Browse Articles

The terminal heme synthetic enzyme, coproheme decarboxylase, negatively regulates heme uptake in Mycobacterium tuberculosis

Real-world time to next treatment in metastatic urothelial cancer patients: Enfortumab vedotin and pembrolizumab vs chemotherapy as first-line treatment.

707 Background: Since 2023, the combination of enfortumab vedotin and pembrolizumab (EV+P) has become a first-line (1L) non-chemotherapy (chemo) standard-of-care option for metastatic urothelial carcinoma (mUC). However, real-world (RW) data on clinical outcomes for EV+P remain limited. We evaluated RW clinical outcomes among patients (pts) with mUC treated with either EV+P or chemo in US community oncology practices in the 1L setting, as well as second-line (2L) utilization patterns of EV+P and chemo. Methods: We used the deidentified Integra PrecisionQ database to identify mUC patients initiating 1L EV+P or chemo after December 1, 2023. Index date was defined as the start of 1L therapy. Baseline pt characteristics collected include age at index date, sex, race, payer, ECOG performance status, and metastatic type (de novo metastatic disease vs. recurrent). Time to discontinuation (TTD) was defined as the time from the index date to 1L discontinuation or death. Time to next treatment (TTNT) was defined as the time from the index date to the date of any subsequent systemic treatment (2L) or death. Multivariable Cox proportional hazards regression modeling was performed to evaluate the association between treatment type and TTNT, adjusting for covariates. Adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) are presented. The distribution of 2L regimens was assessed for pts who initiated 2L therapy. Results: A total of 535 pts met study eligibility, of whom 406 (76%; median age [IQR]: 74 yr [67,81]) received EV+P as 1L therapy, and 129 received chemo (24%; median age [IQR]: 72 yr [65,79]). Overall, 91% of the cohort presented with de novo metastatic disease. The median follow-up for the study cohort was 4.7 mo (range: 0.03-18.9), during which 157/535 pts had died (EV+P: 117/406; chemo: 40/129). The table summarizes TTD and TTNT results. Of the 535 pts, 90 initiated 2L during the follow-up period, with most pts (32/46) who received 1L EV+P initiating chemo in the 2L setting. More than half of pts (24/44) who received 1L chemo received 2L EV+P. Conclusions: The adoption of EV+P as 1L therapy for mUC has been rapid since 2023 in US community oncology practices. Use of EV+P use was observed to be associated with longer time to 1L TTD and TTNT. Among pts who initiated 2L, EV+P treatment crossover between regimens is common. Median Time to Event (95% CI), mo Chemo (n=129) EV+P (n=406) logrank P value aHR for EV+P vs. chemo (95% CI) P value TTD 2.3 (1.9, 2.9) 5.9 (5, 7.5) <0.001 0.41 (0.31, 0.54) <0.001 TTNT 6.6 (3.3, 10.8) 9.7 (8.4, 10.6) 0.038 0.74 (0.55, 1.00) 0.051

Comprehensive analysis of androgen production, uptake, and conversion (APUC) genes to highlight SRD5 family diversity in a large localized prostate cancer cohort.

382 Background: Androgen receptor signaling drives prostate cancer (PC) progression, and genes involved in androgen production, uptake, and conversion (APUC) are key therapeutic targets. We previously defined a 6-APUC gene set ( HSD3B1, HSD3B2, CYP3A43, CYP11A1, CYP11B1, and CYP17A1 ), that identified metastatic PC with favorable prognosis and predict docetaxel benefit. However, the expression landscape and clinical relevance of APUC genes have not been interrogated in localized PC. Methods: We analyzed the expression of 21 APUC genes in 55,329 radical prostatectomy tumor samples that underwent Decipher prostate genomic classifier (GC) testing (Veracyte Inc) between 2016-2024. Baseline clinical/pathologic factors were retrieved from Decipher GRID database (NCT02609269). Associations between gene expression quartiles with PathoGenomic Risk Factors (PGRF) including Very High Decipher score >0.85 (VHD), Grade Group (GG) 4-5, LNI and SVI were examined. Associations with distant metastatic (DM) outcomes and metastasis free survival (MFS) were evaluated using logistic regression in Mayo545 and Cox regression in Meta855 RP cohorts, respectively. Results: High expression of SRD5A2 was associated with favorable PGRF (lower odds ratio (OR), p<0.0001), lower rate of development of DM (OR 0.36, p<0.05), and longer MFS (Hazard ratio (HR) 0.51, p<0.05). HSD17B6 showed similar results for PGRF (lower OR, p<0.0001), DM (OR 0.58, p<0.05) and longer MFS (HR 0.39, p<0.05) despite being associated with GG4-5 and SVI+ in samples with VHD. In contrast, high expression of SRD5A3 and HSD17B10 had high OR for PGRFs (p<0.0001). High expression of SLCO2B1 , an androgen uptake gene, had the strongest association with GG4-5 and SVI/LNI (p<0.001 for both). We noted that SRD5A2 lacked correlation with SRD5A1 and SRD5A3 , which instead correlated with each other. Compared to all APUC genes, SRD5A2 had limited correlations with almost all APUC genes, including ones that exhibited robust cross correlation with each other . Similar to our prior finding, most APUC genes demonstrated negative correlation with AR expression and AR activity signatures. Key outcomes were validated based on transcriptomic data from 492 samples from TCGA database. Conclusions: Comprehensive analysis of 21 APUC genes in over 55,000 PC identified distinct, context-dependent associations with metastatic outcomes and clinical and molecular risk factors. Notably, high SRD5A2 expression was associated with lower odds of high-risk features and metastatic outcomes, whereas SRD5A1 and SRD5A3 linked to adverse outcomes, suggesting critical yet divergent roles among 5-alpha-reductase family members. These findings underscoring androgen-metabolic heterogeneity and highlighting SRD5A2 as a potential biomarker of indolent biology in localized prostate cancer.

<i>VHL</i> wild-type clinically advanced clear cell renal cell carcinoma (ccRCC): A genomic landscape study.

533 Background: The most common alteration in both early and late stage ccRCC is of the von-Hippel Lindau ( VHL ) gene, which occurs in approximately 75% of cases. Here, we sought to identify differences in the genomic landscape between VHL mutated ( VHL mut) and VHL wild-type ( VHL wt) ccRCC to generate hypotheses for future targets and biomarkers. Methods: 2,137 cases of loco-regional or metastatic clinically advanced ccRCC underwent hybrid capture based comprehensive genomic profiling (CGP) using the FoundationOneCDx assay to identify all classes of genomic alterations (GA). Microsatellite instability status (MSI) and tumor mutation burden (TMB) were determined from the sequencing data. PD-L1 expression was determined by IHC using the Dako TPS score (0% = negative; 1-49% = low positive and ≥50% = high positive). All cases had relapsed either loco-regionally or with metastatic disease at the time of sequencing. Results: 1545 (72.3%) ccRCC cases were VHL mut and 592 (27.7%) were VHL wt. When comparing VHL wt vs VHL mut ccRCC, patients were more frequently of female gender (31.4% vs 26.0%; p = 0.013) and featured a similar age distribution (mean 61.3 vs 61.6 yr). When compared for biomarkers associated with potential immunotherapy response, results were overall similar: MSI-High status was extremely rare (0.0% vs &lt; 0.1%) while median TMB was low (2.6 vs 3.2 mutations/Mb). TMB &gt; 10 mutations/Mb was low in both groups but slightly higher in VHL mut (0.8% vs 2.3%; p = 0.022). Low positive PD-L1 expression status was relatively similar (29.6% vs 23.7%; not significant (NS)). The frequencies of GA in non- VHL tumor suppressor genes were similar for PBRM1 (35.3% vs 37.7%; NS), SETD2 (22.5% vs 24.9%; NS) and TP53 (15.4% vs 17.6%; NS), but there was a higher frequency of GA in BAP1 in the VHL mut group (14.4% vs 20.6%; p = 0.0008). GA in cell cycle regulatory genes were also more frequent in the VH Lmut ccRCC, including CDKN2A (16.4% vs 23.8%; p = 0.0002) and CDKN2B (12.5% vs 17.6%; p = 0.004). MTAP GA were similar (9.1% vs 10.2%; NS). GA in MTOR pathway genes including PTEN (10.0% vs 11.1%), PIK3CA (4.2% vs 4.9%), TSC1 (5.6% vs 6.7%), MTOR (5.6% vs 5.1%) and NF2 (6.3% vs 4.8%) were not significantly different between groups. Conclusions: Clinically advanced VHL wt ccRCC differ to some degree in their genomic landscape from VHL mut ccRCC. This may have implications for clinical trial design and future drug development. For example, the differences seen in frequency of CDKN2A/B alterations could impact combination strategies with cyclin dependent kinase 4/6 (CDK4/6) inhibitors that are currently being explored. Limitations include the retrospective nature, possible selection bias and lack of clinical data annotation. VHL mut ccRCC(1545 cases) VHL wt ccRCC(592 cases) p value PBRM1 37.7% 35.3% NS SETD2 24.9% 22.5% NS BAP1 20.6% 14.4% 0.0008 CDKN2A 23.8% 16.4% 0.0002 CDKN2B 17.6% 12.5% 0.004 MTAP 10.2% 9.1% NS PTEN 11.1% 10.0% NS TSC1 6.7% 5.6% NS NF2 4.8% 6.3% NS

Development of a putative liquid biopsy gene panel for predicting liver metastasis in castration-resistant prostate cancer.

226 Background: Liver metastases (LM) in prostate cancer (PCa) while considered rare, are associated with poor clinical outcomes. At autopsy, LM are present in 25% of PCa patients. However, they are rarely detected until late in the disease, as they are often asymptomatic until well-established. Understanding their biological drivers may inform treatment stoppages and could lead to better detection by means such as liquid biopsy. A meaningful panel of genes with altered expression in LM is needed to address these unmet and urgent needs. Methods: To develop a putative gene expression-based panel we acquired 17 samples of single cell RNA seq from primary PCa tumors and distal metastases from PCa from GSE210358 and GSE264573, including 5 from LMs. After quality control and cell type determination via Seurat, epithelial tumor cells were isolated. Using FindMarkers, gene expression was compared in cancer cells from LMs to all other metastatic sites. Significantly differentially expressed (DE, adjusted p-val &lt; 0.05 and log2 fold change &gt;1 or &lt;-1) genes were filtered by keeping only those with a gene encoding surface protein (GESP) score 5 in The Cancer Surfacesome Atlas (TCSA) and that are found in extracellular vesicles (EVs) in either Vesiclepedia or Exocarta. Genes that passed these criteria were queried on enrichR to determine controlling transcription factors (TFs), queried with the terms “liver metastasis” and “prostate cancer” on NCBI’s search API, and validated by their expression on the Human protein atlas (HPA) IHC staining on tissue microarrays in PCa. Results: Comparing LM to all other metastatic sites, 677 DE genes were found. Of these, 69 upregulated genes were confirmed surface proteins in TCSA and found in EVs in Vesiclepedia or Exocarta, and 45 of these were confirmed present in PCa, pancreatic, or colon cancer from the HPA. REST and SUZ12 were the dominant TFs controlling these genes. Twelve genes were found in conjunction with the term “liver metastasis” and 32 with the term “prostate cancer” more than once in NCBI-listed publications, with MET, KIT, and MUC1 being found in 211, 142, and 25 publications with “liver metastasis” and 2633, 805, and 111 publications with “prostate cancer” respectively. Additionally, two genes (DLL3 and GPC3) have been confirmed in plasma samples from PCa with LM via click chemistry mediated PCR. In total, 13 genes (ENO1, MUC1, ASPH, MET, PLXND1, ITGB6, CA9, KIT, DLL3, TGFA, SPHK1, LGR5, and GPC3) either meet all our criteria for being a putative liquid biopsy marker for LM in PCa, or have been confirmed in plasma samples from PCa with LM. Conclusions: Using this unique approach we have identified a candidate gene signature for detection of LM in advanced PCa using platforms such as EV-based liquid biopsy. Further studies are underway to confirm the utility these genes using biobanked plasma samples.

Spin‐Selective Anti‐Perovskite Enables Breakthrough Nitrate‐to‐Ammonia Electrocatalysis

ABSTRACT Electrochemical nitrate reduction to ammonia offers environmental and energy benefits, but progress is hindered by sluggish multistep proton‐coupled electron transfers and competing side reactions. Here, we introduce an antiperovskite CuNCo 3 catalyst featuring a 3 d –3 d interaction framework. This framework stabilizes spin‐selective Co sites even upon surface Co‐N bond cleavage and drives asymmetric nitrate consumption. CuNCo 3 achieves 100% Faradaic efficiency and an NH 3 production rate of 124.6 mg mg cat −1  h −1 at −0.4 V vs. RHE. Operando XAS, XES, and ATR‐FTIR directly link the evolution of spin‐selective Co sites with specific NO 3 RR intermediates, revealing that spin‐selective Co sites lower hydrogenation barriers and accelerate key steps. These results demonstrate that spin‐selective anti‐perovskite frameworks provide a robust, earth‐abundant platform for high‐performance nitrate‐to‐ammonia electrocatalysts.

Multifunctional Hydrogel Interfaces: Reshaping the Future of Flexible Electronics

ABSTRACT Flexible electronics is undergoing a transition from single‐function devices to intelligent systems capable of multimodal perception and closed‐loop operation. Multifunctional hydrogels have emerged as a core platform for next‐generation electronics, owing to their structural tailorability, biomimetic compatibility, dynamic responsiveness, and exceptional interfacial properties. This review outlines a cross‐scale design pathway of hydrogel electronics spanning molecular strategies and microstructural architectures to macroscopic functionalities (mechano‐electro‐thermo‐chemical responses) and system‐level integration. We critically survey recent advancements in hydrogel‐based applications, including wearable health monitoring, electronic skin, soft robotics, and self‐powered devices, highlighting their unique advantages in high‐fidelity signal acquisition, autonomous energy management, and long‐term stability under complex conditions. Furthermore, we explore how AI‐driven inverse design, digital twins, and in situ characterization are accelerating the shift from empirical to model‐driven development of hydrogel electronics. A performance evaluation framework based on the “energy–signal coupling coefficient” is introduced, combining with green design principles promoting circular sustainability. Finally, we outline future challenges and opportunities to achieve extreme environmental adaptability and promote standardization and scalable manufacturing. Interdisciplinary integration and AI‐assisted multimodal data analytics will ultimately advance hydrogel electronics from functional devices to fully intelligent bio‐integrated systems.

Submicron Structure Confined Polymers for High‐Performance Intrinsically Stretchable Light‐Emitting Diodes

Abstract Stretchable polymer light‐emitting diodes (PLEDs) hold promises for skin‐like wearable displays, yet simultaneously achieving high stretchability, efficient luminescence performance, and facile integration remains challenging. Here, a novel strategy introducing microcrystalline elastomer into light‐emitting polymer matrices to fabricate intrinsically stretchable PLEDs that meet all these characteristics is presented. This approach enables the formation of submicron optical self‐gain structures in light‐emitting polymers and the structures confine polymers to form a nanofiber morphology through spatial nanoconfinement effects, which improves polymer crystallinity, facilitates carrier transport, and enhances light outcoupling efficiency through increased reflection and scattering. Leveraging these characteristics, the intrinsically stretchable PLEDs achieved a current efficiency (CE) of 13.70 cd A −1 , an external quantum efficiency (EQE) of 4.70%, a low turn‐on voltage of 3.70 V and a luminance of 32 013 cd m − 2 at 9 V. Additionally, 12 × 12 intrinsically stretchable PLED arrays are fabricated by electrohydrodynamic printing, which exhibit excellent photoelectric stability under tensile and bending strain. This approach holds significant potential for high‐performance stretchable and wearable displays.

The SETD2 L1609P mutation found in leukemia disrupts methyltransferase activity and reduces histone H3K36 trimethylation

Integrating genomic prognostic and hallmark signatures from Decipher GRID to predict adverse outcomes in men on active surveillance for prostate cancer.

402 Background: Active surveillance (AS) has been accepted as the standard management for lower-risk prostate cancer (PCa) by major clinical guidelines. Genomic tools such as Decipher (Veracyte) have improved risk stratification and clinical decision-making in PCa, though their optimal role in AS is still under investigation. Decipher GRID, a proprietary platform including validated prognostic signatures, hallmark pathway scores, and other expression signatures, represents a potential resource for refining risk assessment in AS. Methods: The Urologic Outcomes Database (UODB) at the University of California San Francisco (UCSF) was queried for men on AS with ≥2 biopsies with Decipher testing performed on biopsy tissue. Outcomes were any upgrade (any increase in Gleason Grade Group, GG), major upgrade (upgrade to ≥GG3), and development of unfavorable histology (expansile, or large, cribriform or intraductal carcinoma). An average genomic risk (AGR) score was calculated as previously described. Multivariable Cox proportional hazards regression using stepwise selection models were performed to determine associations between 18 validated prognostic gene signatures and 37 hallmark cancer pathways with risk of outcomes, adjusting for UCSF Cancer of the Prostate Risk Assessment (CAPRA) score. Results: 486 men were included. Median (IQR) follow-up for the cohort was 70 (42-104) months. On diagnostic biopsy, 378 (78%) and 108 (22%) patients had GG1 and GG2, respectively. CAPRA risk at diagnosis was low (0-2), intermediate (3-5), and high risk (6-10) in 359 (74%), 126 (26%) and 1 patients, respectively. Median (IQR) AGR was 0.25 (0.20-0.31). After adjusting for CAPRA, multivariable models demonstrated that genomic signatures Long 2014 and Yu 2007 provided independent prognostic value for both upgrade and major upgrade outcomes and demonstrated that Lapointe 2004 provided independent prognostic value for unfavorable histology outcome. After adjusting for CAPRA, hallmark signatures of PI3K/AKT/mTOR signaling and reactive oxygen species pathways also provided independent prognostic value for all outcomes. Conclusions: Our analysis uncovered multiple prognostic and hallmark gene expression signatures that prognosticated adverse AS outcomes independent of CAPRA, a well-validated risk stratification tool. These findings support further validation of these genomic signatures to enhance risk stratification and guide AS management in PCa.

Comparative real-world survival and prescription patterns of darolutamide versus apalutamide in non-metastatic hormone-resistant prostate cancer.

129 Background: Androgen receptor pathway inhibitors (ARPIs) improve metastasis-free and overall survival in men with non-metastatic hormone-resistant prostate cancer (nmHRPC). Apalutamide and darolutamide were approved by the Federal Drug Administration in 2018 and 2019, respectively, based on pivotal clinical trials showing similar efficacy. However, no head-to-head comparisons exist in real-world settings. We compared prescription patterns and survival outcomes between apalutamide and darolutamide in men with nmHRPC using the Surveillance, Epidemiology and End Results (SEER)-Medicare data. Methods: We identified men aged ≥66 years with localized or locoregional prostate cancer between 2000 and 2021 using the SEER-Medicare linked database. Eligible patients initiated apalutamide or darolutamide between January 2019 and December 2021, defined by Medicare Part D claims. The index date was the first prescription of either agent. Men with distant metastases, prior malignancies and age ≤65 were excluded. Baseline demographics and clinical characteristics were compared using chi-square and Wilcoxon rank-sum tests. Survival was assessed using Kaplan-Meier analysis with log-rank tests. Cox proportional hazards regression was used to estimate adjusted hazard ratios (HRs) for mortality. Results: Among 582 men with nmHRPC, 435 (74.7%) received apalutamide and 147 (25.3%) received darolutamide. The mean age at diagnosis was 73.8 vs 74.1 years (p=0.95). Most patients were White (84.6% vs 81.0%, p=0.21) and resided in metropolitan areas (85.0% vs 88.4%, p=0.39). Darolutamide use was more frequent in the Northeast (42.9% vs 24.6%, p&lt;0.001), while apalutamide was more common in the South (28.7% vs 15.6%, p&lt;0.001). Patients receiving darolutamide had higher-grade tumors (68.0% grade III vs 51.3%, p=0.002) and a longer median time from diagnosis to prescription (93 vs 64 months, p&lt;0.001). Kaplan-Meier curves and adjusted Cox models showed no significant difference in overall survival (HR 1.00; 95% CI 0.51–1.98; p=1.00). Age was independently associated with mortality (HR 1.05 per year; 95% CI 1.00–1.10; p=0.04). Conclusions: Apalutamide and darolutamide demonstrated comparable real-world survival outcomes in nmHRPC. Geographic and clinical factors influenced prescribing patterns, but survival did not differ between agents. Treatment choice may therefore be guided by patient comorbidities, tolerability, and clinician preference. Variable Comparison HR (95% CI) P-Value Treatment Darolutamide vs Apalutamide 1.00 (0.51,1.98) 1.00 Age at Diagnosis 1.05 (1.00, 1.10) 0.04* Race White vs Non-White 0.71 (0.28, 1.80) 0.47 Marital Status Married vs Unmarried 1.29 (0.60, 2.75) 0.51 Geographic Region -Midwest vs West 1.18 (0.34, 4.15) 0.79 -Northeast vs West 1.92 (0.92, 3.88) 0.07 -South vs West 1.01 (0.43, 2.36) 0.99

Immunological clustering from peripheral blood to define prognosis and T cell exhaustion profiles in renal cell carcinoma.

536 Background: Peripheral blood markers such as neutrophil-to-lymphocyte ratio (NLR) and CRP are established prognostic factors in renal cell carcinoma (RCC). However, their association to the tumor immune microenvironment (TME) remains unclear. We developed a novel leukocyte-based clustering system combining NLR and minor leukocyte fractions, and investigated its prognostic and immunological significance. Methods: We retrospectively analyzed 115 treatment-naive RCC patients who underwent nephrectomy or partial nephrectomy between November 2018 and July 2023 at Tokyo Women’s Medical University and Adachi Medical Center. Overall Survival (OS) and RFS (Recurrence Free Survival) were evaluated using Kaplan–Meier analysis, and hazard ratios were estimated by the Cox proportional hazards model. Resected tumor specimens were subjected to flow cytometric analysis to assess tumor-infiltrating immune cells. Patients were classified into three clusters using a novel leukocyte-based stratification: Group1 (NLR&lt;3 and monocyte + eosinophil + basophil &lt;8%), Group2 (NLR&lt;3 and monocyte + eosinophil + basophil ≥8%), and Group3 (NLR≥3).Furthermore, we applied this classification to evaluate its utility in predicting prognosis and guiding the indication of immune checkpoint inhibitors (ICI) in patients with metastatic renal cell carcinoma. Results: This classification clearly stratified outcomes. The median RFS was not reached in Groups 1 and 2, and no significant difference was observed between them, whereas Group 3 showed a significantly shorter RFS (p = 0.0009). Group 1 showed the longest OS, while Group 3 had the shortest (p = 0.0243).Furthermore, multivariate analysis suggested that the leukocyte-based cluster was an independent prognostic factor (p=0.0059).Expression of exhaustion markers was highest in Group3, including PD-1 (p=0.0280) and LAG3 (p=0.0227), suggesting an association with T cell dysfunction. Applying this system to 295 patients receiving first-line ICI-based regimens, OS and PFS (Progression Free Survival) were significantly shorter in Group3 treated with IO-IO therapy (OS: p=0.0011, PFS: p=0.0003). Conclusions: We propose a simple, non-invasive clustering system integrating NLR and minor leukocyte fractions, which reflects TME immune status, predicts prognosis in RCC, and may guide selection of ICI-based therapy. Multivariate analysis of RFS. HR (95% CI) p value Age 1.02 (0.97 – 1.08) 0.5067 Sex Male reference 0.4491 Female 0.59 (0.15 – 2.37) 0.4491 Histological Type Clear cell reference 0.3372 Others 0.34 (0.44 – 3.00) 0.3372 Pathological stage I/II reference 0.0009 III 8.78 (2.01 – 38.21) 0.0038 Peripheral blood cluster EMB low 8.28 (1.03 – 66.78) 0.0059 EMB high reference 0.0471 NLR high 7.78 (1.64 – 36.99) 0.0099

Comparative outcomes of chemoradiotherapy regimens in muscle-invasive bladder cancer: A retrospective cohort study.

738 Background: Bladder-preserving chemoradiotherapy (CRT) is an organ-sparing alternative to radical cystectomy for muscle-invasive bladder cancer (MIBC). This study compared outcomes and toxicity among three CRT regimens: weekly cisplatin, 5-fluorouracil plus mitomycin C (5-FU + MMC), and weekly low-dose gemcitabine. Methods: Patients with cT2–T4a N0-N1–N1 MIBC who underwent maximal TURBT followed by definitive CRT (median 64 Gy) were retrospectively analyzed. Primary endpoints were overall survival (OS) and disease-free survival (DFS). Analyses used Kaplan–Meier, Cox regression, and inverse probability of treatment weighting (IPTW). Results: Ninety-eight patients were included (median age 73; 79% male). Complete response occurred in 84% overall: 75% cisplatin, 84% 5-FU+MMC, 91% gemcitabine (p = 0.39). After 37 months’ follow-up, 5-year OS was 52% (p = 0.63), 3-year DFS 46% (p = 0.40). Distant relapse 50%; bladder-only 3%. Grade ≥3 toxicity 20% overall—22% cisplatin, 23% 5-FU+MMC, 13% gemcitabine (p = 0.58). Nodal disease predicted worse OS (HR 2.5, 95% CI 1.0–6.2; p = 0.04); regimen was not prognostic. IPTW confirmed results. Conclusions: Trimodality CRT achieved durable bladder preservation (~50% 5-year OS) with low local relapse. Efficacy was similar across regimens; gemcitabine showed lower toxicity. Distant relapse predominated, underscoring need for improved systemic therapy. Baseline characteristics, treatment response, survival, and toxicity by chemotherapy regimen. Parameter Cisplatin (n=32) 5-FU+MMC (n=34) Gemcitabine (n=32) p-value N1 disease (%) 28 15 10 0.01 Neoadjuvant chemotherapy (%) 28 12 15 0.10 Complete response (%) 81 85 88 0.38 3-year OS (%) 63 65 72 0.63 5-year OS (%) 50 52 55 0.62 3-year DFS (%) 44 47 48 0.40 Grade ≥3 toxicity (%) 22 21 12.5 0.25 Isolated bladder relapse (%) 3 3 3 0.95 Distant failures (%) 53 48 50 0.80 Comparative outcomes among patients treated with concurrent chemoradiotherapy (CTRT) using cisplatin-, 5-fluorouracil plus mitomycin-C (5-FU+MMC)-, or gemcitabine-based regimens. Percentages denote the proportion of patients per group. Complete response (CR) was defined radiologically and/or cystoscopically after CTRT. OS and DFS were measured from treatment start to death or recurrence. Grade ≥3 toxicity reflects clinically significant events retrospectively classified per CTCAE v5.0 where applicable. p-values were from chi-square or Fisher’s exact test; &lt;0.05 was significant.

Engineered nanobodies facilitate cryo-EM studies of small proteins

Reducing the Strain Required for Ambient‐Pressure Superconductivity in Ruddlesden‐Popper Bilayer Nickelates

ABSTRACT The discovery of high‐temperature superconductivity in pressurized bulk Ruddlesden‐Popper (RP) bilayer nickelates has prompted the conjecture that epitaxial compressive strain might mimic essential aspects of hydrostatic pressure. The realization of superconductivity in films on SrLaAlO 4 (001) (SLAO) supports this correspondence, yet it remains unclear whether the pressure–temperature phase diagram of RP bilayer nickelates can be systematically mapped (and studied at ambient pressure) as a function of epitaxial strain. To this end, experimental access near the elusive edge of the superconducting phase boundary would provide invaluable insight into the nature of the superconducting state and the ground state from which it emerges. Here we report superconducting RP bilayer nickelates grown on LaAlO 3 (001) (LAO), where the compressive strain required for ambient‐pressure superconductivity is nearly halved to −1.2%. These films exhibit a superconducting onset above 10 K and reach zero resistance at 3 K, with normal‐state transport properties differing from those of films grown on SLAO. Our comparative study shows that strain–rather than interfacial structure is the primary factor governing the superconductivity and normal‐state properties. This work offers a new opportunity to probe emergent phenomena near the superconducting phase boundary in the strain–temperature phase diagram of RP bilayer nickelates.

Bioinspired Quinone Redox Cycling Enables Highly Selective Photocatalytic Hydrogen Peroxide Production via Electron–Proton Relay

ABSTRACT Solar‐driven synthesis of hydrogen peroxide (H 2 O 2 ) is an attractive alternative to the anthraquinone process, yet its practical viability is hindered by poor selectivity and rapid charge recombination. Inspired by quinone‐mediated charge management in natural photosynthesis, we design a conjugated polymer, DB‐TABQ, embedding redox‐active benzoquinone units that drive a light‐triggered electron‐proton relay catalysis, thereby enabling selective and efficient H 2 O 2 production. Upon photoexcitation, the benzoquinone moieties undergo proton‐coupled electron transfer to form hydroquinone intermediates that store reducing equivalents as long‐lived radical reservoirs. Subsequently, these hydroquinone intermediates adsorb and activate oxygen and initiate an inner‐sphere, concerted two‐electron transfer to produce H 2 O 2 while regenerating the benzoquinone moieties. Spectroscopic characterizations and computational investigations show that this redox‐state transformation decouples light absorption from interfacial reaction, promotes directional charge separation, enhances oxygen adsorption, and enables a selective two‐electron oxygen reduction pathway, resulting in over 95% selectivity for H 2 O 2 production. Notably, DB‐TABQ achieves a solar‐to‐chemical conversion efficiency of 1.34% under simulated solar irradiation. Embedding redox relays into conjugated polymer frameworks offers a general design principle to regulate electron‐proton coupling and selectivity in solar‐to‐chemical conversion.

Acid ceramidase ASAH1 is a key regulator of epidermal ceramide levels and composition

Prognosis of patients (pts) with synchronous vs metachronous metastatic or locally advanced urothelial carcinoma (la/mUC).

695 Background: There is relatively limited data regarding the prognostic role of the presence of synchronous metastasis or de novo locally advanced (unresectable) tumor in pts with UC. Ιn this retrospective study, we examined the prognosis of pts with synchronous vs metachronous la/mUC (prior localized tumor) in a real-world cohort. We hypothesized that pts with synchronous la/mUC would have worse prognosis. Methods: We included pts from 26 centers in US and Europe treated with anti-PD(L)1 immune checkpoint inhibitors (ICI) in any therapy setting. We calculated overall survival (OS) from the time of initial diagnosis for pts with synchronous la/mUC, and from the time of diagnosis of advanced disease for pts with metachronous la/mUC, until death using Kaplan-Meier method. Pts with diagnosis of la/mUC ≤12 weeks from the initial UC diagnosis and without receiving any interim treatment, were assigned to the synchronous la/mUC group. We also calculated OS, progression-free survival (PFS) from 1st line (1L) Immune Checkpoint Inhibitor (ICI) start until progression or death for PFS, and until death for OS, as well as overall response rate (ORR) in pts with synchronous vs metachronous la/mUC receiving 1L ICI treatment. Multivariable (MVA) models were adjusted using the Khaki risk factors (ECOG PS ≥2, albumin &lt; 3.5 g/dL, neutrophil/lymphocyte ratio &gt; 5, presence of liver metastases). Results: We identified 1537 pts with la/mUC with median age of UC diagnosis 69 years (75% men, 81% White, 20% upper tract primary tumor, 71% pure UC, 40% visceral metastasis (liver/lungs), 75% ECOG PS 0-1, prior platinum-based chemotherapy [19% as neoadjuvant, 46% as 1L metastatic]). Median follow up from time of initial UC diagnosis was 42 months (mo); 511 pts had synchronous la/mUC and 1026 had prior localized tumor. Median ΟS was 22 (95%CI 20-25) mo with synchronous la/mUC vs 25 (95%CI 23-28) mo with metachronous la/mUC (HR 1.18, 95%CI 1.0-1.4, p = 0.045). OS, PFS and ORR MVA analyses with 1st line ICI monotherapy are shown in Table. Conclusions: We found that synchronous la/mUC was associated with worse prognosis vs metachronous la/mUC, but further validation is needed. Limitations include retrospective design, lack of randomization, selection and confounding biases, while 1L therapy did not include enfortumab/pembrolizumab combination. Our hypothesis-generating data could inform prognostic estimates and stratification factors for clinical trials. N mOS, mo(95%CI) HR([95%CI], p) N PFS, mo(95% CI) HR([95%CI], p) N ORR %([95%Cl]) OR(95%CI, p) 1L ICI Synchronous la/mUC 200 15 (10-20) 1.06 ([0.8-1.4], 0.64) 154 4 (2-6) 0.87 ([0.67-1.1], 0.29) 189 32% (25-38) 1.2 ([0.8-1.08], 0.39) Metachronous la/mUC 560 18 (15-21) ref 439 4 (3-5) ref 541 30% (26-34) ref

Quality of life, adherence, and adverse events among patients with advanced prostate cancer treated with relugolix: 6-month results of the OPTYX multicenter registry.

122 Background: Relugolix is the only oral androgen deprivation therapy FDA approved for advanced prostate cancer (PC), based on the phase 3 randomized HERO trial. Data on quality of life (QoL), adherence, and safety in real-world clinical practice are needed. Methods: OPTYX is a prospective multicenter observational study (NCT05467176) of US patients with PC initiating treatment with relugolix ≤1 month before enrollment; androgen receptor pathway inhibitors could be added or withdrawn at physician’s discretion. Patients with an intended treatment plan of &lt;4 months of relugolix were excluded. We report 6-month data on QoL (Functional Assessment of Cancer Therapy – Prostate [FACT-P]), adherence (Simplified Medication Adherence Questionnaire [SMAQ]), and adverse events (AEs). Results: As of March 7, 2025, 999 patients were enrolled in OPTYX median age was 71 years. A total of 364, 772, and 628 patients had FACT-P data assessed at baseline, 3 months, and 6 months, respectively. FACT-P total mean (SD) score was 120.0 (20.3) at baseline, and was maintained at 3 and 6 months (119.1 [20.5] and 120.2 [20.0], respectively). FACT-P subscale scores were also stable over 6 months (Table). Using the SMAQ, the percentage of patients taking relugolix at the appropriate time of day was 95.8%, and the percentage of patients who reported discontinuing relugolix when feeling bad was 4.0% at 6 months (n=618). At 6 months, 83.1% (513/617) reported never forgetting to take relugolix. Of 16.9% who reported forgetting to take relugolix at least once, a mean of 1.3 days of missed relugolix occurred over the past 3 months. Serious AEs were uncommon and occurred in 39 (3.9%) patients; the most common (&gt;2 patients) were anemia (0.4%) and acute myocardial infarction (0.3%). AEs led to treatment discontinuation in 6.2% of patients; 2 deaths were reported (0.2%). Conclusions: Real-world utilization of relugolix was associated with stable QoL, high treatment adherence, and a low rate of serious AEs over the first 6 months. Patients will continue to be followed for a longer-term analysis in this ongoing study. Clinical trial information: NCT05467176 . Assessment Baseline 3 mo 6 mo FACT-P total score  Mean (SD) 120.0 (20.34) 119.1 (20.54) 120.2 (19.95)  Median (range) 122.8 (39-156) 112.9 (44-154) 124.0 (41-156) FACT-P physical well-being  Mean (SD) 24.4 (3.99) 22.8 (4.57) 22.9 (4.25)  Median (range) 26.0 (7-28) 24.0 (3-28) 24.0 (3-28) FACT-P social/family well-being  Mean (SD) 22.7 (4.88) 22.3 (5.03) 22.6 (4.68)  Median (range) 24.0 (4-28) 24.0 (0-28) 24.0 (0-28) FACT-P emotional well-being  Mean (SD) 18.8 (4.03) 20.1 (3.70) 20.2 (3.77)  Median (range) 20.0 (0-24) 21.0 (4-24) 21.0 (0-24) FACT-P functional well-being  Mean (SD) 20.8 (6.19) 20.7 (5.84) 20.9 (5.72)  Median (range) 22.0 (4-28) 22.0 (2-28) 22.0 (0-28) FACT-P prostate cancer subscale  Mean (SD) 33.3 (7.84) 33.2 (7.48) 33.5 (7.28)  Median (range) 34.0 (3-48) 34.0 (4-48) 34.0 (7-48)

Surveillance of patients with complete response following first-line chemotherapy for germ cell tumors: Focus on lifestyle, socioeconomic, and sexual health outcomes.

608 Background: Advances in multimodal therapy have transformed germ cell tumors (GCTs) into a highly curable malignancy, creating a growing population of long-term survivors. This shift demands that surveillance evolve beyond disease monitoring to address broader survivorship challenges. Social reintegration, employment, marital status, and sexual function profoundly influence quality of life but remain under-explored in GCT follow-up care. Understanding these domains is essential for developing comprehensive survivorship strategies. Our study evaluates long-term social, lifestyle, and sexual health outcomes among GCT survivors who achieved complete response (CR) after first-line chemotherapy, and to identify key challenges revealed through surveillance follow-up. Methods: A cross-sectional study was conducted in 66 GCT patients treated between 2010 and 2019 who achieved CR and were followed under standard surveillance protocols. Progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan–Meier methods. Structured interviews and validated questionnaires, including the International Index of Erectile Function-5 (IIEF-5), evaluated lifestyle behaviors, socioeconomic outcomes, and sexual function. Results: Among 66 patients, after a median follow-up of 14.43 years, the mean age at diagnosis was 20.2 years (range 7–52). Primary sites were testis (21%), extragonadal mediastinal/retroperitoneal (16%), and central nervous system (62%). IGCCCG risk classification was favorable in 15.2%, intermediate in 60.6%, and poor in 24.2%. All patients received chemotherapy, and 65% also received radiotherapy. Disease recurrence occurred in 15.1%. The 5- and 10-year disease-free survival rates were 89.4% and 85.5%, respectively, with overall survival of 100%. One patient developed secondary papillary thyroid carcinoma. Overweight and obesity increased from 16.4% at diagnosis to 38.8%. Smoking and alcohol use were reported by 16.6% and 10.6%, respectively. Social outcomes revealed persistent challenges: 25.8% were unemployed, 93.9% remained unmarried, and only 1.53% had children. Sexual function assessment showed 73% had no dysfunction, 23% mild, and one mild-to-moderate dysfunction. Conclusions: Surveillance of GCT survivors reveals that while long-term survival is excellent, significant social and sexual health challenges persist, including high rates of unemployment, low rates of marriage and parenthood, and erectile dysfunction. These findings underscore the need to expand surveillance beyond oncologic endpoints to include targeted interventions for social reintegration, sexual health, and quality-of-life support in survivorship care. Clinical trial information: COA. MURA2024/516.