0.1 O 2 positive electrodes, ensuring compatibility with existing cell manufacturing processes and has the potential to reduce production complexity and cost. Paired with thin Li-metal negative electrodes (N/P (negative-to-positive electrode capacity) ratio = 1.0), pouch-type ASSB full cells demonstrate a specific energy and energy density of 516 Wh kg −1 and 1329 Wh L −1 (excluding the pouch packaging) and stable cycle life at practical operating conditions (25 °C and 0.5 MPa) in such a constrained cell configuration. Solid-state batteries promise high energy and safety but face challenges in ion transport and scalability. Here, authors develop entropy-driven zwitterionic dry polymer electrolytes enabling scalable, high-energy all-solid-state batteries operating efficiently under practical conditions.

Wearable electronic devices are being developed because of their wide potential applications and user convenience. Among them, wearable organic light emitting diodes (OLEDs) play an important role in visualizing the data signal processed in wearable electronics to humans. In this study, textile-based OLEDs were fabricated and their practical utility was demonstrated. The textile-based OLEDs exhibited a stable operating lifetime under ambient conditions, enough mechanical durability to endure the deformation by the movement of humans, and washability for maintaining its optoelectronic properties even in water condition such as rain, sweat, or washing. In this study, the main technology used to realize this textile-based OLED was multi-functional near-room-temperature encapsulation. The outstanding impermeability of TiO 2 film deposited at near-room-temperature was demonstrated. The internal residual stress in the encapsulation layer was controlled, and the device was capped by highly cross-linked hydrophobic polymer film, providing a highly impermeable, mechanically flexible, and waterproof encapsulation.

Pyrolysis is an environmental friendly alternative method compared with incineration, and the least time-consuming and smallest infrastructure footprint method compared with bio-chemical and thermo-chemical conversion. Baseline data for the pyrolysis of food waste was obtained in a kinetic study of the thermal decompositions by thermogravimetric analysis. To simulate the difference in the types of food waste, the study was done using model compounds, such as cereals, meat, vegetable, and mixed food waste; the pyrolysis commenced at 150 °C for most food waste and the process terminated at 450 °C to 500 °C. Between one and three peaks were observed on a differential thermogravimetry (DTG) graph, depending on the type of waste being pyrolyzed, reflecting the difference in the time required for pyrolysis of different components of food waste to take place. Depending on the composition of each food, one or four peaks were found, and the pyrolysis patterns of carbohydrate, protein, fat, and cellulose were found. Activation energies and frequency factors were calculated from the rates of conversion, using differential equation analyses. The activation energy increased from 10 kJ/mol to 50 kJ/mol as conversions increased from the 10% to 90%, regardless of the food waste type. The activation energy was measured as 50 kJ/mol, with a slight variation among the type of the food waste. Due to the activation energy being low, food waste consists of carbohydrates and other substances rather than cellulose, hemicellulose, and lignin.

BACKGROUNDPemphigus, a rare autoimmune bullous disease mediated by antidesmoglein autoantibodies, can be controlled with systemic medication like rituximab and high-dose systemic corticosteroids combined with immunosuppressants. However, some patients continue to experience chronically recurrent blisters in a specific area and require long-term maintenance systemic therapy.METHODSSkin with chronic blisters was obtained from patients with pemphigus. Immunologic properties of the skin were analyzed by immunofluorescence staining, bulk and single-cell RNA and TCR sequencing, and a highly multiplex imaging technique known as CO-Detection by indEXing (CODEX). Functional analyses were performed by flow cytometry and bulk RNA-Seq using peripheral blood from healthy donors. Intralesional corticosteroid was injected into patient skin, and changes in chronically recurrent blisters were observed.RESULTSWe demonstrated the presence of skin tertiary lymphoid structures (TLSs) with desmoglein-specific B cells in chronic blisters from patients with pemphigus. In the skin TLSs, CD4+ T cells predominantly produced CXCL13. These clonally expanded CXCL13+CD4+ T cells exhibited features of activated Th1-like cells and downregulated genes associated with T cell receptor-mediated signaling. Tregs are in direct contact with CXCL13+CD4+ memory T cells and increased CXCL13 production of CD4+ T cells through IL-2 consumption and TGF-β stimulation. Finally, intralesional corticosteroid injection improved chronic blisters and reduced skin TLSs in patients with pemphigus.CONCLUSIONThrough this study we conclude that skin TLSs are associated with the persistence of chronically recurrent blisters in patients with pemphigus, and the microenvironmental network involving CXCL13+CD4+ T cells and Tregs within these structures plays an important role in CXCL13 production.TRIAL REGISTRATIONClinicalTrials.gov NCT04509570.FUNDINGThis work was supported by National Research Foundation of South Korea (NRF-2021R1C1C1007179) and Korea Drug Development Fund, which is funded by Ministry of Science and ICT; Ministry of Trade, Industry, and Energy; and Ministry of Health and Welfare (grant RS-2022-00165917).

Dysbiosis is an environmental factor that affects the induction of axial spondyloarthritis (axSpA) pathogenesis. In the present study, we investigated differences in the gut microbiota of patients with axSpA and revealed an association between specific gut microbiota and their metabolites, and SpA pathogenesis. Using 16S rRNA sequencing data derived from feces samples of 33 axSpA patients and 20 healthy controls (HCs), we examined the compositions of their gut microbiomes. As a result, axSpA patients were found to have decreased α-diversity compared to HCs, indicating that axSpA patients have less diverse microbiomes. In particular, at the species level, and were more abundant in axSpA patients than in HCs, whereas , a butyrate-producing bacteria, was more abundant in HCs. Thus, we decided to investigate whether was associated with health conditions by inoculating (0.1, 1, and 10 μg/mL) or by administrating butyrate (0.5 mM) into CD4 T cells derived from axSpA patients. The levels of IL-17A and IL-10 in the CD4 T cell culture media were then measured. We also assessed osteoclast formation by administrating butyrate to the axSpA-derived peripheral blood mononuclear cells. The CD4 IL-17A T cell differentiation, IL-17A levels were decreased, whereas IL-10 was increased by inoculation. Butyrate reduced CD4 IL-17A T cell differentiation and osteoclastogenesis. We found that CD4 IL-17A T cell polarization was reduced, when or butyrate were introduced into curdlan-induced SpA mice or CD4 T cells of axSpA patient. Consistently, butyrate treatment was associated with the reduction of arthritis scores and inflammation levels in SpA mice. Taken together, we concluded that the reduced abundance of butyrate-producing microbes, particularly , may be associated with axSpA pathogenesis.

Survival outcomes for infants born at 22–23 weeks’ gestation vary widely across neonatal units. This national, prospective cohort study evaluated 919 infants born at 22–23 weeks’ gestation in South Korea between 2013 and 2022, using Korean Neonatal Network data. Infants were categorized based on the level of neonatal care: 785 in lower-level centers (Group A) and 134 in higher-level centers (Group B). Survival was significantly higher in Group B (64.9%) compared to Group A (29.3%) (P < 0.0001). Early deaths occurred more frequently and earlier in Group A. Proactive care—including antenatal corticosteroids, antenatal antibiotics, and immediate surfactant administration—was more common in Group B. Antenatal corticosteroid was significantly associated with reduced risk of death (hazard ratio 0.58; 95% confidence interval, 0.49–0.69; P < 0.0001). The timing of rapid decline in survival was delayed in higher-level centers. In addition, classifying institutions into higher- and lower-level groups according to the survival of infants born at 22–23 weeks’ gestation (≥50% vs. <50%) provides a good reflection of the quality of neonatal care. These findings highlight the importance of proactive care and timely in utero transfer to higher-level units in improving survival for peri-viable infants.