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Activated protein C drives β-arrestin-2- and c-Src-dependent phosphorylation of Cav1 and modulates Cav1 association with PAR1 and GRK5

Real-world data of enfortumab vedotin in patients with advanced urothelial cancer in Spain: The ENFANTS-GUARD study.

700 Background: Urothelial cancer (UC) is the fifth most common cancer in Spain. Advanced UC (aUC) is an aggressive disease with a high mortality rate. Enfortumab vedotin (EV) has been recently approved in Spain for the treatment of adult patients (pts) with aUC, although real-world data remain limited. We aim to describe clinical characteristics, treatment, outcomes and safety of EV treatment in routine practice. Methods: This retrospective observational study included pts with aUC who received EV across 17 hospitals in Spain. Demographic, clinical, treatment-related (efficacy and safety) and healthcare resource utilization data were collected. Progression-free survival (PFS), overall survival (OS) and time to treatment failure (TTF) were measured from EV initiation. Survival was estimated using the Kaplan–Meier method. Investigator-assessed observed response rate (ORR) was assessed for evaluable pts with scans after ≥1 cycle EV. Adverse events (AEs) were recorded and graded by CTCAE 5.0. Hospital admissions during EV treatment were collected. Results: A total of 195 pts were included. Median age was 71 years, 76.9% were male. 49.7% had localized disease at diagnosis with a median time to metastasic progression of 17.9 months. The primary tumor site was bladder in 82.1%, and upper urinary tract in 15.9%. 76.3% had pure urothelial, 22.2% variant differentiation and 3 (1.5%) non-urothelial carcinoma. ECOG PS was 0,1 and ≥2 in 25.1%, 63.6% and 11.3% pts, respectively. Patients received a median of 2 prior lines of systemic treatment. The most common immediate prior treatments were PD-1/L1 inhibitor monotherapy (41.0%) and chemotherapy (13.9%), while 27.7% received these in combination or as maintenance. Median follow-up was 34.4 months. Median PFS, OS and TTF were 7.4 [5.87-8.89], 12.8 [11.2-14.3] and 6.2 [5.54-7.97] months, respectively. ORR was 52.1%. EV related AEs occurred in 68.7% of pts, with ≥ grade 3 in 20.9%. Peripheral sensory neuropathy and rash were the most frequent AEs. 29.7% pts required hospitalization during EV treatment, with a median stay of 7 days. Baseline characteristics are summarized in Table 1. Conclusions: In this multicenter cohort, EV demonstrated efficacy and safety consistent with clinical trials, supporting its role as a standard option for previously treated patients with aUC. Despite the overall clinical burden, EV achieved meaningful disease control with favorable ORR and TTF outcomes in routine practice. Baseline characteristics. Characteristics (n) Results [n(%)] Current/former Smokers (195) 32(16.4%) Bellmunt risk (195) = 0 = 1 = 2 = 3 32 (20.3%)82 (51.9%)38 (24.1%)6 (3.8%) Liver metastasis (%) (195) 43 (22.0%) Exclusive lymph node involvement (192) 38 (19.8%) FGFR2/3 mutation (64) 12(18.8%) Pts with prior response to platinum chemotherapy (194) 100 (51.5%) Pts with prior response to immunotherapy (193) 7 (3.6%)

Predictive value of a pathomics signature in <i>de novo</i> metastatic prostate cancer: An ancillary study of the PEACE-1 phase 3 trial.

221 Background: The addition of abiraterone acetate plus prednisone (AAP) to docetaxel and androgen deprivation therapy (ADT) has become a standard of care for metastatic castration-sensitive prostate cancer (mCSPC) following the PEACE-1 trial. This ancillary study aimed to identify pathomics-based predictive biomarkers associated with radiographic progression-free Survival (rPFS) and overall survival (OS) to guide therapeutic decision-making. Methods: Hematoxylin-Eeosin-Safran (HES) slides were digitized using an Olympus VS120 scanner at a 20x magnification. A multiple-instance learning framework was applied integrating patch-level treatment attention with tissue composition inferred from HoVer-Net segmentation to generate a composite pathomic treatment-benefit score. Patients were stratified into high- and low-score groups using the median value. Cox proportional hazards models adjusted for age, ECOG performance status, disease burden, Gleason score, type of castration, and other treatment received (radiotherapy, docetaxel) assessed prognostic and predictive associations. Interaction tests evaluated whether the pathomic score predicted AAP benefit. Results: Among the 1172 patients (pts) randomized in PEACE-1 (NCT01957436), 595 had available FFPE tumor samples and 526 HES slides were analyzable by pathomics after central review. Baseline characteristics were comparable between the full and pathomics cohorts. In patients with low AAP-benefit scores (n=263), the addition of AAP to standard of care (SOC) did not significantly improve rPFS or OS (HR = 0.80; 95% CI 0.59–1.07; p = 0.14 and HR = 1.00; 95% CI 0.72–1.40; p = 0.98, respectively). Conversely, patients with high AAP-benefit scores (n=263) derived substantial benefit from AAP (rPFS: HR = 0.38; 95% CI 0.28–0.51; p &lt; 0.001; OS: HR = 0.48; 95% CI 0.34–0.67; p &lt; 0.001). Interaction tests confirmed the predictive effect of the pathomic signature for both rPFS (p &lt; 0.001) and OS (p = 0.001). In term of model performance, the area under the curve (AUC) for interaction between AAP and the two score groups to predict rPFS and OS were AUC 0.712 and AUC 0.722 respectively. Pts with low AAP-benefit scores displayed lower ki67 log score in IHC (p=0.013), higher mean AR z-score in transcriptomics (p=0.033), more non-neoplastic cells (p&lt;0.001), fewer neoplastic cells (p=0.004) and less necrosis (p&lt;0.001). No additional predictive biomarker was identified across (IHC), genomic or transcriptomic analyses. Conclusions: This study identified a pathomics-derived histological signature predictive of benefit from AAP in patients with de novo mCSPC treated with ADT ± docetaxel. External validation is warranted to confirm these findings and evaluate its potential for clinical implementation in precision treatment selection.

A two stage optimization model for sustainable location routing problem with capacity and time window constraints in smart parcel lockers

Abstract The rapid expansion of e-commerce has significantly increased the demand for sustainable delivery methods to mitigate urban congestion, emissions, and rising logistical costs. Addressing the challenges of last-mile delivery requires logistics providers to respond to operational demands and market dynamics with both urgency and efficiency. Smart parcel lockers, as a known solution, reduce the negative externalities of urban transportation while improving delivery performance. This research introduces a sustainable location-routing model for smart parcel lockers using a two-stage optimization approach. The model aims to minimize operational costs, fuel consumption, and CO₂ emissions while ensuring customer demand is met. Exact solution techniques are applied, and multiple scenarios are evaluated through extensive sensitivity analysis. The model is validated using a real-world case study in Tehran, Iran. In addition, metaheuristic algorithms, such as the Keshtel, Genetic, and Simulated Annealing methods, were benchmarked to evaluate model performance under varying problem scales, with the Keshtel algorithm showing superior scalability and runtime efficiency in large instances. Findings indicate that optimally positioned lockers combined with efficient routing can lead to substantial reductions in both transportation costs and environmental impacts. Practical implications for logistics managers include the integration of electric vehicles and renewable-powered lockers to further advance sustainability goals.

Multi-omics profiling of residual cancer burden after neoadjuvant hormonal therapy guides subtype-directed treatment in high-risk and locally advanced prostate cancer.

245 Background: Residual cancer burden (RCB) in patients failing to achieve pathological complete response (non-pCR) after neoadjuvant hormonal therapy (NHT) are a major cause of recurrence for high-risk localized and locally advanced prostate cancer (HRLPC). This study aimed to identify molecular subtypes of residual cancer and develop a precision framework to guide treatment of HRLPC. Methods: We performed integrated genomic, transcriptomic, proteomic, and N-glycoproteomic profiling of residual cancers from 138 HRLPC cases treated 3-6 months of ADT+ARPIs NHT. A molecular ssGSEA classification model was developed and translated into a clinically applicable immunohistochemistry (IHC)-based stratification scheme. Patient-derived organoids (PDOs) representing each molecular subtype were established and characterized, followed by drug sensitivity assays to validate potential therapeutic targets. Results: Three subtypes were characterized: C1 (AR and MYC signaling activation, poorest prognosis), C2 (upregulation of JAK-STAT pathway and high sialylation), and C3 (intermediate). A proteomic molecular classification model based on ssGSEA was constructed. Key biomarkers (CANT1, MRE11 for C1; CD8A, GSDME for C2) were identified, and developed an IHC-based classification strategy. The consistency between the ssGSEA and IHC model was validated (retrospective: Cohen’s Kappa = 0.719; prospective: Cohen’s Kappa = 0.747). PDOs representing C1–C3 subtypes were established for target prediction and drug validation, revealing the therapeutic potential of BETi for C1 and JAKi for C2. Conclusions: This study comprehensively elucidated the molecular characteristics of RCB in HRLPC after NHT, established a clinically translatable classification system, and proposed subtype-guided precision therapeutic strategies.

Toward Energy Efficient Electrochemical Valorization of Waste Nitrate and Sulfide

ABSTRACT With the continuously decreasing levelized cost of renewable electricity, electrocatalytic waste treatment and valorizations have attracted increasing attention as sustainable routes for converting waste molecules into valuable chemicals. Here, we report an energy‐efficient strategy that couples nitrate‐reduction (NO 3 R) with sulfide‐oxidation reaction (SOR) to simultaneously remediate pollutants and produce value‐added chemicals. By utilizing a dual‐catalyst composite in which cobalt polyphthalocyanine (CoPc) and copper polyphthalocyanine (CuPc) are co‐anchored on carbon nanotubes, we achieve enhanced cathodic ammonia (NH 3 ) production that is well matched with efficient anodic thiosulfate formation. This paired NO 3 R‐SOR system enables the direct synthesis of ammonium thiosulfate, a valuable fertilizer feedstock, via simple mixing of the anolyte and catholyte. Kinetic analysis reveals that the improved NH 3 production originates from a relay of the * NO 2 from Cu‐ to Co‐sites, allowing both active‐sites to bypass their respective rate‐limiting steps. Based on these insights, we demonstrate an integrated NO 3 R||SOR system that substantially lowers the required cell voltage compared with conventional NO 3 R||OER (oxygen evolution reaction) systems, achieving a 64% reduction in energy consumption at 200 mA cm −2 . Preliminary techno‐economic analysis further suggests a substantial increase in energy‐normalized product value, highlighting a sustainable approach for coupled waste treatment and chemical production.

Metal Single Atoms Beyond Catalysis as Quantum Modulators for Programmable Electronic Structures and Adaptive Electronics

ABSTRACT Metal single atoms have long been recognized for their catalytic activity through strong local interactions with host substrates. Beyond catalysis, their potential to reconfigure substrate electronic structures surpassing the host's intrinsic limits remains largely unexplored. Here, we develop an atomically engineered band‐modulation strategy, in which representative d ‐series (Fe, Co, Ni, Cu) and p ‐series (In, Sn, Sb, Te) atoms are anchored on 2D frameworks, including MXenes, graphene, g‐C 3 N 4 , and MoS 2 . These atoms act as quantum modulators, precisely reconfiguring substrate structures and inducing anomalous quantum effects, which yield distinctive phenomena, including band inversion, flattening, and van Hove singularities, features rarely attainable through conventional band‐engineering strategies. The tailored electronic landscape enables linear, voltage‐driven tuning of electrical behavior, achieving several tens of times enhancement in dielectric permittivity and a dynamic and continuous transition from semiconducting to conductive states, all realized under an exceptionally low bias (&lt;1.0 V). These functionalities are extended to a flexible electromagnetic switch that achieves programmable control of signal transmission, absorption, and reflection, overcoming the persistent difficulty of dynamic electromagnetic regulation while operating at a record‐thin microscale thickness (∼600 µm). This work establishes an atomically engineered band‐modulation strategy as a versatile platform, paving the way for reconfigurable electronics and quantum devices.

Biochemical analysis of a TrkB receptor mutation that causes a developmental epileptic encephalopathy

Incidence of immune-related adverse events (irAEs) and treatment discontinuation rates (TDR) in the adjuvant and metastatic setting in patients with urological malignancies: A systemic review and meta-analysis.

716 Background: Immune checkpoint inhibitors (ICI) are the standard treatment for numerous cancer types, in both the metastatic (MET) and adjuvant (ADJ) settings. Cancer induces an immunosuppressive effect not only in the tumor but also systemically. In patients (pts) with localized cancer, the surgical removal of the tumor can potentially restore immune system function (Allen, Nat Med 2020); however, this immune system reactivation may paradoxically place these pts at higher risk for irAEs. This study aimed to compare the incidence of irAEs and TDR in ADJ and MET urological cancers. Methods: A systematic review and meta-analysis of tumors treated with ICI was conducted. Herein we analyzed anti-PD-1/PD-L1 genitourinary (GU) clinical trials (CT) published until December 2024 that reported irAEs, treatment-related AEs (TRAEs) or AEs. CT of neoadjuvant therapies, radiotherapy or combination regimens were excluded. Primary outcomes were incidence of irAEs and TDR. Data were analyzed using random-effects model and heterogeneity was assessed with I². Summary measures are presented as proportions with 95% confidence intervals. The study protocol was registered with PROSPERO (CRD42024590667). Results: We identified 209 records, of which 39 CT (6 and 33 in the ADJ and MET setting, respectively) met the inclusion criteria (8904 pts). 14 CT reported irAEs (3508 pts). The incidence of all-grade irAEs in the ADJ setting was 45.3% and 28.6% in the MET setting (p = 0.03). No differences were shown in grade 3 or higher (g3+) irAEs (9.6% vs. 8.4%). TDR due to AEs (16.5% vs. 11.4%, p = 0.008) and TRAEs (15.5% vs. 6.5%, p &lt; 0.001) was higher in the ADJ setting. The incidence of all-grade TRAEs was higher in the ADJ setting (76% vs. 69.7%, p = 0.03) but no differences were found in g3+ TRAEs (16.8% vs. 18.2%) or all-grade AEs (96.5% vs. 94.6%). g3+ AEs were higher in the MET setting (37.8% vs. 51.9%; p = 0.002). Conclusions: GU cancer pts had higher incidence of irAEs and TDR in the ADJ setting vs. MET pts, potentially due to restoration of the immune system after tumor resection. Further research is needed to explore the interplay among immune system function in cancer pts, ICI, and irAEs.

Obesity-associated epigenetic remodeling under androgen deprivation therapy: Implications for cardiometabolic risk in prostate cancer.

237 Background: Androgen deprivation therapy (ADT) is central to prostate cancer care but accelerates cardiometabolic toxicity, particularly among men with obesity. The biological basis of this differential vulnerability is unknown. We hypothesized that obesity modifies chromatin accessibility responses to ADT, reflecting distinct transcriptional programs linked to inflammation and metabolism. Methods: Matched peripheral blood mononuclear cell samples (pre- and on-ADT) from 11 men with prostate cancer were analyzed by bulk ATAC-seq. Reads were aligned to GRCh38 with Tn5 correction and ENCODE blacklist removal. Peaks were called using MACS2 and unified via DiffBind. Differential accessibility was normalized by library size ( FDR &lt; 0.05). Pathway enrichment used MSigDB Hallmark sets and GSEA. Participants were stratified by BMI &lt; 25 kg/m² (lean) or ≥ 30 kg/m² (obese). While pre vs on-ADT changes were assessed across all pairs, BMI-stratified differences showed the most distinct patterns and are presented in the results. Results: Median age was 69 years; 50% White, 42% Black; BMI 30.0 ± 7.6 kg/m² (range 21.8–51.4); 66 % had hypertension, 50 % diabetes, and 42 % baseline cardiovascular disease. Most (83 %) received combined ADT + XRT. ADT induced widespread chromatin remodeling without locus-level significance after FDR correction but demonstrated divergent pathway activation by BMI. Obese men showed up-regulation of immune-metabolic programs (TNF-α/NF-κB, IL2–STAT5, Complement, mTORC1), whereas lean men showed repression of these same modules (Table). Conclusions: This first-in-human bulk ATAC-seq study reveals BMI-dependent epigenetic remodeling during ADT. Obese men exhibit activation of immune-metabolic pathways consistent with a pro-inflammatory, cardiometabolic phenotype, while lean men show reciprocal suppression. Integrating adiposity metrics with epigenomic profiling may refine cardio-oncologic risk stratification and guide precision mitigation strategies for men receiving ADT. Differential pathway enrichment during ADT by BMI group. Pathway (Obese ≥ 30) NES / Adj p Pathway (Lean &lt; 25) NES / Adj p TNF-α via NF-κB 1.96 / 1.8×10⁻⁶ TNF-α via NF-κB –2.20 / 1.1×10⁻⁸ IL2–STAT5 signaling 1.63 / 6.8×10⁻⁴ IL2–STAT5 signaling –1.84 / 9.1×10⁻⁵ Complement 1.54 / 1.4×10⁻³ UV Response –1.70 / 0.004 Inflammatory response 1.67 / 6.8×10⁻⁴ Inflammatory response –1.65 / 0.005 KRAS Signaling 1.4 / 0.0203 KRAS signaling –1.51 / 0.035 Allograft Rejection 2.01 / 8.09 × 10⁻⁷ Allograft rejection –1.59 / 0.006 Apoptosis 1.68 / 6.84 × 10⁻⁴ Interferon-γ Response 1.44 / 0.018 mTORC1 signaling 1.33 / 0.032 Hypoxia 1.39 / 0.02 NES = normalized enrichment score; positive = activation; Negative = suppression after ADT vs pre-ADT.

Seepage characteristics of fractured sandstone under deep high-confined water and mining-induced stress

A phase II study of luxdegalutamide in combination with abiraterone in adult patients with metastatic hormone-sensitive prostate cancer (mHSPC).

TPS275 Background: Androgen deprivation therapy (ADT) remains the cornerstone of mHSPC treatment, yet patients with high-volume disease experience poorer outcomes and faster progression. Combining agents that target androgen receptor (AR) signaling at multiple steps has been demonstrated to improve overall survival (OS) among patients with mHSPC. Luxdegalutamide is a novel potent oral proteolysis-targeting chimera (PROTAC) AR degrader that has shown complementary antitumor activity when combined with abiraterone in preclinical models. In a prior phase I/II study (NCT05067140), luxdegalutamide combined with abiraterone showed promising antitumor activity with manageable safety in patients with metastatic prostate cancer and no prior AR pathway inhibitor (ARPI) exposure. This phase II, randomized, open-label, multicenter study will evaluate the efficacy and safety of luxdegalutamide at 2 doses (100 mg and 300 mg once daily [QD]) combined with abiraterone in patients with mHSPC (NCT06991556). Methods: Patients are considered eligible if they have high-volume mHSPC (visceral metastases and/or ≥4 bone lesions, with ≥1 lesion located outside the vertebral column and/or pelvis) and no prior ARPI in the metastatic setting. Using the stratified Miettinen and Nurminen method, a sample size of 150 patients randomized in a 1:1:1 ratio is considered appropriate to obtain the minimum response rates required for the lower bound of 90% confidence interval of PSA90 (proportion of patients achieving ≥90% reduction in prostate-specific antigen [PSA] from baseline) difference to exceed 0% (clinical benefit) and 10% (strong clinical benefit) between the pooled combination arm and control arm. The patients will be randomized into 3 treatment arms: Arm 1: Luxdegalutamide 100 mg QD + abiraterone 1000 mg QD. Arm 2: Luxdegalutamide 300 mg QD + abiraterone 1000 mg QD. Arm 3 (control): Abiraterone 1000 mg QD or enzalutamide 160 mg QD (Investigator’s choice). All patients will receive concomitant ADT. Randomization will be stratified by visceral metastases (yes vs no) and Gleason score at diagnosis (&lt;8 vs ≥8). The primary objectives are to (1) determine the recommended phase III dose of luxdegalutamide combined with abiraterone and (2) evaluate the efficacy, safety, and tolerability of the combination versus standard therapy. The primary efficacy endpoint is PSA90 rate. Secondary endpoints include radiographic response, PSA0 (PSA level &lt;0.2 ng/mL at any timepoint), progression-free survival, OS, and pharmacokinetics. Exploratory endpoints include assessment of biomarkers associated with treatment response and/or resistance. As of October 9, 2025, 4 patients have been enrolled. Clinical trial information: NCT06991556 .

Tip‐Induced Self‐Enhanced Concentration Gradients Catalyst for Sustainable Electrocatalytic Urea Synthesis

ABSTRACT Electrocatalytic C─N coupling via the co‐reduction of CO 2 and NO 3 − represents a promising route for sustainable urea synthesis under ambient conditions, simultaneously addressing critical challenges in energy sustainability and environmental remediation. However, its practical implementation is hindered by sluggish C─N coupling kinetics and the competing hydrogen evolution reaction (HER), which severely restricts energy conversion efficiency. Herein, we propose a tip‐induced local electric field strategy that generates a self‐enhanced concentration gradient to promote electrocatalytic C─N coupling. By constructing densely aligned Co 3 O 4 nanoneedles on carbon cloth, an outstanding electrocatalytic performance was achieved, requiring only an ultra‐low potential of −0.60 V versus reversible hydrogen electrode (RHE) while delivering a high urea yield rate of 49.63 umol h −1 cm −2 and a Faradic efficiency of 21.37%. Finite element simulations reveal that the nanoscale high‐curvature tip generates an intensified local electric field, enriching potassium ions (K + ) at the electrode‐electrolyte interface to stabilize key intermediates and direct the reaction pathway toward C─N coupling. Moreover, a series of operando spectroscopic characterizations provide direct evidence for enhanced C─N coupling process under an intensified local electric field. This work offers a generalizable strategy for energy‐efficient C─N coupling, paving the way for sustainable utilization of nitrogen and carbon resources.

Intracellular pH regulates β-catenin with low pHi increasing adhesion and signaling functions

Randomized phase II trial of maintenance oral etoposide versus observation following high-dose chemotherapy and peripheral blood stem cell transplant in relapsed non-seminomatous germ cell tumors.

TPS625 Background: High-dose chemotherapy (HDCT) followed by peripheral-blood stem-cell transplant (PBSCT) remains an effective salvage approach for patients with relapsed germ-cell tumors (GCT). When administered in the second-line setting, this strategy leads to durable remissions in roughly 60% of those with relapsed non-seminoma (NSGCT). Prior retrospective evidence suggests that maintenance therapy with oral etoposide after HDCT improves progression-free survival (PFS) and overall survival (OS). We intend to evaluate the efficacy and safety of maintenance daily oral etoposide after HDCT+PBSCT in patients with relapsed non-seminoma. Methods: This is a randomized, open-label, phase II clinical trial evaluating oral etoposide maintenance therapy after completion of HDCT and PBSCT. Eligible patients are adults with metastatic NSGCT who have experienced progression after first-line cisplatin-based chemotherapy. All participants will complete two tandem cycles of HDCT using the Indiana carboplatin/etoposide protocol. At randomization, patients must demonstrate normal or decreasing serum tumor markers (AFP and/or hCG), no evidence of radiographic progression, and recovery from treatment-related toxicities to grade ≤2. Randomization will occur within 16 weeks after the second HDCT cycle. Patients with primary mediastinal non-seminoma are eligible. Patients with relapsed pure seminoma are excluded. Participants will be randomized 1:1 to receive either maintenance oral etoposide or observation, stratified by platinum-refractory status (progression within four weeks of first-line therapy). The intervention arm will receive oral etoposide at 50 mg daily for 21 days of each 28-day cycle, for a total of three cycles. Weekly labs including CBC with differential will are planned for hematological toxicity monitoring. The primary endpoint is 12-month progression-free survival (PFS), while secondary endpoints include toxicity and 12-month overall survival (OS). Exploratory analyses will assess circulating microRNA-371 levels at screening and their association with relapse risk. As of October 10, 2025, 38 patients have been enrolled out of the planned 64. Fourteen patients declined randomization, and ten were found ineligible after screening. Accrual and follow-up are ongoing. Clinical trial information: NCT04804007 .

Efficacy of subsequent therapy in patients with metastatic renal cell carcinoma of intermediate and poor risk following first-line immuno-oncology combinations.

478 Background: In the era of immune-oncology (IO) combinations, specifically IO-IO or IO + tyrosine kinase inhibitors (TKIs), overall survival (OS) of patients (pts) with metastatic renal cell carcinoma (mRCC) of International mRCC Database Consortium (IMDC) intermediate and poor risk has significantly improved. However, disease progression makes the investigation of subsequent therapies’ efficacy challenging since no evident standard exists. Methods: This multicenter retrospective study included pts with mRCC of IMDC intermediate and poor risk who received subsequent therapy after disease progression following first-line treatment with either dual immunotherapy (ipilimumab and nivolumab) or IO-TKI since 2020. The primary endpoints were objective response rate (ORR) and progression-free survival (PFS). Results: A total of 101 pts were enrolled. The following second-line regimens included: TKIs (pazopanib, axitinib or sunitinib) as monotherapy in 37 pts (37%), lenvatinib plus everolimus in 46 pts (46%), cabozantinib in 14 pts (14%) and everolimus as monotherapy in 4 pts (3%). The median follow-up time was 27 months. The ORR with TKI monotherapy was 16%, cabozantinib – 29% and lenvatinib + everolimus – 30%, p=0,1. An objective response was observed in 19 of 62 pts (31%) who received prior IO-IO combination compared to 5 of 39 patients (13%) treated with first-line IO-TKI (p=0.04). Irrespective of the first-line therapy, median PFS was 7 months (HR 0.87, 95% CI [0.5–1.4]). In the overall cohort, median PFS was 11 months with lenvatinib plus everolimus, compared to 5 months with TKI monotherapy (HR 0.7, 95% CI [0.4–1.1]). Median time from the initiation of second-line therapy to death from any cause was longer in the IO-IO group (24 months) than in the IO-TKI group (10 months; HR 0.56, 95% CI [0.3–0.96]). However, overall survival (OS) from the start of first-line therapy did not differ significantly between groups, likely due to the longer PFS achieved with first-line immuno-targeted therapy. The 2-year OS rates were 83% and 72%, respectively (HR 0.88, 95% CI [0.58–1.34]). Conclusions: In real-world clinical practice, second-line therapy demonstrates comparable progression-free survival in patients with mRCC regardless of prior IO-IO or IO-TKI treatment. The combination of lenvatinib and everolimus showed the most promising outcomes among second-line regimens, supporting its role as a preferred option in this setting.

Investigating the factors influencing vertical stress ahead of the undercutting line in block caving

Phase 1, dose-escalation study of KTX-2001 (an NSD2 inhibitor) alone and in combination with darolutamide for metastatic castration-resistant prostate cancer.

TPS276 Background: Metastatic castration-resistant prostate cancer (mCRPC) can evolve into a neuroendocrine-like subtype with aggressive behavior and poor outcomes (1). Nuclear Receptor-Binding SET Domain Protein 2 (NSD2) is overexpressed in prostate cancer and is a driver of both androgen-receptor (AR)-dependent signaling and of neuroendocrine differentiation, where cancer cells lose AR dependence and response to AR pathway inhibitors (ARPIs) (2,3,4). In studies of patient-derived neuroendocrine prostate cancer (NEPC) models, genetic depletion of NSD2 led to restoration of AR expression, reversal of adeno-to-neuroendocrine differentiation, and re-sensitization to ARPI (4). We hypothesize that NSD2 inhibition can reverse resistance to ARPIs in patients with progressive mCRPC, including with neuroendocrine differentiation. KTX-2001 is an oral, potent and selective small molecule inhibitor of NSD2. It is the sponsor’s second NSD2 inhibitor to enter the clinic. The sponsor’s first in class NSD2 inhibitor, KTX-1001, was shown to be tolerable and have preliminary efficacy in patients with relapsed/refractory multiple myeloma (5). Methods: STRIKE-001 (NCT07103018) is a multicenter, open-label phase 1 dose escalation trial of KTX-2001 monotherapy (Part A) and KTX-2001 + darolutamide (Part B). Key inclusion criteria are males age ≥18 years with mCRPC, progression after receiving ARPI, Eastern Cooperative Oncology Group performance score of 0-1, willingness to undergo biopsy if safe and feasible, and life expectancy of ≥6 months. Participants take KTX-2001 by mouth once daily alone (Part A) or with darolutamide 600 mg twice daily (Part B). Dose escalation of KTX-2001 in Parts A and B will follow a 3+3 design and occur in parallel at multiple planned dose levels. Primary objectives are to assess the safety and tolerability, determine MTD, and determine RP2D(s) for further study of KTX-2001 alone and in combination with darolutamide. Secondary objectives include characterization of efficacy and PK parameters for both KTX-2001 monotherapy and in combination with darolutamide. Exploratory objectives include study of pharmacodynamic effects, circulating tumor cells, and cell-free DNA. 1. Conteduca V, Eur J Cancer 2019. 2. Parolia A, Nat Genet 2024. 3. Aytes A, Nat Commun 2018 4. Li J, bioRxiv 2023.07.18.549585 5. Bories P, Blood Vol 144, Suppl 1,2024. Clinical trial information: NCT07103018 .

Magnetically Controlled Delivery of Injectable Magnetoactive Adhesive Hydrogel for Vascular Repair in the Challenging Blood Environment

ABSTRACT Repairing abnormal vessels in the complex fluidic and biological environment of blood remains challenging. Current approaches, such as non‐adhesive polymeric sealants or vessel coiling, have unsatisfactory outcomes. Here, we present an injectable magnetoactive adhesive hydrogel (iMAH) for vascular repair in the challenging blood environment. Designed with biocompatible functional components, including the superparamagnetic component, a bio‐inspired tissue adhesive, and quick‐crosslinking agents, the catheter‐deployable iMAH can be magnetically guided to a targeted site, quickly crosslink within approximately 2 s, and strongly adhere to the vessel surface in dynamic conditions with circulating and pressurized blood. Moreover, magnetic actuation enables targeted gel deployment and can drive the iMAH into a narrow and confined space, squeezing out interfacial fluid to facilitate high‐strength tissue adhesion, as systematically investigated in vitro. Magnetically controlled delivery of iMAH for vascular repair has been demonstrated in a large‐animal beagle dog model; branching lumbar arteries from the abdominal aorta, mimicking the opening of a ruptured artery, were successfully embolized under magnetic guidance using a 5‐axis magnetic vascular robot. With these demonstrated features, magnetically controlled delivery of injectable magnetoactive adhesive hydrogel provides a promising solution for vascular repair such as sealing ruptured vessels or embolizing abnormal arteries in the challenging blood environment.

Charge‐Directed Self‐Assembly of Carbon Dot‐Loaded Cellulose Nanocrystal Chiral Superstructures With Tailorable Circularly Polarized Luminescence

ABSTRACT Surface charge critically influences the self‐assembly and functional performance of colloidal liquid crystals. However, in circularly polarized luminescence (CPL) systems, the regulatory role of guest surface charge in their self‐assembly remains fundamentally unclear, hindering the rational design of adjustable high‐performance CPL materials. Herein, we judiciously synthesize a series of positively and negatively charged carbon dots (P‐/N‐CDs) with satisfactory solid‐state emission and incorporate them into colloidal cellulose nanocrystal (CNC) liquid crystal with phase adjustability via evaporation‐induced self‐assembly (EISA). By precisely modulating the surface charge of CDs, the resulting P‐/N‐CD‐loaded CNC (P‐/N‐CDCNC) chiral superstructures exhibit tailorable CPL with luminescence dissymmetry factor values from +0.16 to −0.91. The decisive role of surface charge in the EISA process is further elucidated. In situ microscopy demonstrates divergent charge‐directed assembly pathways: N‐CDs allow CNC tactoid fusion to proceed, whereas P‐CDs arrest fusion through electrostatic crosslinking. This triggers unprecedented Janus P‐CDCNC superstructures, leading to side‐dependent CPL handedness. Such CDCNC superstructures with different polarization states are readily designed to patterns and sophisticated codes, which offer powerful avenues for high‐security anticounterfeiting and multilevel information encryption. This work pioneers guest charge modulation as a universal strategy for controlling chiroptical assembly, overcoming limitations to attain handedness‐adjustable, high‐performance CPL from natural chiral materials.