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A direct interaction of JAM-C with the tight junction scaffold protein ZO-2
Abstract Tight junctions are sites of cell-cell contacts at the apical region of epithelial junctions that are involved in barrier formation, cellular signaling, and cell-cell adhesion. Tight junctions are formed by integral membrane proteins associated with cytoplasmic scaffolding and adapter proteins through which they are linked to the underlying actomyosin and microtubule cytoskeletons. Here, we have addressed the interaction of the Junctional Adhesion Molecule (JAM)-C with the zonula adherens (ZO) protein ZO-2. Using a combination of cell-based recruitment assays and biochemical in vitro experiments, we find that JAM-C and ZO-2 directly interact in a PDZ domain-dependent manner. Notably, the interaction requires PDZ domain 3 as well as the SH3 domain of ZO-2, indicating that ZO-2 forms a functional supramodule to interact with JAM-C. We also found that JAM-C is specifically localized to tight junctions in polarized epithelial cells and that JAM-A suppresses JAM-C mRNA expression in these cells. Our findings have implications for important aspects of tight junction biology, including mechanosensing and liquid–liquid phase separation.
Darovasertib plus crizotinib vs investigator’s choice as first-line treatment for patients with HLA-A2 negative metastatic uveal melanoma: Primary results from the OptimUM-02 trial.
LBA9503 Background: Uveal melanoma (UM) is the most common ocular cancer in adults with up to 50% of patients developing metastasis with high mortality. No FDA-approved systemic treatments exist for HLA-A*02:01 (HLA-A2) -negative metastatic UM (mUM), and therapies effective in other melanoma subtypes have limited efficacy. Darovasertib (darova) is a first-in-class, oral PKC inhibitor that showed encouraging clinical outcomes in a prior phase 1/2 study in combination with the MET inhibitor crizotinib (crizo). Here we present primary safety & efficacy results from the nested phase 2/3 OptimUM-02 trial of darova+crizo as first-line treatment for HLA-A2 negative-mUM. Methods: OptimUM-02 is an open-label study of HLA-A2 negative first-line mUM patients who were randomized 2:1 to receive darova 300 mg plus crizo 200 mg BID or investigator’s choice (IC) of treatment (pembrolizumab, ipilimumab + nivolumab, or dacarbazine). The primary endpoint for efficacy for phase 2 was progression-free survival (PFS) by RECIST (BICR). Other endpoints included investigator assessed PFS (PFS inv ), objective response rate (ORR), duration of response (DOR), disease control rate (DCR: CR+ PR + SD ≥ 12 weeks), and safety. Overall survival, the phase 3 primary endpoint, will be presented as the data matures. Results: Overall 338 patients received at least one dose of study treatment (safety population), 313 comprised the efficacy population. The median PFS by BICR was 6.9 months for darova+crizo (5.6, 8.3) and 3.1 months for IC (1.8, 4.2); HR: 0.42, p<.0001. Median PFS inv was 6.7 months (5.6, 8.2) and 2.7 months (1.7, 4.1) resp; HR 0.36, p< 0.0001. BICR ORR {37.1% [CR 2.4%; PR 34.8%] vs. 5.8% [CR 0%, PR 5.8%], DCR (73.3% vs 31.1%), DOR (median 6.8 months vs. Non-Evaluable) as well as ORR inv [39.5% vs. 1.9%], DCR inv [74.3% vs. 27.2%] and DOR inv (6.8 months vs. NE) all favored darova+crizo (p-value < 0.0001). Preliminary OS is also trending favorably. The most common treatment emergent adverse events (AEs) for darova+crizo were diarrhea (89.5%), nausea (78.2%), peripheral edema (70.7%), & vomiting (53.6%). In the IC arm, these were nausea (41.4%), diarrhea (36.3%), fatigue (33.3%), AST & ALT elevation (31.1%). AEs led to discontinuation & dose reduction of darova in 3.8% & 23.8% and crizo in 10.9% & 27.2% subjects. In the IC arm, 19.2% discontinued due to AEs. The most common Grade 3 or 4 AEs for darova + crizo were diarrhea (10.9%) & syncope (7.9%) and for IC, AST & ALT increase (8.1%), diarrhea (6.1%) & hepatitis (5.1%). Treatment related serious AEs occurred in 9.2% and 25.3% on darova + crizo and IC respectively. One treatment related fatal AE occurred in each arm. Conclusions: In patients with HLA-A2-negative-mUM treated in the first-line setting, darova+crizo demonstrated a clinically and significantly longer PFS, and improved ORR and DCR compared with the investigator’s choice treatment. AEs were consistent with the previously reported safety profiles in each arm. These results support a potential new therapeutic standard for a disease with limited treatment options and poor prognosis. Clinical trial information: NCT05987332 .
Self-powered dual-electrode hydrogen production using a composite ion exchange membrane
Evidence of Local Structural Variations and Their Influence on Magnetic Properties in Mn- and Cr-Containing High-Entropy Oxide Thin Films Using Electron Microscopy
Non-invasive characterization of the relationship between skin microrelief and dermal–epidermal junction topography using line-field confocal optical coherence tomography (LC-OCT)
Disease-free survival (DFS) and time to recurrence (TTR) with circulating tumor (ct) DNA–based decision for adjuvant treatment in colon cancer stage II (CIRCULATE): An AIO (KRK-0217)/ABCSG trial.
LBA3500 Background: Adjuvant chemotherapy (ACT) provides limited benefit in unselected stage II colon cancer patients (pts). Postoperative ctDNA has higher prognostic value than classical clinical or molecular markers but has not been proven to predict benefit from ACT. Methods: Pts with UICC II, pMMR/MSS colon cancer were tested for ctDNA using an academic, tumor-informed, NGS based test (Stasik, Front Genet 2022). ctDNA positive (pos) pts were randomized (planned 2:1) to CHEMO (6 mo capecitabine [cape] or 3-6 mo cape+oxaliplatin) vs observation without ACT (OBS). ctDNA negative (neg) pts were randomized 1:4 to OBS vs OFF-STUDY. Patients in OBS and their investigators remained blinded to the ctDNA status. The primary endpoint was DFS in ctDNApos pts (CHEMO vs. OBS), the TTR was reported as 3-y recurrence rate. Differences were tested using one-sided log-rank tests. The planned sample size was 1,540 randomized pts assuming 10% ctDNApos. Because the funding period expired, the trial ended early and was finally analyzed. Results: From 06/2020 to 07/2025, 2,126 pts were screened at 138 sites in Germany/Austria. The ctDNApos rate was lower than expected among randomized pts (2.9%) and screened but not randomized pts (4.3%). Overall, 1,396 pts were randomized: 1,083 to OFF-STUDY, 287 to OBS (15 ctDNApos), and 26 pts to CHEMO (all ctDNApos). Median age was 64 y, 63% were male. Classical risk factors were present in 9.5% (4.8% pT4, 5.0% unplanned resection). In CHEMO, 21/26 pts (81%) started cape, 33% of them received oxaliplatin, median no of cycles was 6. There was one treatment-related death. DFS and OS were significantly higher in ctDNAneg vs ctDNApos pts (3-y-DFS 87% vs 52%, HR 0.23 [95%CI 0.13-0.43], p < 0.001; 3-y-OS 98% vs 88%, HR 0.18 [95%CI 0.05-0.61], p = 0.001). In the per-protocol (PP) analysis (excluding CHEMO pts not treated), CHEMO improved recurrence rates and DFS compared to ctDNApos/OBS (3-y recurrence rate19% vs 62%, HR 0.21 [95%CI 0.06-0.80], p = 0.009; 3-y-DFS 77% vs 38%, HR 0.28 [95%CI 0.09-0.94], p = 0.022). Cancer-specific survival (CSS) was numerically higher with CHEMO (3-y-CSS 100% vs 84%, HR 0.25 [95%CI 0.03-2.44]). In the ITT cohort (including the non-treated pts), the differences between arms were not significant (3-y recurrence rate 35% vs 62%, HR 0.48 [95%CI 0.17-1.33], p = 0.08; 3-y-DFS 61% vs 38%, HR 0.52 [95%CI 0.20-1.39], p = 0.12; 3-y-CSS 94% vs 84%, HR 0.40 [95%CI 0.07-2.38], p = 0.15). Conclusion: This is the first prospective randomized trial demonstrating that ctDNA guided ACT improves TTR and DFS in stage II colon cancer pts without clinical risk factors, supporting ctDNA testing for adjuvant decision making in the clinical practice. Limitations include the relatively low number of randomized ctDNApos pts, the sensitivity of the academic test developed 10 y ago and the reliance on PP analysis. Clinical trial information: NCT04089631 .
SEC14L2 couples chaperone-mediated autophagy to microtubule stability by targeting Stathmin 1
Unraveling Zeolite Heterogeneity and Its Impact on Catalysis
Machine learning–assisted design of a wideband Fe–SiO2–MXene metamaterial solar absorber for angle-insensitive thermal energy harvesting
Abstract The manuscript proposed an efficient broadband metamaterial-inspired multilayered solar absorber for efficient energy harvesting. Its structure is a periodic assembly of Fe, SiO₂, MXene, and Fe layers, thus facilitating the scalable fabrication. Finite element method (FEM) simulations are employed to evaluate and optimise the optical performance. The novel geometry and arrangement of the radiating elements result in peak absorptance exceeding 90% across 0.87–1.79 μm, 2.07–2.425 μm, and 3.045–3.295 μm. Parametric optimisation is conducted by varying resonator geometries (filled and solid), material combinations for resonator and ground layers (Au, Fe), and dielectric thicknesses to achieve optimal absorption characteristics. Angular stability is examined for both TE and TM polarisations over an incidence range of 0°–80°, demonstrating robust wide-angle performance. The TE and TM mode field are analysed at peak absorption wavelength. Furthermore, different machine learning models are implemented to analyse and predict absorption characteristics, validating the agreement between simulated and predicted results. The proposed design was compared and analysed with other similar works to identify performance improvements. The proposed design exhibits strong potential for broadband photothermal and solar-thermal energy harvesting applications.
A phase III CHIPRO study of chiauranib plus weekly paclitaxel for platinum-resistant or refractory ovarian cancer.
LBA5504 Background: Platinum-resistant or refractory ovarian cancer is associated with poor prognosis and has limited treatment options. Chiauranib (Ibcasertib) is an oral, novel small-molecule multi- kinase inhibitor that targets tumor cell proliferation, neoangiogenesis, and immunosuppressive tumor microenvironment through inhibition of Aurora B, VEGFR1/2, PDGFRα/β, and CSF-1R. Prior studies suggested clinical activity with chiauranib in combination with etoposide or weekly paclitaxel in this setting. Methods: We conducted a randomized, double-blind, placebo-controlled, multicenter phase III trial (CHIPRO) to evaluate the efficacy and safety of chiauranib plus weekly paclitaxel in patients with platinum-resistant or refractory ovarian cancer. Patients were randomized 1:1 to receive weekly paclitaxel plus either chiauranib (CP group) or placebo (PP group). Randomization was stratified by prior lines of chemotherapy (1-2 vs ≥3) and platinum-free interval (≥6 months vs <6 months). Patients received up to six cycles of combination therapy followed by maintenance chiauranib or placebo in those without progression. Dual primary endpoints were progression-free survival (PFS) per blinded independent review committee according to RECIST v1.1 and overall survival (OS). The study was designed to demonstrate superiority of the experimental regimen in either endpoint. Results: Between December 20, 2021, and July 29, 2025, 459 patients were enrolled; 70% had received prior anti-angiogenic therapy. At the data cutoff (July 29, 2025), the median follow-up was 16.0 months (95% CI, 14.3–17.7). Median PFS was 4.57 months (95% CI, 4.14–5.52) in the CP group versus 2.69 months (95% CI, 1.58–2.76) in the PP group (HR, 0.427; 95% CI, 0.34–0.54; P < 0.001), representing a 57% reduction in progression risk. PFS benefit was observed with CP regardless of prior anti-angiogenic exposure. Median OS was 12.09 months (95% CI, 10.51–15.18) in the CP group and 12.12 months (95% CI, 10.25–13.31) in the PP group (HR, 0.932; 95% CI, 0.73–1.20; P=0.583). A statistically significant OS benefit was observed in patients who did not receive subsequent anticancer therapy (HR, 0.599; 95% CI, 0.39–0.91; P = 0.016). Favorable OS trends were also noted in subgroups previously treated with PARP inhibitors and in those received subsequent platinum-based chemotherapy. The most common grade ≥3 treatment-emergent adverse events in the CP group were leukopenia, neutropenia and anemia. Safety was consistent with prior experience, and no new safety signals were identified. Conclusion: Chiauranib plus weekly paclitaxel significantly prolonged PFS in patients with platinum-resistant or refractory ovarian cancer, with a manageable and predictable safety profile. Significant benefit was also observed in the subgroup previously treated with anti-angiogenic agents, supporting this regimen as a promising new treatment option. Clinical trial information: NCT04921527 .
Exciton dispersion fine structure and deep ultraviolet optical conductivity of freestanding two-dimensional h-BN
Evolution of the Intertwining Correlated Topological Phases in Iron-Based Superconductor Fe(Te,Se)
The impact of 222Radon escape on 210Pb-based sediment chronology and dating accuracy in lacustrine systems
Abstract The accuracy of 210 Pb-based sediment chronology relies on determining atmospheric 210 Pb inventory by subtracting 226 Ra-supported 210 Pb. This standard analytical approach assumes a closed system where the gaseous intermediate, 222 Rn, remains in secular equilibrium with 226 Ra. However, in lacustrine systems characterized by slow sedimentation and high porosity, 222 Rn escape can invalidate this assumption, significantly distorting age models. This study investigated 222 Rn mobility across three distinct systems: Lake Balaton (Hungary), Lake St. Anna, and Red Lake (Romania). In Balaton, high 226 Ra (25–55 Bq/kg) and porosity (70–90%) induced significant 222 Rn loss (3 ± 0.2–37 ± 4 Bq/l) within the upper 30 cm, leading to in situ 210 Pb deficits (14–56%) and chronological errors reaching 200%. Lake St. Anna, with slow sedimentation and high organic content, showed the highest discrepancies (8–87%) despite lower 222 Rn levels (0.2 ± 0.01–3 ± 0.2 Bq/l). Conversely, Red Lake exhibited the smallest deviations (1–32%) due to faster accumulation and sandy sediment, notwithstanding measurable 222 Rn escape (2 ± 0.2–28 ± 4 Bq/l) relative to its 226 Ra content (35 Bq/kg). The results confirm that these sediments cannot be treated as closed systems regarding radon. Significant gas escape leads to an underestimation of supported 210 Pb if equilibrium is assumed. We conclude that pore water analysis and subsequent correction for radon diffusion are critical for reliable 210 Pb chronologies, particularly in slow-accumulating, porous sediments spanning the last 150 years.
Reply to: Yttrium-90 Radioembolization Provides Durable Local Control and Definitive Radiation Therapy
O-linked glycan-dependent gating of TPC2 controls lysosomal excitability and organelle remodeling
Employing AC and DC Electrolysis to Modulate Electroenzymatic Pathways for Efficient and Stereoselective H-D Exchange
Effect of ZeeFree algorithm on the reduction of stair-step artifacts for coronary computed tomography angiography
SARC041: A phase 3 randomized double-blind study of abemaciclib versus placebo in patients with advanced dedifferentiated liposarcoma.
LBA2 Background: Dedifferentiated liposarcoma (DDLS) remains a difficult disease to treat with limited systemic therapy options. Approved drugs offer modest benefit such as trabectedin (median progression-free survival [mPFS] 2.2 months [m]) or eribulin (mPFS 2.0m). The Cyclin-dependent kinase 4 (CDK4) oncogene is ubiquitously amplified in DDLS and is a rational therapeutic target. In single-arm phase 2 studies, treatment with selective CDK4 inhibitors resulted in mPFS 4.2m with palbociclib and mPFS 7.7m with abemaciclib. We hypothesized that treatment with abemaciclib would improve PFS compared to placebo in patients with recurrent or metastatic DDLS. Methods: SARC041 was a phase 3 randomized double-blind study of abemaciclib versus placebo. The study was open at 9 academic medical centers in the USA. Eligible patients (pts) had recurrent or metastatic DDLS (purely well-differentiated liposarcoma excluded), progression of disease by RECIST 1.1 in the 6 months prior to study entry, any number of prior systemic therapies, and adequate organ function and performance status. Pts were stratified by prior lines of therapy (0 vs 1 or more) and randomized 1:1 between abemaciclib 200 mg PO twice a day or matching placebo. Scans were every 6 weeks (every 12 weeks after week 36) and pts with progression of disease on placebo could cross over to open label abemaciclib. The primary endpoint was PFS. The design provided 80% power with two-sided 10% significance level to detect a hazard ratio of 0.6 by log-rank test. Secondary endpoints were overall response rate (ORR), PFS and response rate after crossover, and overall survival (OS). Data cutoff was March 1, 2026. Results: In total, 108 pts were randomized to receive abemaciclib (n = 54) or placebo (n = 54). Demographic/baseline characteristics were generally similar across treatment arms. Abemaciclib demonstrated a statistically significant improvement in PFS at 9.67m vs placebo at 1.52m (hazard ratio [HR] 0.39; 95% confidence interval [CI], 0.25–0.59; p < 0.001). ORR was 9.3% for abemaciclib vs 0% for placebo (p = 0.057). mOS was not reached with abemaciclib vs 25.45m with placebo (HR 0.55; 95% CI, 0.28–1.07; p = 0.077). mPFS after crossover from placebo to abemaciclib was 3.44m (95% CI 2.66, 6.84). ORR after crossover was 4.3% (95% CI 0.53%, 15%). mOS after crossover was 24.03m (95% CI: 11.7, NA). Grade 3 or higher adverse event rates were similar in both arms (p > 0.99). No new safety signals were observed. Conclusions: Abemaciclib demonstrated a statistically significant improvement in PFS vs placebo in pts with dedifferentiated liposarcoma, with an encouraging OS trend. These results support abemaciclib as a new treatment option for dedifferentiated liposarcoma. Clinical trial information: NCT04967521 .
Ligand-Controlled Oxidant-Free Gold(I)/(III)-Catalyzed Synthesis of Benzocyclobutenes via [2 + 2] Annulation
Abstract Benzocyclobutenes (BCBs) represent a highly strained, privileged structural motif with significant applications in drug discovery, medicinal chemistry, organic synthesis, polymers and materials science, yet efficient synthetic methods remain limited. Here, we report an oxidant-free Au(I)/Au(III)-catalyzed [2 + 2] annulation strategy for the synthesis of BCBs leveraging a unique class of rationally designed hemilabile C,N-bidentate N-heterocyclic carbene ligand (NHC). This approach employs readily available aryl halides and olefins under mild conditions, demonstrating broad functional group compatibility and the applications in late-stage functionalization. The ligand tunes the electronic and steric environment of gold center to promote selective migratory insertion while suppressing undesired β-hydride elimination. Density functional theory (DFT) calculations elucidate the reaction pathway and underscore the critical role of electron-withdrawing substituents within the C,N-carbene framework. This work establishes an efficient strategy for BCBs synthesis and highlights the potential of NHC ligands in advancing oxidant-free gold catalysis.