Browse Articles

Enhancing the molecular assessment of MRI targeted prostate biopsies utilizing near real time stimulated Raman histology and artificial intelligence.

384 Background: Stimulated Raman histology (SRH) produces rapid, label-free optical sections of fresh tissue that can be interpreted within minutes by artificial intelligence (AI). Standard tissue processing hinders molecular assessment of prostate cancer (PCa) necessary for advancement of precision medicine. Our objectives were to prospectively validate the NYU SRH-AI algorithm in an MRI targeted biopsy cohort and to test whether SRH-guided tissue banking improves downstream tissue for precision oncology in a real-world biopsy workflow. Methods: 200 men with a PI-RADS 3-5 (n=256 regions of interest (ROI)) undergoing a transperineal targeted prostate biopsy (TB) were prospectively enrolled in an IRB approved study. The TB were kept fresh before scanning with the NIO SRH microscope (Invenio Imaging Inc, Santa Clara, CA) using two Raman spectra: 2845cm -1 and 2930cm -1 . Both spectra are required for human interpretation but AI interpretation can use rapid scanning parameters utilizing only 2845cm -1 . The NYU SRH-AI algorithm was incorporated into the SRH microscope to provide a near real-time PCa identification and area quantification. After SRH imaging, TB were placed in liquid nitrogen for tissue biobanking or formalin for routine pathologic processing and ground truth diagnosis. Of the 200 men, 163 participants with 200 ROIs biopsies were assessed for tissue banking. Seventeen samples were selected for DNAseq, and the selection was stratified to reflect the cohort distribution across PCa grade groups, SRH-AI estimated cancer area, core length, and the number of trimming iterations. DNA were extracted from cryobanked tissues, sequenced, and then compared against standard workflows utilizing formalin fixed paraffin embedded (FFPE) tissues. Results: The full-scan model achieved a concordance index of 0.935 for PCa identification in 5 mins. The rapid-scan model achieved a concordance index of 0.930 for PCa identification in 2.5 mins. Among 200 ROIs, SRH-guided triage significantly enriched tumor content in banked cores: median SRH suspected tumor area of TB-banked with PCa 71% (IQR 58–81; N=65) vs non-banked ROI with PCa 11% (IQR 5–20; N=51), and non-banked benign ROI 5% (IQR 3–8; N=84). DNAseq showed SRH-AI selected cryopreserved samples demonstrated tumor fraction enrichment of 0.61 (0.49-0.73), compared to conventional FFPE sampling 0.48 (0.22-0.64), (p<0.001). In addition, DNA seq copy number noise was significantly reduced in SRH/AI samples 0.013 (0.012-0.013) compared to FFPE 0.11 (0.085-0.16), (p<0.001). Conclusions: SRH-AI identified PCa in diagnostic biopsies in 2.5 mins guiding biobanking of tumor enriched tissues, yielding higher-quality DNA for molecular analyses.

Modular Opto‐Magnetic Oscillators: Harnessing Light to Drive Versatile Materials and Functionalities

ABSTRACT Self‐sustained oscillations are fundamental to dynamic systems in nature, such as heartbeats, ocean waves, and firefly flashes. However, creating similar autonomous, out‐of‐equilibrium behaviors across diverse materials and structures in artificial settings remains challenging due to the lack of a universal, platform‐independent control method. Here, we present an opto‐magnetic feedback control strategy that achieves reliable self‐excited oscillations through combined light, magnetic, and mechanical interactions based on a modular design approach. The dynamic, plug‐and‐play assembly of driving and deforming modules endows the platform with exceptional versatility in material type, structural setup, mechanical response, and functional use. Notably, this system can be tuned to produce continuous or intermittent self‐oscillations, demonstrating its adaptability. We showcase the broad utility of the system by integrating optical modules for reconfigurable dynamic displays and wide‐field‐of‐view light scanning, together with a thermo‐mechano‐electrical transduction module for high‐efficiency energy harvesting. The proposed approach establishes a universal feedback pathway linking autonomous soft machines with various technological platforms, enabling on‐demand adaptation across different application scenarios.

Chiral Photochromic Carbon Dots with Photoactivated Radical Emission, Circularly Polarized Luminescence and Organic Afterglow

ABSTRACT Open‐shell organic luminescent radicals have received considerable attention recently, but it remains a formidable challenge to obtain circularly polarized luminescent (CPL) organic afterglow radicals, especially in nanomaterial systems. Here, we report the design and fabrication of intrinsically chiral carbon dots (CDs) with in situ generated radicals for CPL emission, followed by polyvinylpyrrolidone encapsulation to suppress non‐radiative decays for long‐lived afterglow. Upon UV irradiation, the CDs’ electron‐deficient naphthalimide (NI) moiety transforms gradually to the luminescent radicals, and the Förster resonance energy transfer from the pristine chiral CDs to the photoactivated radicals leads to the dynamically enhanced radical‐based CPL afterglow with luminescent dissymmetry of 10 −3 and an afterglow lifetime up to 265 ms. Moreover, owing to the photo‐induced formation of NI‐radical anions, photochromism from colorless to yellow and steady‐state emission from blue to yellow were also observed, and these optical responses are reversible and highly sensitive to stimuli of light, temperature, humidity, and atmosphere. With the rich and dynamic photophysical features of the stimulus‐responsive chromic and luminescent chiral nanomaterial, advanced anti‐counterfeiting and multilevel information encryption on flexible substrates were realized, representing a remarkable step forward in integrating radical luminescence, CPL, photochromism, afterglow, and stimuli‐response together for constructing multifunctional chiral nanomaterials.

RNA-binding protein tristetraprolin inhibits Th2 cell activation and differentiation in allergic rhinitis by promoting TRIM18 mRNA decay

Sequencing of therapeutic agents before and after metastatic castration-resistant prostate cancer (mCRPC) diagnosis in an international real-world setting.

100 Background: Over the last decade, many new approaches to mCRPC management have evolved. However, information is lacking on sequencing of active agents used pre- and post-mCRPC diagnosis in an international setting. In this real-world evidence study, we utilized an international registry of advanced prostate cancer patients to provide an overview of the use and sequencing of therapeutic agents. Methods: From an international (15 countries) advanced prostate cancer registry (IRONMAN, NCT03151629), we analyzed data from participants newly diagnosed with mCRPC between Jan 2018 and Dec 2021, who were followed through to Jul 2022. Eligible patients may have been diagnosed with metastatic hormone-sensitive prostate cancer (mHSPC) or m0CRPC before mCRPC. Demographic/clinical characteristics were reported, as well as pre-mCRPC diagnosis treatments, treatment after progression to mCRPC, and treatment sequence between last received pre-mCRPC and first-line (1L) treatment for mCRPC. Androgen deprivation therapy (ADT) was considered a backbone therapy in this analysis, meaning that we assumed patients likely received ADT along with the listed regimens; only ADT monotherapy is specifically called out. Results: 520 men were identified, predominantly from the USA (24%), Spain (20%), Canada (19%), and the UK (12%). At mCRPC diagnosis, median age was 72 years (interquartile range [IQR] 67–78), 73% of participants were White, and median PSA at mCRPC diagnosis was 9.15 ng/mL (IQR 2.57–41.49). Pre-mCRPC, the most common treatments were ADT monotherapy (57%) or in conjunction with chemotherapy (23%) or androgen receptor pathway inhibitors (ARPIs; 11%). Among participants receiving ARPIs pre-mCRPC (n=59), abiraterone (51%) and enzalutamide (47%) were most common. Post-mCRPC diagnosis, among all participants, ARPIs (79%) and chemotherapy (34%) were most prescribed through end of follow-up. Among those receiving ARPIs (n=413 participants), abiraterone (51%) and enzalutamide (55%) remained the most common (participants could have received >1 ARPI). The most frequent pre-mCRPC to 1L mCRPC sequence was ADT monotherapy to ARPI (37%) followed by chemotherapy to ARPI (15%). Of 190 participants receiving ADT monotherapy to ARPI, most were aged ≥75 years (54%), not metastatic at diagnosis (83%), and from Canada (29%), Spain (23%), or the USA (21%). Of 78 participants receiving chemotherapy to ARPI, many were aged 65–74 years (44%), diagnosed with de novo metastatic disease (54%), and from the UK (38%). Conclusions: Within the study period in the pre-mCRPC setting, ADT monotherapy was most frequently prescribed, and most patients did not receive ARPI. The most common mCRPC setting treatment was ARPI use. Management of patients pre- and post-mCRPC diagnosis may vary by country. In all, an unmet need exists for optimal therapy use at the earliest opportunity.

A feasibility trial investigating inductive apalutamide therapy combined with radical prostatectomy in patients with locally advanced T4 high risk prostate cancer: First results of the prospective phase II INDUCTA study.

370 Background: Locally-advanced, inoperable T4 prostate cancer (PCa) is a challenging scenario usually treated by combined systemic treatment and/or radiotherapy. To date, no prospective trial examining inductive hormonal therapy to achieve operability in such patients exists. Retrospective data demonstrated successful treatment with radical prostatectomy at PSA nadir. While only a minority of these patients was cured, long-term survival with persistent sensitivity to androgen deprivation therapy (ADT) was observed in the majority. The INDUCTA trial aimed to prospectively investigate whether combined inductive treatment with ADT and Apalutamide reliably induces operability in T4 PCa. Methods: INDUCTA enrolled patients with cT4 PCa, considered inoperable (confirmed by DRE and mpMRI) with no prior radio- or antihormonal therapy and without metastases in conventional imaging (CT and bone scan). After 6 months of ADT and Apalutamide 240 mg daily, local disease stage and operability were reassessed. If operable, patients received robot-assisted radical prostatectomy (RARP). We report the proportion of patients achieving operability after combined inductive therapy (primary endpoint), together with peri- and early postoperative results. Results: Of 27 patients screened, 21 (mean age 69.4±7.2 yrs) entered the trial and completed treatment (compliance 96.8%). At diagnosis, median PSA was 47.4 ng/mL (5.4-395). Operability was confirmed in all 21 after inductive therapy. Median PSA nadir after ADT was 0.05 ng/mL (0.01-1.32). While one operable patient did not undergo surgery due to cardiac deterioration, RARP was performed in 20 patients. There were no rectal injuries and no grade IV or V complications, while grade III occurred in only two cases. Table 1 illustrates the perioperative parameters and final RARP pathology. Quality of life (FACT-G, FACT-P,EQ-5D-3L) showed no baseline deterioration. Conclusions: Inductive therapy with ADT and Apalutamide leads to essential downstaging enabling RARP in 100% of patients. These results set the stage for a new standard of care treatment concept for T4 PCa. Besides disease control preventing future complications, removal of the locally advanced primary tumor should positively influence the further course of disease and even give those affected a chance to be cured. Clinical trial information: 2021-003523-16. Perioperative and pathological parameters. Total, N = 20 Duration of surgery [min, median (range)] 163 (106 - 244) Blood loss [mL, median (range)] 175 (30 - 800) Duration of hospitalization [days, median (range)] 7 (3 - 53) Catheter: days in situ [median (range)] 5 (3 – 93) n % Pathological T stage pT2c 1 5 pT3a 7 35 pT3b 12 60 Pathological evaluation of regional lymph nodes pN0 9 45 pN1 11 55 Surgical margin status negative 13 65 positive 7 35

Association of non-luminal subtype with overall survival in high-risk non-muscle invasive bladder cancer patients: Biomarker results from the Bladder Cancer Prognosis Programme.

843 Background: High-risk non-muscle-invasive bladder cancer (HR-NMIBC) is associated with substantial progression and recurrence rates. Some patients with HR-NMIBC will die from their disease, and aggressive tumors could be treated earlier with radical cystectomy (RC). Previous work revealed higher rates of pathological upstaging at RC for NMIBC with a non-luminal molecular subtype. Methods: The Decipher Bladder genomic subtyping classifier (GSC; Veracyte, San Diego, CA, USA) was performed on bladder TURBT specimens from HR-NMIBC patients included in the prospectively followed Bladder Cancer Prognosis Programme (BCPP) registry (University of Birmingham, UK). GSC, a classifier originally developed for MIBC were evaluated for the primary endpoint of overall survival (OS) using Kaplan-Meier and Cox hazards analysis. Subgroup analyses included very high-risk NMIBC (VHR-NMIBC) as categorized by the 2025 Guidelines on NMIBC by the European Association of Urology (EAU). Results: A total of 259 HR-NMIBC patients were analyzed of which 67 patients (26%) were stage Ta and 192 patents were stage T1 (74%). 83 patients (32%) died. The median follow-up time for censored patients was 5.2 years (IQR 4.1-5.9 years). Molecular subtyping identified 219 luminal and 40 non-luminal tumors. Comparing luminal and non-luminal HR-NMIBC we found no significant differences for patient age and sex, whereas cT1 disease was significantly more present among non-luminal disease (p=0.007). Patients with non-luminal tumors had worse OS with 22 (55%) deaths in patients with non-luminal tumors and 61 (28%) deaths in patients with luminal tumors, corresponding to 5-year OS estimates of 44% for non-luminal and 72% for luminal HR-NMIBC. Multivariable analyses (MVA) revealed a significant association between molecular tumor subtype and OS after adjusting for baseline clinical variables (HR: 1.91 [95% CI; 1.16 - 3.15], p=0.01). Application of the EAU 2025 guidelines revealed 56 patients (22%) were classified as very-high risk. Among these, non-luminal subtype at baseline was significantly associated with OS on MVA (HR 2.55 [95% CI; 1.08 – 6.00], p=0.03). Conclusions: Non-luminal tumors at initial presentation harbor more aggressive disease among HR-NMIBC, reflected by worse OS on long-term follow-up as compared to luminal tumors.

Concordance between clinical, genomic, and AI-based risk stratification in prostate cancer.

388 Background: An expanding number of tests utilizing clinical criteria, genomic classifiers, and machine learning are available to assist clinicians on treatment options for patients with localized prostate cancer. The degree of concordance among these tools (Decipher, Artera AI) and traditional clinical stratification systems remains unclear. We conducted a retrospective analysis of 40 patients to evaluate the degree of concordance among these prognostic and risk stratification tools in a localized prostate cancer cohort. Methods: After IRB approval, we analyzed data from 40 patients with localized prostate cancer treated between January and October 2025 who had available NCCN risk classification, Decipher genomic classifier, and Artera AI predictive model results. Each patient was assigned a categorical risk level (low, intermediate, or high) according to each tool’s standard criteria. Concordance was defined as agreement in risk classification between two systems. Pairwise comparisons were performed (NCCN vs Artera AI, Artera AI vs Decipher, and NCCN vs Decipher). Cross-tabulation matrices were generated, and overall concordance rates were calculated as the proportion of patients classified in the same category by both tools. Results: 40 patients were included. Artera AI and NCCN showed an overall concordance of 47.5%, with perfect agreement in the high-risk group (12/12, 100%). Artera AI frequently up-classified NCCN intermediate-risk patients to high risk (15/19). Artera AI and Decipher demonstrated the highest concordance (60.0%), with most discordance when Artera AI assigned intermediate and Decipher assigned high risk (15/19). NCCN and Decipher had a concordance rate of 55.0%, with frequent reclassification of NCCN intermediate-risk patients to Decipher high risk (5/8). High-risk assignments were more consistent, aligning in 25 of 31 cases. Conclusions: Moderate concordance was observed among NCCN, Decipher, and Artera AI, with the highest agreement between Artera AI and Decipher. Discordance was most notable in NCCN intermediate-risk patients, who were often up-classified to high risk by genomic or AI-based tools. These findings suggest that each system captures distinct clinical and biological features, underscoring the limitations of relying on a single classifier. Integrating clinical, genomic, and AI-based assessments may enhance risk stratification and support more individualized treatment decisions.

Emergent Freestanding Complex Oxide Membranes for Multifunctional Applications

ABSTRACT Correlated complex oxides feature tightly coupled charge, spin, orbital, and lattice degrees of freedom, which give rise to rich correlated behavior. Freestanding oxide membranes render these materials into tunable quasi‐2D platforms that enable multifunctional and reconfigurable devices. This Review surveys recent advances in the research of freestanding oxide membranes, highlighting their coupled correlated properties. We focus on three development pathways: (i) strain‐free membranes, (ii) strained membranes, and (iii) van der Waals‐integrated heterostructures. This organization begins with the intrinsic properties of oxide membranes, then examines mechanical tuning, heterogeneous integration, and multiphysics coupling to provide a comprehensive account of the field's development. Finally, we evaluate practical challenges, including high‐quality surfaces, robust multiphysics coupling, wafer‐scale transfer, and silicon‐compatible heterogeneous integration. Addressing these challenges will enable scalable, high‐yield manufacturing and expand the design space for oxide‐based architectures, thereby accelerating the transition from laboratory demonstrations to industry‐ready systems.

Photo‐Reconfigurable Supercoupling Induced Transparency in On‐Chip Topological Edge State Cavities

ABSTRACT Electromagnetically induced transparency is a quantum interference effect that eliminates optical absorption in an opaque medium. The resulting narrow transparency window, accompanied by a pronounced slow‐light effect, has enabled extensive applications in light storage, quantum information processing, and nonlinear optics. Recently, topological photonic systems have emerged as a powerful platform for robust on‐chip light manipulation with topological protection. Here, we demonstrate a form of induced transparency enabled by the supercoupling between a leaky and a guided topological edge state cavity (TESC). The local valley vortices facilitate coupling between TESCs even across a distance of 4.3 wavelengths and induce a transparency window with negligible reflection due to the valley‐locked momentum. When the supercoupled TESCs system operates in the strong‐driving regime, frequency detuning of TESCs leads to strong mode splitting and a clear avoided crossing. Using an optical pump to photoexcite the all‐silicon TESCs in the weak‐driving regime, we achieve photo‐reconfigurable supercoupling induced transparency (SIT), allowing dynamic control of group delay while maintaining constant transmittance. SIT opens new possibilities for manipulating light flow and controlling slow‐light effects, offering promising applications in on‐chip optical and quantum information processing.

SIRT7 safeguards ERα proteostasis via deacetylation-dependent degradation of unliganded and misfolded receptors

Skeletal muscle index as a prognostic and predictive biomarker in de novo hormone sensitive prostate cancer: An exploratory analysis of the STAMPEDE trials.

173 Background: Sarcopenia is common in advanced prostate cancer and worsened by androgen deprivation therapy (ADT). Routine staging CT scans provide an opportunity to screen for sarcopenia. The STAMPEDE trials have demonstrated treatment intensification beyond ADT improve cancer outcomes; however, benefits are heterogeneous. This study investigates CT-derived skeletal muscle index (SMI), a validated marker of total muscle mass, as a prognostic and predictive biomarker in the STAMPEDE docetaxel and ARPI trials. Methods: Men with newly diagnosed non-metastatic high-risk (M0) and metastatic (M1) hormone-sensitive prostate cancer (HSPC) with available staging CT imaging in the STAMPEDE docetaxel or ARPI trials were included. These trials compared standard of care (SOC) with addition of docetaxel ± zoledronic acid (ZA) or abiraterone acetate with prednisolone (AAP) ± enzalutamide (Enz). SMI (cm²/m²) was calculated as mean muscle area divided by height squared. Outcomes were overall survival (OS) in M1 patients and metastasis-free survival (MFS) in M0. Prognostic utility of SMI was evaluated in Kaplan–Meier analyses and Cox regression models. Predictive value was assessed by comparing hazard ratios of the treatment effect in Cox models for high vs low SMI cohorts. Likelihood ratio tests were used to identify treatment-SMI interactions. Continuous predictive effects were examined using multivariable fractional polynomial interaction (MFPI) models. Results: 2,267 patients (1,578 M1, 689 M0) met inclusion criteria. The median SMI was 47.2cm²/m² (IQR 42-52) in M1 patients and 48.2cm²/m² (IQR 44-54) in M0. SMI and CHAARTED burden were identified as independent prognostic biomarkers in M1 patients, with a 10 cm²/m² increase in SMI associated with a 15% reduction in risk of death (HR 0.85, 95% CI 0.79–0.92, p<0.001). SMI was not an independent prognostic biomarker in M0 patients. SMI was identified as an independent predictive biomarker of MFS benefit upon addition of AAP±Enz in M0 patients; high SMI cohorts had greater MFS benefit from addition of AAP±Enz compared with the low SMI cohort (HR 0.44 [0.3-0.66] vs 0.59 [0.38-0.91]). Likelihood ratio tests confirmed that adding a treatment-SMI interaction improved prediction of treatment benefit (χ²: 4.67, p=0.03). MFPI modelling demonstrated a significant MFS benefit with addition of AAP±Enz in M0 patients (χ²=9.95, p=0.006) with increasing SMI, however this benefit was observed in the range of 41-63 cm 2 /m 2 only. 20% of our cohort lay outside this range (13% lower, 7% higher) and did not observe MFS benefit from addition of AAP±Enz to SOC. Conclusions: SMI is an independent prognostic biomarker in trial patients with de novo metastatic HSPC. SMI is predictive of improved MFS with addition of AAP±Enz to SOC in M0 disease. Further research is required to validate our findings in real-world cohorts.

Deep spatial analysis of the tumor-immune interface in localized prostate cancer.

377 Background: Prostate cancer (PC) has been historically considered immunologically “cold” due to low immune infiltration and a predominantly immunosuppressive tumor microenvironment (TME). However, this dogma is largely based on immune profiling studies of metastatic castration-resistant prostate cancer (mCRPC) and may not apply to earlier stages of disease. Furthermore, the composition and organization of the immune microenvironment in primary PC remains poorly defined, especially in relation to Gleason score, the gold standard of pathologic PC grading. A deeper understanding of the localized PC immune TME is necessary to elucidate the mechanisms of immunosuppression and identify targets for immunotherapy, especially in high Gleason (HG) PC. We hypothesized that the localized PC immune TME is heterogeneous with distinct immunosuppressive features and spatial organization in HG versus low Gleason (LG) PC. Methods: We analyzed 29 radical prostatectomy samples (15 LG and 14 HG PC) using a 40-marker immunofluorescence panel to profile immune and tumor cells at single-cell resolution. Immune subsets were quantified and spatially mapped to evaluate immune infiltration, regulatory populations (tumor-promoting T-regulatory cells (Tregs) and M2-like macrophages), and interactions between cell types. Results: HG PC exhibited significantly increased total immune cell infiltration and tertiary lymphoid structures (TLSs) relative to LG PC. Advancing Gleason grade was associated with increasing T cell infiltration and M2-like macrophage density. There were more Tregs in the stroma and TLSs of HG PC compared to LG PC. M2-like density was increased in the stroma in HG PC relative to LG PC. TLSs harbored higher proportions of exhausted CD4 and CD8 T cells and these exhausted T cells were found closer to Tregs in TLSs compared to their surrounding tumor and stroma. TLSs were also found to have higher ratios of M2-like to M1-like macrophages compared to surrounding tumor and stroma. Conclusions: Our findings demonstrate significantly more immune cell infiltration in HG vs LG PC, challenging the notion that PC is immunologically “cold” across all stages of disease. HG PC exhibits elevated levels of Tregs and M2-like macrophages in specific TME compartments, highlighting the distinct spatial organization of immunosuppressive populations. We observed more TLSs in HG PC, which contain exhausted T cells in proximity to Tregs and high M2/M1 macrophage ratios, suggesting that TLSs may paradoxically serve as local hubs of immunosuppression in high-grade disease. Overall, these data provide a mechanistic rationale for immunotherapeutic targeting of the TLS-rich immunosuppressive landscape of HG PC to improve clinical outcomes in the neoadjuvant setting.

A phase II study of zanzalintinib for patients with advanced urothelial carcinoma following prior therapy.

TPS889 Background: Advanced urothelial carcinoma (aUC) remains an aggressive malignancy with limited options in refractory disease. Multiple VEGF receptor tyrosine kinase inhibitors (TKIs), including cabozantinib, have demonstrated activity in the salvage setting of aUC alone and in combination with checkpoint inhibitors. Zanzalintinib, a second generation TKI, has a target profile similar to cabozantinib but with a significantly shorter half-life, which is expected to confer a better therapeutic index and reduce the time to resolution of toxicities. We hypothesize that given the important role of the VEGF pathway in UC, Zanzalintinib will demonstrate single-agent activity in refractory aUC. We propose a Phase II trial to evaluate the activity of Zanzalintinib for aUC progressing after prior therapy. Methods: This is a multicenter, open-label, single-arm investigator-initiated phase II trial conducted at four sites through the Hoosier Cancer Research Network. Patients receive oral zanzalintinib 60 mg once daily in 28-day cycles until disease progression or unacceptable toxicity. Major eligibility criteria include histologically confirmed aUC, prior treatment with EV and a PD1/L1 inhibitor, ECOG performance status 0-2, measurable disease, adequate hematologic, renal, and hepatic function. Exclusion criteria include prior exposure to VEGF inhibitors, >3 prior lines of therapy, active central nervous system metastases, uncontrolled hypertension, left ventricular ejection fraction <50% and serious cardiovascular events within 6 months. Radiographic imaging is done every 2 cycles x 3, then every 3 cycles. The primary endpoint is objective response rate (ORR) per RECIST v1.1. Secondary endpoints include progression-free survival (PFS), overall survival (OS), and safety. Exploratory endpoints include biomarker correlations with clinical outcomes. A Simon two-stage design will be used to assess efficacy, with an initial cohort of 25 patients and expansion to 40 if predefined criteria are met. ORR ≥20% is considered important, while ORR <10% is not considered clinically meaningful. Archival tumor is collected and blood is collected at baseline, cycle 2 day 1, and end of therapy for correlative studies of circulating tumor DNA, circulating markers of angiogenesis, and immune pathways. Funder: Exelixis, ClinicalTrials.gov Identifier: NCT07185945. Clinical trial information: NCT07185945 .

Bone fractures with androgen pathway inhibitors (ARPi) in patients (pts) with prostate cancer (PCa): A systematic review and network meta-analysis.

144 Background: Androgen receptor pathway inhibitors (abiraterone acetate [AAP], apalutamide [APA], enzalutamide [E], darolutamide [DARO] have become the cornerstone for pts with PCa due to survival benefits. Comparative data on fracture risk among ARPi are limited. This study quantified the risk of bone fractures with ARPi plus androgen deprivation therapy (ADT) and compared fracture risk across different ARPi agents. Methods: MEDLINE and EMBASE were searched from inception through September 1 st 2025 to identify positive phase III trials assessing ARPi in addition to ADT in pts with PCa (m0CRPC, mCSPC, mCRPC). Trials were included if they reported bone fractures in either arm. Pairwise, random-effects meta-analysis was conducted using Paul-Mendel approach. Sensitivity analyses using Hartung-Knapp (HK) adjustment was performed to assess robustness of results. To assess the comparative risk of bone fractures among different ARPi agents, mixed treatment comparisons were made using frequentist network meta-analysis. P-scores were computed to assess relative treatment rankings. Treatment effect was expressed as odds ratio (OR) with 95% confidence intervals (CI). Results: This systematic review included 13 phase III trials with 15468 pts (8890 received ARPi+ADT, 6578 received ADT alone). A total of 596 (6.7%) bone fractures were observed with ARPi+ADT compared to 180 (2.74%) with ADT alone. Patients receiving ARPi+ADT were associated with an increased risk of bone fractures compared to those receiving ADT (OR: 2.40; 95% CI: 1.93-2.98). Sensitivity analyses with HK adjustment showed consistent results (2.40; 1.88-3.06). There was no statistically significant effect modification by PCa clinical setting (p: 0.27). Mixed treatment comparisons showed a statistically significant increased risk of bone fractures with AAP+ADT (2.35; 1.29-4.27), APA+ADT (2.04; 1.47-2.86), and E+ADT (3.13; 2.44-4.00) but not with DARO+ADT (1.30; 0.80-2.08) when compared to ADT alone. Among different ARPi agents, E+ADT was associated with an increased risk compared to APA+ADT (1.54; 1.01-2.33) and DARO+ADT (2.44; 1.41-4.17). Ranking analysis showed that E+ADT was ranked as potentially the least safe treatment (P score: 0.05) in terms of relative fracture risk followed by AAP+ADT (P score: 0.30), APA+ADT (P score: 0.43), DARO+ADT (P score: 0.76). Sensitivity analyses limiting to mCSPC trials only showed consistent results. Conclusions: The risk of bone fractures varies among different ARPi agents, with enzalutamide posing the highest relative risk and darolutamide the lowest. These differences may guide treatment selection, particularly in pts with mCSPC and bone metastases. Prospective studies adjusting for covariates are needed to evaluate bone-protective strategies to mitigate fracture risk particularly in mCSPC patients who are considering treatment with ARPi.

Progress in stem cell-based embryo models and their applications in developmental biology and biomedicine

Redirecting Charge Distribution and Spatial Proximity of Co−O−Cu Motif with 4f−2p−3d Orbital Hybridization for High‐Efficiency Urea Electrosynthesis

ABSTRACT Electrocatalytic CO 2 /NO 3 − co‐reduction to access urea typically relies on the tailored two‐site catalysts, with the complexity of C/N‐intermediate generation and C─N coupling that limit urea synthesis efficiency. Here, a 4f (Ce)−2p (O)−3d (Co) orbital hybridization maneuver is demonstrated to customize a spin‐polarized Co‐site and a relatively electron‐rich Cu‐site for generating *NH 2 and *CO species to undergo C─N coupling to access urea, respectively, delivering a production rate of 2612.4 µg mg −1 h −1 at −0.27 V RHE , with an ultrahigh Faradaic efficiency (85.7%). Mechanistic investigations elucidate that the 4f−2p−3d motif enables the high‐spin Co 2+ (t 2g 5 e g 2 ) translation toward low‐spin Co 3+ (t 2g 6 e g 0 ), which enhances the electronic interaction between the e g ‐orbital of Co and 𝜎‐orbital of *NO, favoring *NH 2 formation. Further, the electron‐deficient Co 3+ ‐site formed can act as a localized electron acceptor to manipulate the electron structure of the adjacent Cu‐site, strengthening the hybridization degree between the catalyst's Cu 3d and C 2p of CO 2 to foster *CO generation. Then, interposed Ce narrows the Co─O─Cu distance, which spatially benefits *NH 2 and *CO coupling to form the C─N bond, overall promoting urea synthesis. The synergy of electronic interaction and geometric effect offers a feasible paradigm to precisely customize activity centers for high‐efficiency waste feedstock valorization.

Suppressing Hydrogen Transfer and Aromatization Reactions Enables Efficient Photothermal Recycling of Polyethylene into Platform Olefins

ABSTRACT The recycling of polyethylene (PE) into highly selective platform olefins holds great promise as a potential closed‐loop recycling route that minimizes dependence on the petrochemical industries, whereas the selectivity of olefins is mainly limited by two side reactions: hydrogen transfer and aromatization. Herein, we present a photothermal recycling pathway that effectively converts various types of PE into highly selective olefins using ZnCrO x /HZSM‐5 composite catalyst, with efficaciously suppressing both side reactions. The inclusion of ZnCrO x modifies catalyst acidity to inhibit the hydrogen transfer reaction, while jointly establishing an intra‐catalyst spatial temperature gradient through distinct photothermal responses between ZnCrO x and HZSM‐5 whereby the endothermic aromatization can be suppressed. This strategy achieves an impressive selectivity of 75.4% for C 2 –C 5 hydrocarbons, with 84.7% of them being C 2 –C 5 olefins, in the photothermal recycling of low‐density PE (LDPE) under atmospheric pressure using Xe lamp irradiation. Further, the demonstrated universality across various PE feedstocks (e.g., high‐density PE and commercial LDPE bags) and concentrated sunlight operation highlights a solar‐powered plastic‐to‐olefin platform with industrial viability.

Transcriptional plasticity of stromal cells amplifies their differentiation efficiency in vitro

A randomized phase 2 trial of lenvatinib plus pembrolizumab with or without stereotactic body radiotherapy in patients with metastatic renal cell carcinoma, low tumor burden, and stable disease (LASER).

TPS583 Background: Lenvatinib plus pembrolizumab (Len+P) is an established first-line regimen for metastatic clear cell renal cell carcinoma (mRCC). In the CLEAR study, patients with low tumor burden derived substantial benefit; however, ~20% achieved only stable disease (SD) as best response. In the VOLGA study, outcomes were improved when even a single lesion was irradiated during targeted therapy. We hypothesize that adding stereotactic body radiotherapy (SBRT) to multiple lesions in patients with SD during Len+P therapy will increase the objective response rate (ORR) and potentially improve overall survival (OS). Methods: LASER is a randomized, multicenter, phase 2 study. Eligible patients must have histologically confirmed mRCC, sum of target lesion diameters ≥7 cm, ECOG PS 0–2, and no prior systemic therapy for metastatic disease. All patients receive 12 weeks of induction therapy with Len (20 mg daily) plus P (200 mg Q3W). Imaging is performed per RECIST v1.1 to classify response as complete/partial response, SD, or progression. Patients with SD are randomized 1:1 to: (1) Len+P+SBRT or (2) Len+P alone. In the SBRT arm, up to 3 lesions are selected for irradiation by a multidisciplinary team. The primary endpoint is ORR of non-irradiated lesions after randomization, assessed every 12 weeks per RECIST v1.1. Secondary endpoints include progression-free survival (PFS), OS, response from irradiated lesions, and safety. The study is powered to detect an increase in ORR from 15% (control) to 50% (SBRT arm), with α = 0.05 and 80% power, requiring 27 patients per arm (54 randomized). Total planned enrollment is 150 patients to account for the proportion achieving SD following induction. Clinical trial information: KCRB-092025/2.