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Interface‐Enriched Fluorinated Covalent Organic Framework Enables Stable, High‐Performance n‐i‐p Perovskite Solar Cells
ABSTRACT Buried interfacial integrity remains a major bottleneck limiting both the efficiency and long‐term stability of perovskite solar cells (PSCs). Existing surface‐modification strategies often introduce additional interfacial discontinuities, thereby exacerbating rather than alleviating buried‐interface vulnerabilities. Here, we report an in situ buried‐interface modification strategy that reinforces the SnO 2 /perovskite interface using a fully conjugated covalent organic framework (COF) grafted with polyfluoroalkyl side chains. During perovskite crystallization, strong dipolar interactions between the polyfluoroalkyl chains and the SnO 2 drive the COF toward the buried SnO 2 /perovskite interface. The COF anchors at the SnO 2 /perovskite interface and forms a robust and functionally active interlayer. This dynamic interfacial assembly simultaneously 1) establishes a continuous, graded energy landscape that enhances electronic coupling and accelerates charge extraction; 2) induces facet‐selective SnO 2 ‐COF‐perovskite interactions that guide the oriented growth of perovskite grains; and 3) suppresses interfacial defects and halide migration, thereby stabilizing carrier transport. Consequently, n‐i‐p PSCs achieve a power conversion efficiency of 26.24% with a fill factor of 85.4%, and retain 86% of their initial efficiency after 2000 h of continuous operation. By transforming spontaneous molecular self‐assembly into a processing advantage, this work establishes a new materials paradigm for achieving high‐efficiency, stable, and scalable perovskite photovoltaics.
Hydrogel Thermostat Inspired by Photoprotective Foliage Using Latent and Radiative Heat Control
Abstract Plants such as Populus alba feature photoprotective foliage that dynamically modulates optical properties to dissipate excessive heat under high temperatures, while condensation‐induced latent heating preserves warmth under cold conditions—enabling tolerance to fluctuating thermal and hydric environments. Inspired by this natural strategy, a hydrogel‐based thermostat is presented that balances latent and radiative heat fluxes. The system integrates lithium ions and hydroxypropyl cellulose into a polyacrylamide matrix, providing dynamic solar reflectance, high infrared emissivity, and reversible water sorption–desorption capabilities. Thermochromic and hygroscopic responses are tunable via adjustments in hydroxypropyl cellulose and lithium ions concentrations, allowing environment‐specific adaptation. Mechanical robustness is enhanced by incorporating titanium dioxide nanoparticles and applying surface treatments. Experiments and simulations demonstrate both sub‐ambient cooling and above‐ambient heating across diverse conditions, establishing the system as an all‐season thermal regulation platform.
A phase II trial of cabozantinib in relapsed refractory germ-cell tumors (GCT).
587 Background: Vascular endothelial growth factor overexpression, increased angiogenesis, and activation of the c-MET pathway have biologic importance in GCT. Cabozantinib is an oral tyrosine-kinase inhibitor targeting c-MET, VEGF, RET, and AXL. We report results from a phase II trial of cabozantinib in refractory GCT. Methods: This single arm phase II trial used a Simon two-stage design investigating cabozantinib 60mg in pts with incurable relapsed/refractory GCT. Pts age≥18 with progressive metastatic GCT after first line cisplatin-based chemo and at least 1 salvage regimen were eligible. Primary endpoint was clinical benefit rate (CBR) [proportion of complete response (CR), partial response (PR), and stable disease (SD) for ≥3 mos using RECIST 1.1, modified to include AFP and hCG]. Simon’s 2-stage required clinical benefit in ≥ 2/18 pts to proceed to stage 2 and then enrolled up to 50 pts. Results: Simon stage I was met and expanded to stage 2. 44 pts were evaluable. 2 pts were female. Median age was 34.2 (21.4-63.2). 42 pts (95.5%) had nonseminomatous GCT. Primary site was testis for 79.5%, mediastinal 13.6%, ovary 4.6%, and retroperitoneal 2.3%. IGCCCG risk at initial diagnosis was good for 22.7%, intermediate 25%, poor 47.8%, and unknown 4.5%. 18 pts had late relapse disease. Median prior chemo regimens was 4. 63.6% of pts previously received high-dose chemotherapy with peripheral blood stem-cell transplant. Median AFP was 210.3 (1.1-120,693); hCG was 0.95 (0.6-72,759). CBR was 43.2%, with 2 pts (4.5%) achieving a PR and 17 (38.6%) achieving SD for ≥3 months. No CRs were seen. Median duration of treatment was 74 days (27-848). For those with SD as best response, median duration of SD was 3.7 mos (2.0-18.5). Stable radiographic disease was seen in 50% of pts, with median duration of 4.1 mos (2.01-27.9). Any measurable disease decrease was seen in 18 pts (46.2%). 95.5% of pts had AFP or hCG reduction, with 65.9% achieving at least 50% AFP or hCG reduction and 27.3% achieving at least 80% AFP or hCG reduction. The most common adverse event (AE) was diarrhea, occurring in 59.1% of pts, with 96.2% being G1/G2. Most common grade ≥3 AE was increased AST, occurring in 6.8% of pts. Table 1 lists AEs occurring in >25% of pts. 11 pts required dose reduction. 2 remain on treatment. Conclusions: Cabozantinib is the first non-cytotoxic chemotherapeutic agent with clinical benefit in refractory GCT. While no CRs were seen, clinical benefit was achieved in > 40% of pts, with half with stable radiographic response for a median of 4.1 mos. The AE profile has little overlapping toxicities with cytotoxic GCT chemo, presenting a unique opportunity to have less cumulative toxicity of further platinum chemo. Clinical trial information: NCT03375320 . AEs occurring in >25% of pts. Any Grade (%) Grade ≥3 (%) Diarrhea 26 (59.1) 1 (2.3) AST increased 24 (54.5) 3 (6.8) ALT increased 24 (54.5) 1 (2.3) Hypothyroid 22 (50) - Fatigue 20 (45.5) - Palmar-plantar erythrodysesthesia syndrome 19 (43.2) - Oral mucositis 13 (29.6) -
Single-cell transcriptomic characterization of NECTIN-4 expression in penile squamous cell carcinoma.
9 Background: NECTIN-4, a cell adhesion molecule and target of the antibody–drug conjugate enfortumab vedotin, has emerged as a promising therapeutic target within genitourinary malignancies. Given the limited treatment options and high morbidity associated with penile cancer, there is a critical need to identify novel therapeutic opportunities. We investigated NECTIN-4 expression and its associations with HPV status, disease stage, lymphovascular invasion (LVI), and copy number variation (CNV) using single-cell RNA sequencing (scRNA-seq) of human penile squamous cell carcinoma (PSCC) tissues. Methods: scRNA-seq was performed on ten PSCC tissue samples spanning stages pT1–pT3, pN0–pN3, and M0–M1, including five penile primaries, four lymph node metastases, and one distant metastasis. HPV status was determined by high-risk HPV in situ hybridization and p16 immunohistochemistry. Single-cell suspensions were processed using Cell Ranger (v7.1.0, 10x Genomics) and analyzed with Seurat V4. Cells with < 200 detected genes, log10(genes/UMI) < 0.8, > 15% mitochondrial reads, or doublets were excluded. Malignant cells were identified using inferCNV, and group comparisons were performed using the Wilcoxon rank-sum test. Results: NECTIN-4 transcripts were detected exclusively in epithelial cells and were absent in endothelial and immune populations. Median expression was higher in HPV-positive versus HPV-negative tumors (1.19 [IQR 2.07] vs 0.53 [1.59]; p < 2.2×10⁻ 16 ; n = 9227 vs 1101) and in LVI-positive versus LVI-negative tumors (1.33 [2.22] vs 0.71 [1.41]; p < 2.2×10⁻ 16 ; n = 7744 vs 2584). Advanced disease demonstrated elevated NECTIN-4 expression compared to localized tumors (1.19 [2.06] vs 0.00 [1.54]; p < 2.2×10⁻ 16 ; n = 9398 vs 930). NECTIN-4 levels correlated inversely with CNV burden, decreasing from low (1.47 [2.41]) to median (1.13 [2.00]; p < 2.2×10⁻ 16 ) to high (1.03 [1.58]; p < 3.4×10⁻ 10 ) CNV categories. Conclusions: NECTIN-4 shows variable expression across PSCC with increased expression in HPV-positive, LVI-positive, and advanced-stage tumors, and an inverse correlation with CNV burden. These findings highlight NECTIN-4 as a potential biomarker of tumor aggressiveness and a promising therapeutic target in PSCC. Ongoing and future studies evaluating enfortumab vedotin and other NECTIN-4–directed therapies may provide new treatment avenues for patients with this rare malignancy.
Impact of age on outcomes in metastatic non–clear cell renal cell carcinoma (mnccRCC): A real-world TriNetX analysis.
453 Background: Malignancies arising in young adults often exhibit biological and clinical behaviors distinct from those in older patients (pts). Currently, little information is available regarding the prognostic impact of age in mnccRCC. This study aimed to compare survival outcomes by age group using data from the large-scale TriNetX database. Methods: We used the TriNetX research database to conduct a retrospective, large-scale outcome analysis of pts with mnccRCC who received at least one line of treatment across major healthcare institutions within an internationally connected, TriNetX-mediated network. Pts were stratified by age (< 45 vs ≥45 years), and clinical and demographic characteristics were compared using standard statistical methods. Kaplan-Meier analysis estimated progression-free survival (PFS) and overall survival (OS). Propensity score matching (PSM) was applied for sex, race, sites of metastases, type of treatment and comorbidities. Results: Among 758 pts with mnccRCC, 382 received first-line therapy between 2015 and 2025 and were included in the analysis. 257 had papillary histology, 23 chromophobe, 18 collecting duct, 60 unclassified, and 24 other rare entities. Median age was 62.7 years, and 69% were male. At diagnosis, 27% had stage IV disease and 69% underwent radical nephrectomy. First-line regimens included immune checkpoints inhibitors (ICI) monotherapy in 24.9%, tyrosine kinase inhibitors (TKI) monotherapy in 53.9%, ICI + TKI combinations in 5%, and mTOR inhibitors in 5.2%. 54 pts were < 45 years and 328 ≥45. The two age cohorts showed no significant differences in sex (p = 0.59), race (p = 0.21), comorbidities (p = 0.22), histology (all p > 0.05) or treatment categories (all p > 0.05). Lung metastases were more frequent in older pts (p = 0.018), whereas liver, bone, lymph node, and brain metastases were more common in younger pts (all p < 0.001). Pts < 45 years had shorter PFS than those ≥45 years (14.9 vs 30 months [mos]; p = 0.029) and a trend toward shorter OS (17.7 vs 36 mos; p = 0.10). After multivariate adjustment, a trend toward shorter PFS remained (14.9 vs 19.6 mos; p = 0.058), whereas OS differences were not significant (17.9 vs 40.4 mos; p = 0.16). In a subgroup analysis of papillary mnccRCC, younger pts also showed shorter PFS (20.4 vs 26.9 mos) and OS (22.5 vs 33.3 mos), with non-significant trends (PFS p = 0.11; OS p = 0.93). Conclusions: In this large, real-world cohort of mnccRCC, younger pts (< 45 years) had metastases at sites historically associated with worse prognosis (i.e., liver, brain) and exhibited significantly shorter PFS and a trend toward shorter OS, suggesting more aggressive disease biology. These findings support consideration of tailored or more intensive therapeutic strategies in younger pts.
The ITALIC-RCC study: A randomized study of clinical and humoral impact of primary tumor ablation in metastatic renal cell carcinoma treated with immunotherapy.
TPS584 Background: The role and optimal timing of cytoreductive nephrectomy (CN) have long been subject of debate in the management of metastatic renal cell carcinoma (mRCC) due to the potential role in control of bleeding and pain and also in reducing the risk of future metastatic spread by removing a potential source of immunosuppressive or tumor-promoting growth factors. In the VEGFR-TKIs era, the CARMENA and SURTIME trials, investigated the role of the CN: the CARMENA study compared immediate CN + sunitinib over sunitinib alone showing similar overall survival (OS) in intermediate- and poor-risk patients, except for those with only one IMDC risk factor who benefited from CN. The SURTIME trial assessed deferred CN after sunitinib versus upfront CN followed by sunitinib. Deferred CN was associated with improved OS compared to upfront CN (HR 0.57, 95% CI 0.34–0.95; p = 0.03). Nowadays, CheckMate 214, Keynote 426, CheckMate 9ER and the CLEAR studies showed that immunotherapy (IT)-based combinations therapies significantly improve OS and progression-free survival (PFS) compared to the previous standard of care (SOC) with sunitinib. Furthermore, radiotherapy (RT) in RCC has demonstrated excellent renal function and oncological outcomes in several clinical trials: safety data reported a low risk of high-grade toxicity, accounting for only 3.8% of cases. This trial investigates the potential role of CN and RT in the therapeutic algorithm of mRCC. Methods: The ITALIC-RCC study (NCT06903312) is a phase IV, randomized, multi-arm, multicenter, low- interventional clinical trial, aiming to evaluate whether intensifying treatment by adding local therapy of the primary tumor to the standard IT-based therapy, improves OS in patients with mRCC. The study aims to enroll 409 patients affected by metastatic or locally advanced renal cell carcinoma with predominantly clear cell histology, aged ≥18 years, with ECOG performance status 0–1 and without evidence of progressive disease after at least 24 weeks, but not more than 52 weeks from the time of the signed informed consent. Eligible patients will be randomized 1:1:1 to receive deferred cytoreductive nephrectomy + SOC or RT on primary tumor + SOC (only in those with primary kidney cancer ≤ 4 cm) or SOC alone. The primary endpoint of the study is to assess the difference in OS between patients who undergo CN and those who do not, while receiving therapy with SOC for mRCC. Secondary endpoints include the difference in PFS between patients who receive or not the deferred CN or the RT during SOC therapy for mRCC, the difference in OS between patients who receive or not the RT on primary tumor while on therapy with SOC for mRCC among those with primary tumor up to 4 cm, as well as assessments of quality of life and safety. Exploratory biomarkers analysis will also be performed. The trial is currently actively enrolling participants. Clinical trial information: NCT06903312 .
Micropore‐Confined ROS‐Responsive 3D‐Printed Shell‐Core Scaffolds for Long‐Term NO Release to Orchestrate Immunomodulation and Angiogenesis in Diabetic Bone Defect Repair
ABSTRACT The healing of diabetic bone defects is critically impaired by multifaceted pathological factors, including immune dysregulation, persistent inflammation, excessive reactive oxygen species (ROS), and impaired vascular‐osteogenic coupling. Although nitric oxide (NO) holds promise for its anti‐inflammatory and regenerative properties, its clinical translation is limited by a short half‐life and uncontrolled release, failing to match chronic diabetic bone repair. Herein, we present an MP‐LAS scaffold based on a micropore‐confinement strategy, which transforms release kinetics from a “burst‐exhaustion” mode to a sustained, on‐demand output. The scaffold is fabricated by 3D printing coupled with phase separation, featuring a core of ROS‐degradable hydrogel loaded with L‐arginine (L‐Arg) and a shell of nano‐hydroxyapatite/polycaprolactone (nHA/PCL) with interconnected microporosity. The well‐designed micropores precisely confine the ROS/L‐Arg reaction, triggering localized degradation of the core and controllable L‐Arg release for subsequent in situ NO generation. This system maintains a stable NO supply for 3 months, avoiding burst‐release toxicity while continuously neutralizing pathological ROS. Both in vitro and in vivo evaluations demonstrate that this dual action synergistically modulates macrophage M2 polarization, angiogenesis, and osteogenic differentiation, ultimately facilitating diabetic bone regeneration via NO‐mediated vascular‐osteogenic coupling. This work offers a novel, versatile micropore‐confined platform for precise molecule delivery in complex pathological microenvironments.
Axial π─Bond Tuning of Anchored FeN <sub>4</sub> for Electrocatalytic Oxygen Reduction
ABSTRACT The curvature change of the support can control the induced local stress strain and directly change the properties and performance of the layered materials. Herein, we successfully in situ grew graphdiyne (GDY) on the surface of carbon nanotubes (CNTs) to form a heterojunction material with curved structure and highly surface‐active. Our results indicated that the surface‐grown GDY can deform into a curved‐GDY (cGDY) due to internal stress. Such structural rearrangement regulates the charge distribution on interface of graphdiyne/CNTs and increases the charge density of C sp ─C sp bonds within bent diacetylene linkages (−C sp ≡ C sp −C sp ≡C sp −). While loading iron phthalocyanine (FePc) to this bent surface, the interactions and the interfacial repulsive force in the system were greatly enhanced, resulting in the elevated energy level of Fe 3d z 2, which was beneficial to the adsorption of O 2 , and the hybridization between Fe (3d xz , 3d yz , and 3d z 2) and *OO (2p x , 2p y , and 2p z ) orbitals, significantly enhancing activation of O 2 . Therefore, compared with the FeN 4 moiety on pure CNTs or GDY, this heterojunction structure through axial π ─ bond tuning demonstrates superior performance with a half‐wave potential of 0.905 V and a Tafel slope of 31.7 mV dec −1 .
Improving delivery of prostate cancer germline testing at the Department of Veterans Affairs: A cluster-randomized trial.
TPS270 Background: ~15,000 men with metastatic prostate cancer (MPCa) receiving care in the Veterans Administration (VA) could benefit from germline testing to inform treatment options. However, there are insufficient genetics providers to arrange for germline testing. In 2021, the VA implemented multiple strategies to shift the task of germline testing to oncologists (i.e., mainstreaming) to increase guideline-concordant germline testing. These efforts led to improved adoption of germline testing by oncologists, and mainstreaming was more efficient and timely than genetics referral. However, germline testing remains low for many oncologists due to numerous barriers, e.g., lack of preparedness and confidence in germline testing, from identifying eligible patients to results-informed management. Methods: We will conduct a cluster-randomized trial comparing the effectiveness of implementation strategies to increase mainstreaming through randomization of oncologists not meeting a pre-specified test-order benchmark of 25%. Eligible participants include VA oncologists who: 1) have authored progress notes in oncology clinics for ≥10 patients with MPCa in the past two years, 2) are practicing at VA facilities with germline test orders in the electronic health record (EHR), and 3) <25% of their MPCa patients have had mainstream germline test orders. In the first 6 months, we will disseminate a germline testing handbook with provider education materials, information resources and EHR tools. At month 7, for oncologists who do not exceed the 25% benchmark, we will administer audit-feedback reports describing their germline testing rates compared to peers and the 25% benchmark. At month 12, oncologists whose order rates are <25% will be randomized to either continue audit-feedback or receive facilitation (interactive problem-solving and support) and audit-feedback. At month 24, we will stop the audit-feedback and facilitation strategies. Throughout the project, we will conduct semi-structured interviews to understand local germline testing workflows, challenges and enabling factors. We will assess fidelity to the implementation strategies and any adaptations made using the Longitudinal Implementation Strategy Tracking System. To evaluate the effectiveness of the implementation strategies on germline testing, we will use a mixed-effects model to account for the clustered nature of the data and the effect sizes of the implementation strategies. The project is informed by the RE-AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance) framework. The study has not yet enrolled participants. There is no clinical trial registry number for this quality improvement project. This Department of Defense-funded project is a part of a greater quality improvement effort to increase guideline-concordant germline testing in the VA.
A binary dual-stain immunohistochemistry classifier to predict pathologic downstaging after neoadjuvant chemotherapy in muscle-invasive bladder cancer.
842 Background: Luminal and basal bladder cancers exhibit differential chemosensitivity, yet intratumoral heterogeneity limits treatment prediction. We hypothesized that tumors arising through papillary versus carcinoma in situ pathways show differential neoadjuvant chemotherapy (NAC) response. We developed a dual CK20/GATA3 scoring system to test this hypothesis in a pilot study. Methods: Pre-treatment transurethral resection specimens from 92 consecutive radical cystectomy patients receiving cisplatin-based NAC underwent dual CK20/GATA3 staining. Three patterns were identified: Luminal-Papillary (CK20-/GATA3+, grade 3), Luminal-CIS (CK20+/GATA3±, grade 4), Basal-CIS (CK20-/GATA3-, grade 5). Using Gleason-like methodology, a genitourinary pathologist assigned primary grade (most prevalent pattern) plus secondary grade (highest additional pattern present in any amount); pure single-pattern tumors received doubled grade, yielding scores 6-10. Pre-specified binary classifier: Low (6-7, papillary-enriched) versus High (8-10, CIS-predominant). Primary endpoint was pathologic downstaging (ypT1 or less). Results: Low (n = 48) and High (n = 44) groups balanced for age, sex, clinical T stage (cT2: 38% versus 33%). Downstaging occurred in 26 of 48 (53.1%) Low versus 15 of 44 (33.3%, absolute difference ≈20 percentage points; Fisher p = 0.066) and the direction of effect persisted after adjustment for clinical T stage (logistic OR 0.52 for High vs Low; 95% CI 0.21–1.25; p = 0.142). For DFS, the cT-adjusted Cox model showed HR 1.22 for High vs Low (95% CI 0.50–3.02; p = 0.662), OS was underpowered. Conclusions: This pilot study identifies a clinically meaningful downstaging signal (20 percentage-point difference) using dual-stain immunohistochemistry without sequencing and may enable preoperative enrichment for response. Prospective multi-institutional validation is warranted.
Prospective, blinded validation of a urinary cfDNA methylation assay in bladder cancer.
820 Background: Cystoscopy is the standard for local bladder cancer (BC) detection and follow-up, but is invasive and costly. Noninvasive, accurate molecular assays could transform screening and surveillance. To address this need, we evaluated the performance of a targeted 21-locus methylation assay for urinary cell-free DNA (cfDNA) as a noninvasive tool for disease assessment and monitoring in BC. Methods: Candidate loci were identified from TCGA Illumina HumanMethylation450K tumor–normal methylation array comparisons. Differentially methylated CpGs were expanded to CpG regions/blocks for primer design and down-selected to a 21-locus panel. The loci were incorporated into a targeted assay optimized for urinary cfDNA analysis of BC. Urine samples were prospectively collected from 53 individuals, including 37 referred for cystoscopy and 16 healthy volunteers. Investigators were blinded to the reason for referral, and samples were obtained immediately before any diagnostic procedures. cfDNA was extracted, PCR-amplified, and analyzed by deep bisulfite sequencing to quantify methylation across the 21 selected loci. Results: Data from 53 participants were analyzed. Diagnostic classification was based on cystoscopy and biopsy pathology obtained after urine collection: 21 had histologically confirmed active BC, 11 had a history of BC but no evidence of disease (NED), 5 had benign urologic findings, and 16 were healthy controls. The assay correctly classified 19 of 21 participants with active BC (sensitivity = 90.5%) and 28 of 32 non-cancer participants (specificity = 87.5%), yielding an overall diagnostic accuracy of AUC = 0.93. Cancer-derived urinary cfDNA levels were higher in participants with active BC than in all non-cancer groups combined. Participants with prior BC but NED showed intermediate methylation levels, consistent with residual epigenetic alterations despite clinical remission. The assay did not distinguish between non–muscle-invasive and muscle-invasive disease. Conclusions: This prospective, blinded study demonstrates the feasibility of a novel, low-cost urinary cfDNA methylation assay for disease assessment and monitoring in BC using a compact 21-locus panel. Deep bisulfite sequencing enabled accurate quantification of cancer-specific methylation patterns, supporting the potential of this minimally invasive approach for follow-up and surveillance of bladder cancer. Further studies are planned to assess clinical performance and longitudinal application in real-world settings.
Internet-based lifestyle intervention to eradicate obese frailty in prostate cancer survivors: The iLIVE trial.
TPS274 Background: Obese frailty is a growing national problem as trends towards aging and obesity converge. This problem is especially acute in men with prostate cancer treated with androgen deprivation therapy (ADT). ADT is essential to control advanced prostate cancer, a disease which affects mostly older men, but accelerates muscle loss and gains in adiposity which threaten physical functioning and overall quality-of-life. Diet and resistance training exercise may mitigate obese frailty but have rarely been combined in an accessible delivery format. Methods: The Internet-Based Lifestyle Intervention to Eradicate Obese Frailty in Prostate Cancer Survivors (iLIVE) Randomized Controlled Trial (RCT) aims to mitigate obese frailty among men with prostate cancer treated with ADT. Participants (N=250) are being recruited across North America to participate in this RCT that is implemented entirely over the internet. Eligibility criteria include prostate cancer history, at least 6 months of ADT in the last 10 years, body mass index ≥25 kg/m 2 and ≥2 frailty symptoms [illness, fatigue, inactivity, weakness, slowness]), no regular participation in strength training or on a medically-supervised diet, ability to participate in moderate intensity strength training, ability to provide informed consent, complete surveys, participate in performance testing and study interventions. Consented participants undergo assessments that include: online surveys (medical status, falls, physical activity, quality-of-life, healthcare utilization); dietary recalls (kilocalories, diet quality); body weight (Bluetooth scales); physical activity (Fitbits); 4) internet-based physical performance (chair stand, timed up-and-go, gait speed tests); and 5) muscle mass (D3 creatine dilution). Participants are then randomized to one-of-two 6-month interventions: 1) Enhanced Usual Care (EUC): Encouraged to continue Aria scale and Fitbit use with monthly emails of publicly available diet- and exercise-related information; or 2) iLIVE: Same as EUC, plus website access to weekly serialized sessions on weight loss and diet quality and thrice-weekly live remote supervised group resistance training sessions. Assessments are repeated at 6-months; at 12-months, questionnaires are repeated and data from digital devices are captured. Intent-to-treat analysis will compare EUC vs. iLIVE (baseline-to-6-months) using a composite measure of obese frailty as the primary outcome. Designed as a type I hybrid-effectiveness implementation trial, data on intervention feasibility (including safety), acceptability, adoption, appropriateness, fidelity, sustainability, and cost are assessed, tracked, and analyzed. Trial registration: ClinicalTrials.gov: NCT06011499 (5.31.2025: https://clinicaltrials.gov/study/NCT06011499). Clinical trial information: NCT06011499 .
Multistage Phase Programming in Fibrillated Peptide Coacervates
ABSTRACT Natural protein condensates respond to external stresses through stimuli‐triggered multistage phase transitions. Reprogramming such transitions in synthetic systems is critical for rational design of self‐adaptive materials with precisely regulated stimuli‐responsiveness. Nevertheless, the sequence complexity of intrinsically disordered proteins (IDPs) and their competing assembly pathways often impede effective programing of multistage transitions in physiological conditions. Here, a class of short peptide synthons (Mw≈1500 Dalton) is synthesized by integrating intrinsically disordered and transiently ordered motifs derived from the low‐complexity domain of IDPs. Remarkably, these peptide synthons exhibit thermoreversible quadruple phase transitions among monomers, self‐coacervates, liquid crystals, and semi‐crystallized solid gels. Mechanistic study reveals that the phase transitions are governed by two distinct assembly pathways, namely coacervation and fibrillization, which interact in both collaborative and competitive manners. Modifying the peptide sequence or molecular decorations allows for precise control over the phase transition temperatures, enabling sequential, multi‐stage transitions to be activated by dose‐dependent pathological cues (e.g., lactic acid) at the body temperature (37°C). These findings establish a highly versatile and programmable material platform to sequentially encode multistage phase behaviors into synthetic peptide assemblies, inspiring the development of next‐generation disease biosensors, drug‐delivery vehicles, and self‐adaptive microrobots.
Boron Vacancy Enhanced Ru─Mo Electron Bridge as an Efficient Electrocatalyst for Anion Exchange Membrane Electrolysis
ABSTRACT Hybrid electrocatalysts combining noble metals with tailored supports are crucial for efficient hydrogen evolution reaction (HER) across a wide pH range. Here, we report a ruthenium cluster catalyst anchored on molybdenum boride support engineered with boron vacancies (Ru/MoB‐B V ) for highly efficient HER. The introduced boron vacancies optimize the electronic interactions between molybdenum boride and the Ru cluster via a Ru─Mo electron bridge, leading to enhanced catalytic performance and stability. Combined electrochemical analysis and density functional theory calculations reveal that Ru/MoB‐B V possesses a favorable water‐dissociation energy and optimal desorption energies for hydrogen/hydroxide intermediates on Ru clusters. These merits confer exceptional HER performance, with overpotentials of 40 and 34 mV at 10 mA cm −2 in alkaline freshwater and seawater, respectively; 24 mV in acidic electrolyte; and 67 mV in neutral electrolyte. Importantly, the activated Ru and Mo sites enable an anion exchange membrane electrolyzer employing Ru/MoB‐B V as the cathode to exhibit remarkable stability, operating for 100 h at 500 mA cm −2 . This work provides insights into the design of highly efficient and stable catalysts through the precise engineering of surface vacancies.
Benign persistent elevation of alphafoetoprotein (AFP) after curative treatment for germ-cell tumors.
598 Background: Follow-up of patients with germ-cell tumours (GCT) relies on monitoring serum markers (SM) including alpha-fetoprotein (AFP), human chorionic gonadotropin (hCG), and lactate dehydrogenase (LDH). Instances of benign, non-GCT related elevation of AFP have been reported as case reports. Identifying such occurrences is crucial to prevent misdiagnosis of residual disease and subsequent overtreatment, which may lead to increased morbidity. Methods: We conducted a national retrospective study in nine GETUG institutions. Patients with isolated persistent elevation of AFP levels above the normal range after receiving curative treatment for GCT without detectable disease on CT scan imaging were identified. Data on patient characteristics, treatment response, changes in SM values over time, and serum AFP levels from first- and second-degree relatives were collected. Familial AFP elevation was defined as AFP levels above the normal range in at least one first- or second-degree relative. Results: From June 1990 to April 2024, 31 patients were identified. Median age was 35 years (range, 19 to 49 years). 15 patients (48%) had pure seminoma, and 16 (52%) had non-seminomatous GCT. Overall, 19 patients (61%) had a clinical stage I disease, 17 (23%) had stage II, and 5 (16%) had stage III. No patient had a history of chronic alcoholism or consumption of medications with hepatic toxicity. Median AFP level after curative treatment was 12 ng/mL (range, 8.8 to 36 ng/mL). No evidence of disease was found on CT scan. An ultrasound examination of the contralateral testis and an FDG-PET/CT were performed in 15 (48%) and 7 patients (23%), respectively, also showing no evidence of disease. Serum AFP levels from family relatives were obtained for 14 patients (45%), with a family elevation identified for 10/14 patients (71%). After a median follow-up of 35 months (range: 7-253 months), AFP levels remained elevated in all 31 patients without documented disease relapse. Conclusions: Benign and often familial elevations of serum AFP levels are rare occurrences, which can be a chance finding following curative treatment for GCT. Ultrasound examination of the contralateral testis and AFP measurement in family members are recommended. Surveillance alone is appropriate.
Is it time to redefine the Phoenix criterion for biochemical failure in the era of PSMA PET/CT?
319 Background: Biochemical recurrence (BCR) of prostate cancer (PCa) is traditionally defined by the Phoenix criterion (PSA rise ≥ 2 ng/ml above nadir). However, prostate-specific membrane antigen (PSMA) PET/CT can identify recurrent or metastatic disease at much lower PSA levels. This study evaluated the detection rate and clinical relevance of PSMA PET/CT across varying PSA values in patients with PCa following curative-intent radiotherapy (RT). Methods: We retrospectively analysed 182 patients managed between January 2021 and December 2024 who received curative-intent RT for PCa. Clinical data included PSA at the time of imaging, Gleason score, disease distribution, and prior primary treatment. Results: Of 182 patients, 167 (91.7%) underwent PSMA PET/CT; 149 (81.8%) demonstrated PSMA-avid lesions indicating local recurrence and/or metastatic disease, while 18 (9.8%) had negative scans. Thirty patients (17.9%) did not meet the Phoenix criterion (PSA < 2 ng/ml) yet had positive PSMA findings. Of these, 20 (66%) had nodal metastases, 2 (6.6%) had local recurrence with nodal and bone metastases, 3 (10%) had nodal and bone disease, and one patient (3.3%) had local recurrence with visceral and/or bone metastases. No correlation was observed between Gleason score and PSMA positivity in this subgroup (Gleason 7 = 53.3%, Gleason 8 = 26.6%, Gleason 9 = 20%). A further 23 patients (15%) had PSA > 2 but < 3 ng/ml; 14 (60.8%) demonstrated nodal metastases, 7 (30.4%) bone metastases, 4 (17.3%) combined local/nodal/bone disease, and 2 (8.6%) visceral metastases. Most had higher-grade tumours (Gleason 9 in 39%). Eighteen patients (12%) had PSA > 3 but < 4 ng/ml; 6 (33.3%) had nodal metastases, 6 (33.3%) bone metastases, 3 (16.6%) nodal plus bone disease, and 2 (11.1%) visceral metastases. Within this group, 44.4% had Gleason 9 and 38.8% had Gleason 7 disease. Conclusions: PSMA PET/CT demonstrates high sensitivity for detecting recurrent and metastatic PCa even at PSA ≤ 4 ng/ml, identifying disease in over 40% of scanned patients. Detection of nodal and distant metastases below the Phoenix threshold challenges the current reliance on biochemical criteria to trigger imaging. Early PSMA PET/CT may enable prompt therapeutic intervention and improved clinical outcomes. Prospective studies are warranted for validation.
Detecting <i>MTAP</i> loss in liquid biopsies from patients (pts) with clinically advanced urothelial bladder cancer (CAUBC).
819 Background: MTAP loss is an emerging biomarker guiding investigational assessment of protein arginine methyltransferase 5 (PRMT5) and methionine adenosyltransferease-2A (MAT2A) inhibitors in a wide variety of tumor types including CAUBC. Detecting homozygous loss and copy number changes in solid tumors is often challenging and requires a robust assay and analysis pipeline, especially when the amount of extracted DNA is small. In CAUBC, there is sometimes small tumor size from trans-urethral resection of bladder tumor (TURBT) and/or metastatic tissue biopsy, which may limit immunohistochemistry (IHC) and comprehensive genomic profiling (CGP) required for treatment selection and clinical trials enrollment. We queried whether blood-based liquid biopsy (LBx) CGP could provide information regarding MTAP loss in pts with CAUBC. Methods: Hybrid capture–based CGP was performed on 10,532 CAUBC tissue-based (TBx) samples using the FoundationOne CDx assay and on 1,637 CAUBC LBx samples using the FoundationOne Liquid CDx assay. The ctDNA tumor fraction (TF) for each LBx sample was determined using assessments of aneuploidy and variant allele frequencies, as previously described. Analyses were conducted on independent TBx and LBx cohorts; samples were not matched within the same patients. Results: For the TBx group, 7,685 (27.0%) CAUBC featured MTAP loss. For the LBx group, MTAP loss detection increased as the TF increased (Table). For CAUBC LBx samples with TF < 5%, MTAP loss detection was only 5.4%. As the LBx TF increased, the frequency of detection of MTAP homozygous loss increased significantly reaching > 18.0% when TF was ≥30%. Regarding complete vs partial MTAP exon loss, TBx and LBx showed similar identification rates: 92.2% and 85.3% of MTAP losses were complete or near complete (loss of 7-8 of 8 exons) in TBx and LBx, respectively; 7.4% and 11.8% were partial losses (loss of 1-5 of 8 exons). Conclusions: LBx emerges as a promising tool for detecting MTAP loss in CAUBC. Importantly, LBx TF plays a crucial role in CGP evaluation, as MTAP loss detection rates using LBx approach those of TBx when TF is ≥10-20%. However, when TF levels are < 10%, homozygous MTAP loss can be challenging to detect and may be missed. Study limitations include retrospective nature, lack of outcomes data, lack of paired/matched samples in the same patient, selection and confounding biases. Our findings have the potential to increase clinical trial accrual for pts with this disease, who have relatively limited treatment options and may sometimes lack sufficient tumor tissue for CGP. Tissue and liquid biopsies can have complementary value. CAUBC MTAP no loss CAUBC MTAP loss MTAP loss freq TBx 7685 2846 27.0% LBx TF ≥0% 590 34 5.4% LBx TF ≥1% 288 34 10.6% LBx TF ≥5% 190 34 15.2% LBx TF ≥10% 142 33 18.9% LBx TF ≥20% 96 22 18.6% LBx TF ≥30% 68 14 17.1%
Interim analysis of vorolanib combined with cadonilimab in previously untreated patients with advanced renal cell carcinoma.
499 Background: Targeted therapy combined with immunotherapy is the first-line standard for advanced renal cell carcinoma (aRCC). Anti-angiogenic agents plus PD-1/PD-L1 inhibitors significantly improve progression-free survival, while ~40% of patients show suboptimal response. Vorolanib, a novel tyrosine kinase inhibitor, and cadonilimab is a PD-1/CTLA-4 bispecific antibody. Vorolanib has demonstrated OS benefit and safety as monotherapy or combined with everolimus in later-line settings. This combination has shown potential in other cancers but has not been evaluated in aRCC. This study evaluates their efficacy and safety as 1L treatment for aRCC and explores circulating CTCs as predictive biomarkers. Methods: This single-arm, multicenter trial enrolled patients with untreated aRCC or recurrence >6 months after prior (neo)adjuvant therapy. The study includes Phase I dose escalation and Phase II expansion. Phase I used a 3+3 design (vorolanib 200 mg QD, cadonilimab 10 mg/kg Q3W IV) with 3 + 3 Dose De-escalation Design based on dose-limiting toxicities. Phase II plans to enroll 37 patients treated at the recommended dose(Q3W) until progression or intolerable toxicity. Primary endpoint is ORR, secondary endpoints include PFS, OS, DCR, DoR, 12-month PFS rate, 12/24-month OS rates, safety and quality of life. The exploratory endpoint is CTC clearance and its association with treatment efficacy. Results: By Oct 2025, 15 patients enrolled (12 males, 3 females; median age 60). Disease staging included: T1b in 2, T2 in 5, T3 in 7, and T4 in 1 patient.6 discontinued (3 liver dysfunction, 1 infusion reaction, 2 brain metastases). Among 15 patients, 11 underwent efficacy assessment: 5 achieved PR and 6 had SD, resulting in an ORR of 45.5% and DCR of 100%. Median follow-up was 3.7 months, with a 6-month PFS rate of 85.71%. No SAEs were reported. Treatment-related AEs (abnormal liver function, elevated urinary protein) were mostly grade 1–2, 53.3%. The incidence of common AEs (liver function, elevated urine protein, diarrhea, hypertension) did not show increase compared to other 1L targeted-immunotherapy combination. Dose reductions were minimal (vorolanib: 2; cadonilimab: 1) and did not affect subsequent treatment. Among 8 with ≥2 CTC tests, 7 showed a consistent and significant decrease in CTCs and PD-L1+ CTCs from baseline. ORR was associated with CTCs and PD-L1+ CTCs reduction. Conclusions: The combination of vorolanib and cadonilimab represents a 1L treatment option for aRCC, demonstrating a high ORR and favorable tolerability. Further large-scale studies are warranted to validate OS, PFS, and long-term safety. PD-L1+ CTCs show potential as predictive biomarkers for treatment efficacy. Clinical trial information: NCT06577961 . Correlation analysis of circulating blood CTCs. Spearman's ρ Pearson's r CTC Change vs. Efficacy 0.435 0.476 PD-L1+ CTC Change vs. Efficacy 0.417 0.513 PD-L1+ Proportion vs. Efficacy 0.786 0.702
Spin‐Dependent Photoluminescence in Carbon‐Based Quantum Dots
ABSTRACT The ability to modulate the photoluminescence (PL) of nanomaterials via spin‐related effects is vital for many emerging quantum technologies, with nanoscale quantum sensing and imaging being particular areas of focus. Carbon‐based quantum dots (CQDs) are among the most common forms of luminescent nanomaterials, appealing due to their ease of synthesis, tunability through organic chemistry, high brightness, and natural biocompatibility. However, the observation of room‐temperature, spin‐dependent PL has remained elusive. Here, we report on the observation of PL modulation of CQDs by magnetic fields ( mT) under ambient conditions. Using pyrolysis, we synthesize a series of CQDs using 19 different amino acids as the starting material. These provide samples with a range of PL emission spectra. Surprisingly, the vast majority of them exhibit a clear magneto‐PL effect (up to change) in dry form, which generally persists in solution. Furthermore, an electron spin resonance is detected in the PL with a ‐factor of , suggesting a process similar to the radical pair mechanism is responsible for the spin‐dependent PL. Finally, we show that the magneto‐PL contrast decreases in the presence of paramagnetic species, which we attribute to an increase in magnetic noise‐induced spin relaxation in the CQDs. Our work brings new functionalities to these commonly used and biocompatible luminescent nanoparticles, opening new opportunities for in situ quantum sensing and imaging of biological samples.
Real-world overall survival (OS) improvements in metastatic urothelial carcinoma (mUC) across three key therapeutic eras.
686 Background: Over the past 3 decades, treatment of mUC has been transformed by 3 landmark backbone therapies: platinum-based chemotherapy (PBC), immune-checkpoint inhibitors (ICIs), and antibody–drug conjugates (ADCs), either alone or in combination therapies. Temporal trends of OS improvement in patients (pts) with mUC are instrumental to identify research gaps and unmet needs. Methods: We used the TriNetX research database to conduct a retrospective, large-scale outcome analysis of pts with mUC who received ≥1 line of treatment across worldwide healthcare institutions. Pts were stratified into 3 therapeutic temporal periods: PBC era (1999–2015), ICIs era (2016–2018), and ADC era (2019–2025). Baseline clinical and demographic characteristics were compared using standard statistics. Kaplan–Meier analysis estimated OS, and propensity score matching (PSM) adjusted for sex, age, stage at diagnosis, lines of treatment and comorbidities. Results: Among 4,720 pts with mUC, 2,383 received 1st-line therapy between 1999 and 2025 and were included in the analysis. Overall, 783, 663, and 937 pts were treated in the PBC, ICI, and ADC eras. Median age was 70 years across PBC, ICI, and ADC eras, respectively; the proportion of male pts was 72.9%, 69.4%, and 73.1%. Across treatment eras, 51.7% of pts in PBC era received PBC (49.3% non-PBC), 32% in the ICI era received ICIs (35.3% only PBC, 32.6% non-PBC), and 20% in the ADC era received ADCs (20.9% only PBC, 30.2% only non-PBC, 28.9% ICIs). Regarding subsequent therapies, in the PBC, ICI, and ADC eras, 51.4%, 52.6%, and 53.2% of pts received 2nd-line and 25.4%, 25.9%, and 26.7% 3rd-line therapy, respectively. The three cohorts yielded no significant differences in sex, race, comorbidities, lines of treatment, or stage at diagnosis (all p > 0.05). Median OS was 13.5 months (mo) in the PBC era, 17.5 mo in the ICIs era, and 21.1 mo in the ADC era with a significant difference between the ADC vs PBC eras (p = 0.0017). After PSM, median OS was 13.4, 17.3, and 22.3 mo in the PBC, ICI, and ADC eras, respectively, with the difference between the PBC vs ADC eras remaining significant (p = 0.005). Notably, a subgroup analysis of pts who received only chemotherapy (PBC or non-PBC) in their respective temporal period showed a median of OS 13.5, 14.6, and 17.1 mo in the PBC, ICI, and ADC eras, respectively, with a trend toward significance for the PBC vs ADC eras comparison (p = 0.006). Conclusions: OS in mUC has significantly improved over the past 3 decades, with the greatest gains observed in the ADC era during which an over 7.5 month improvement in median OS was observed (vs PBC era). Notably, improvements were seen even among many pts not receiving era-specific systemic therapies, suggesting that advances in diagnostics, staging, supportive care, and healthcare delivery —should be considered when interpreting real-world survival gains.